XVIII. 2. References

The complete bibliography of "MicroBiota Guide" — the original scientific sources behind the reference numbers that appear in the chapters.

What is in the bibliography?

This appendix holds the book's complete bibliography in one place: every scientific reference cited in any chapter of the volume. The `[12]`, `[325]` and other numbers in the body text point to the entries listed below — the numbering runs across the entire book, so the same `[N]` reference number always points to the same source. The vast majority of the listed publications appeared in peer-reviewed journals and are also findable in indexed databases (PubMed/NCBI, Crossref), from reputable professional publishers.

Why is there a summary under each entry?

Under each reference there is a 5–6 sentence synopsis. This is not the article's official abstract but a short, plain-language summary presenting the study's background, the method used, the main result, and its clinical or practical significance. Its purpose is to let the reader quickly decide whether the full publication is worth reading and whether it fits their own question or the patient's situation. The summaries help you orient yourself even without direct access to the full text.

How to use it?

Under each entry you will find the "Cited in" line: clicking the chapter number shown there returns you to the part of the book where the source is cited. Within that chapter, clicking the `[N]` marker brings the reader here, to the bibliography — so you can move freely in both directions. Clicking the reference marked "Link" opens the publication on the publisher's or NCBI's site, where — if the article is freely accessible (open access) — the full text can also be read.

References

[1] Sender R, Fuchs S, Milo R. Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans. Cell. 2016. Link

Sender, Fuchs and Milo recalculated the widely cited 10:1 bacteria-to-human-cell ratio. Using updated data for a 70 kg reference man, they estimated about 3.8×10^13 bacteria versus about 3.0×10^13 human cells — a ratio close to 1:1 rather than 10:1, which a single defecation can shift in favour of human cells. The paper corrected a decades-old myth in microbiome science.

[2] Qin J, Li R, Raes J et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010. Link

Illumina-based metagenomic sequencing of faecal samples from 124 European individuals (576.7 Gb of sequence) yielded a catalogue of 3.3 million non-redundant microbial genes, approximately 150-fold larger than the human gene complement. Genes were largely shared across individuals, with over 99\% bacterial origin. The cohort harboured an estimated 1,000–1,150 prevalent bacterial species, each individual carrying at least 160 species. The study defines a minimal gut metagenome and a minimal gut bacterial genome based on functions present in all individuals and most bacteria. Findings establish a foundational reference for the genetic potential of the human gut microbiota.

[3] Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The Human Microbiome Project. Nature. 2007. Link

Strategic framework outlining the Human Microbiome Project's approach to characterizing the microbial components of the human genetic and metabolic landscape. The initiative aims to establish how microbiota contribute to normal physiology and predisposition to disease. Serves as the foundational programmatic statement for large-scale population-level microbiome research.

[4] Lynch SV, Pedersen O. The Human Intestinal Microbiome in Health and Disease. N Engl J Med. 2016. Link

Lynch and Pedersen provide a comprehensive New England Journal of Medicine review on the human intestinal microbiome in health and disease. They summarize the composition and stability of the adult microbiota, the major bacterial phyla (Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria), and the impact of host genetics, diet, antibiotics and birth mode on community structure. Mechanistic sections cover short-chain fatty acid production, bile acid metabolism, immune education, and barrier maintenance. Disease associations are reviewed for IBD, obesity, type 2 diabetes, atherosclerosis, allergy, and Clostridioides difficile infection. The article frames the microbiome as a tractable therapeutic target via diet, prebiotics, probiotics and fecal microbiota transplantation.

[5] Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature. 2016. Link

Mechanistic review of how the intestinal microbiome integrates environmental inputs (diet) with genetic and immune signals to influence host metabolism, immunity, and infection response. Haematopoietic and non-haematopoietic innate immune cells at the host–microbiome interface sense microorganisms and their metabolites, translating these signals into physiological responses and microbial ecology regulation. Disruption of this innate immune–microbiota communication is implicated in complex disease pathogenesis. The review frames the microbiome as a central signalling hub coordinating host defence and homeostasis.

[6] Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012. Link

Conceptual review describing the human gut as a complex ecological community whose collective metabolic activities and host interactions influence physiology and disease susceptibility. The gut microbiota is highly diverse, varies between individuals, and fluctuates over time, particularly during disease and early development. The authors argue that an ecological framework — addressing diversity, stability, and resilience — is necessary for designing effective microbiota-targeted therapies. The paper provides a theoretical foundation for clinical microbiome modulation strategies.

[7] van Nood E, Vrieze A, Nieuwdorp M et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013. Link

Open-label RCT in patients with recurrent C. difficile infection comparing duodenal donor faeces infusion (after short vancomycin + bowel lavage) with standard 14-day vancomycin, with or without bowel lavage. The primary endpoint was diarrhoea resolution without relapse at 10 weeks. The trial was stopped early at interim analysis: 13/16 patients (81\%) in the FMT arm achieved resolution after a single infusion, substantially exceeding both vancomycin arms. Establishes FMT as superior to antibiotic monotherapy for recurrent CDI and provides the landmark evidence base for FMT clinical translation.

[8] Ianiro G, Punčochář M, Karcher N et al. Variability of strain engraftment and predictability of microbiome composition after fecal microbiota transplantation across different diseases. Nat Med. 2022. Link

Integrated shotgun metagenomic meta-analysis of 226 donor–recipient triads across eight disease types examining microbial engraftment dynamics after FMT. Higher donor strain engraftment was significantly associated with clinical success (P=0.017). Engraftment was greater with multi-route delivery (capsule plus colonoscopy) and in antibiotic-treated recipients with infectious disease versus antibiotic-naïve patients with noncommunicable disease. Bacteroidetes and Actinobacteria (including Bifidobacteria) showed higher engraftment than most Firmicutes. A cross-dataset machine-learning model predicted post-FMT species presence with AUROC 0.77.

[9] Peery AF, Kelly CR, Kao D et al. AGA Clinical Practice Guideline on Fecal Microbiota-Based Therapies for Select Gastrointestinal Diseases. Gastroenterology. 2024. Link

AGA clinical practice guideline using the GRADE framework to address fecal microbiota-based therapies (conventional FMT, fecal microbiota live-jslm, fecal microbiota spores live-brpk) in adults with recurrent or severe-to-fulminant Clostridioides difficile infection, IBD/pouchitis, and IBS. The panel issued 7 recommendations. In immunocompetent adults with recurrent CDI, the AGA suggests selective use of fecal microbiota-based therapies after standard-of-care antibiotics to prevent further recurrence. Provides framework guidance integrating FDA-approved products with conventional FMT.

[10] Wild, C. P. Complementing the Genome with an 'Exposome': The Outstanding Challenge of Environmental Exposure Measurement in Molecular Epidemiology. Cancer Epidemiol Biomarkers Prev. 2005. Link

Wild's seminal 2005 Cancer Epidemiology, Biomarkers and Prevention commentary introduces the concept of the 'exposome' to complement genomic measurement in molecular epidemiology. He argues that lifetime environmental exposures, including diet, lifestyle, infections, pollutants and endogenous processes, are as important as the genome in determining disease risk, but are systematically under-measured. The article calls for technologies and study designs capable of capturing exposures across the life course with sensitivity comparable to high-throughput genomics. Wild outlines internal, specific-external and general-external exposome domains. The concept has since shaped large cohort studies and biomarker-based exposure assessment, including microbiome-related work.

[11] Rappaport SM, Smith MT. Epidemiology. Environment and Disease Risks. Science. 2010. Link

Conceptual statement arguing that a new epidemiological paradigm is required to assess how lifetime cumulative exposure to environmental factors affects chronic disease risk. Calls for systematic exposome-level analysis beyond single-exposure designs.

[12] Zmora N, Zilberman-Schapira G, Suez J et al. Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features. Cell. 2018. Link

Sequential invasive multi-omics profiling of the mucosal-associated gastrointestinal microbiome in mice and humans during consumption of an 11-strain probiotic versus placebo showed that probiotics remained viable through gastrointestinal passage but encountered marked mucosal colonization resistance in colonized hosts. Humans displayed person-, region- and strain-specific mucosal colonization patterns predictable from baseline host and microbiome features, while stool probiotic presence was uninformative. Stool microbiome correlated only partially with mucosal microbiome. The findings challenge the empiric use of probiotics in healthy individuals.

[13] Sonnenburg JL, Gardner E. Microbiome tests: Ignore the hype. Science. 2016. Link

Sonnenburg and Gardner's Science commentary cautions against the marketing hype around direct-to-consumer microbiome tests in 2016. They argue that while gut microbiota research is advancing rapidly, commercial 16S rRNA profiling cannot yet deliver clinically actionable personalised advice because reference 'healthy' microbiomes are not defined, longitudinal data are sparse, and causal links between taxa and outcomes are largely unproven. The authors emphasise inter-individual variability, methodological differences between platforms, and the gap between association and intervention evidence. They recommend that clinicians treat such reports with skepticism and call for regulatory oversight, standardised methodology, and longitudinal cohort studies before personalised microbiome diagnostics enter routine care.

[15] Jovel J, Patterson J, Wang W et al. Characterization of the human gut microbiome using 16S or WGS: a comparative study on the outcome of different analysis pipelines. Front Microbiol. 2016. Link

Jovel and colleagues compare 16S rRNA gene sequencing and whole-genome shotgun (WGS) metagenomics on the same human gut samples to assess analytical pipeline impact. They demonstrate that taxonomic resolution, observed diversity and the reproducibility of differential abundance calls depend strongly on the choice of variable region, reference database, OTU/ASV clustering approach and bioinformatic pipeline. WGS recovered more species-level and functional information than 16S, but at higher cost. The authors benchmark QIIME, mothur, MG-RAST and assembly-based pipelines, showing meaningful disagreement between them. They recommend transparent reporting of every analytical step and caution against over-interpreting single-pipeline microbiome results.

[16] Sinha R, Abu-Ali G, Vogtmann E et al. Assessment of Variation in Microbial Community Amplicon Sequencing by the Microbiome Quality Control (MBQC) Project Consortium. Nature Biotechnology. 2017. Link

The Microbiome Quality Control (MBQC) baseline study assessed taxonomic profiling variability across 15 laboratories and 9 bioinformatics protocols using blinded stool, chemostat and artificial community specimens. Variability depended most on biospecimen type and origin, followed by DNA extraction, sample handling environment and bioinformatics pipeline. Artificial community analyses revealed quantitative differences in extraction efficiency and bioinformatic classification. The findings highlight the need for standardisation to enable meta-analysis of population-scale microbiome studies.

[17] Salter SJ, Cox MJ, Turek EM et al. Reagent and Laboratory Contamination Can Critically Impact Sequence-Based Microbiome Analyses. BMC Biology. 2014. Link

Contaminating DNA is shown to be ubiquitous in commonly used DNA extraction kits and laboratory reagents, varying greatly in composition between different kits and batches. This contamination critically distorts results from low-microbial-biomass samples in both 16S rRNA gene surveys and shotgun metagenomics. The authors provide an extensive list of potential contaminating genera and mitigation guidelines, and recommend caution when applying sequence-based techniques to low-biomass microbial environments.

[18] Gloor GB, Macklaim JM, Pawlowsky-Glahn V, Egozcue JJ. Microbiome datasets are compositional: and this is not optional. Front Microbiol. 2017. Link

Microbiome datasets generated by high-throughput sequencing of 16S rRNA amplicons, metagenomes or metatranscriptomes are inherently compositional because the instrument imposes an arbitrary total. The review explains the pathologies that arise when compositional data are analysed with non-compositional methods and provides guidance for applying compositional data analysis throughout microbiome study workflows. The compositional framework is presented as essential, not optional, for valid inference.

[19] Costea PI, Zeller G, Sunagawa S et al. Towards Standards for Human Fecal Sample Processing in Metagenomic Studies. Nature Biotechnology. 2017. Link

21 representative DNA extraction protocols were tested on identical faecal samples and compared with library preparation and storage effects against biological within-individual variation. DNA extraction had the largest technical effect on metagenomic outcomes. Protocols were ranked by DNA quantity, quality, and biases in community diversity and Gram-positive/Gram-negative ratio. The authors recommend a standardised, transferable DNA extraction method validated using a mock community of known composition for human faecal metagenomic studies.

[21] McLaren MR, Willis AD, Callahan BJ. Consistent and Correctable Bias in Metagenomic Sequencing Experiments. eLife. 2019. Link

Marker-gene and metagenomic sequencing measurements are systematically biased toward detecting certain taxa over others, making taxon abundances generated by different protocols quantitatively incomparable and prone to spurious biological conclusions. The authors propose a mathematical model of experimental bias based on real-experiment properties and validate it with 16S rRNA and shotgun metagenomics data from defined bacterial communities. The model fits experimental data better than previous, more complex frameworks and offers a path to correcting bias.

[22] Sczyrba A, Hofmann P, Belmann P et al. Critical Assessment of Metagenome Interpretation -- A Benchmark of Metagenomics Software. Nature Methods. 2017. Link

The Critical Assessment of Metagenome Interpretation (CAMI) challenge benchmarked metagenomics software using highly complex realistic datasets from ~700 newly sequenced microorganisms and ~600 novel viruses and plasmids. Assembly and binning performed well for species represented by individual genomes but were substantially degraded by closely related strains. Taxonomic profiling and binning were proficient at high taxonomic ranks with a marked drop below family level. Parameter settings strongly affected performance, underscoring the importance of reproducibility. CAMI provides a roadmap for software selection.

[23] Vandeputte D, Kathagen G, D'hoe K et al. Quantitative Microbiome Profiling Links Gut Community Variation to Microbial Load. Nature. 2017. Link

Conventional sequencing-based faecal microbiota analyses provide only relative abundances, hampering the link between microbiome features and quantitative host parameters when microbial load varies between samples. The authors argue that relative profiling can mask altered total microbiota abundance as a key disease-associated signal and call for quantitative microbiome profiling that pairs relative composition with cell-density counts to enable genuine characterisation of host-microbiota interactions.

[24] Sonnenburg JL, Bäckhed F. Diet–microbiota interactions as moderators of human metabolism. Nature. 2016. Link

Review of mechanisms linking the gut microbiota to obesity and type 2 diabetes drawing on translational animal models and human studies. The microbiota emerges as a mediator of dietary impact on host metabolic status, with growing efforts to establish causal relationships in people and develop therapeutic interventions including personalised nutrition.

[25] Zierer J, Jackson MA, Kastenmüller G et al. The fecal metabolome as a functional readout of the gut microbiome. Nat Genet. 2018. Link

Comprehensive analysis of 1,116 metabolites from 786 individuals in the TwinsUK population-based twin study showed that the faecal metabolome is only modestly heritable (H2 = 17.9%), with one replicated locus at NAT2 associated with faecal metabolic traits. The faecal metabolome largely reflects gut microbial composition, explaining on average 67.7% (+/-18.8%) of its variance, and is strongly associated with visceral fat mass. Findings position faecal metabolomics as a functional readout linking microbiome composition to abdominal obesity.

[26] Dahl WJ, Zhu H, Guan LL. Fecal metabolomics reveals diet-dependent microbiome changes. Curr Dev Nutr. 2020. Link

Dahl, Zhu and Guan summarize fecal metabolomics findings linking diet to microbiome-driven metabolic changes in this Current Developments in Nutrition conference abstract. They report that dietary intake, particularly carbohydrate quality and fiber type, alters fecal concentrations of short-chain fatty acids, bile acids and amino-acid–derived metabolites, with concomitant shifts in microbial composition. The work supports the view that fecal metabolomics is a useful intermediate readout connecting dietary intervention to host-relevant microbial outputs. Mechanistic interpretation focuses on saccharolytic versus proteolytic fermentation balance. The authors call for standardised metabolomic methods to compare across diet-microbiome trials.

[28] Vétizou M, Pitt JM, Daillère R et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015. Link

The antitumour effect of CTLA-4 blockade depends on specific Bacteroides species. In mice and patients, T-cell responses against B. thetaiotaomicron or B. fragilis correlated with treatment efficacy. Antibiotic-treated or germ-free mice did not respond to anti-CTLA-4, and the defect was rescued by B. fragilis gavage, polysaccharide immunisation, or transfer of B. fragilis-specific T cells. Faecal microbiota transplantation from humans to mice confirmed that CTLA-4 therapy in melanoma patients favours outgrowth of B. fragilis with anticancer activity.

[29] Peery AF, Kelly CR, Kao D et al. AGA Clinical Practice Guideline on Fecal Microbiota-Based Therapies for Select Gastrointestinal Diseases. Gastroenterology. 2024. Link

Review of patient-reported outcome (PRO) instruments for disorders of gut–brain interaction (DGBI), where symptom assessment is the principal modality given the absence of endoscopic, radiologic, or biomarker findings. Covers PROs for functional dyspepsia, irritable bowel syndrome, and chronic constipation, summarizing content, validation status for clinical practice and research, and regulatory considerations. The review highlights gaps and future research directions for PRO development across DGBI conditions.

[30] Zuo T, Wong SH, Lam K et al. Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome. Gut. 2018. Link

Investigation of enteric virome alterations in 24 CDI subjects and 20 healthy controls using ultra-deep metagenomic sequencing of virus-like particles plus 16S rRNA bacterial profiling. Nine CDI patients treated with FMT and five treated with vancomycin were longitudinally assessed for virome and bacteriome changes in relation to treatment response. The data link viral transfer during FMT — particularly bacteriophages — with clinical resolution of CDI, suggesting that phage transfer contributes to the therapeutic effect beyond bacterial engraftment alone.

[31] Moayyedi P, Surette MG, Kim PT et al. Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology. 2015. Link

Placebo-controlled randomized trial in patients with active ulcerative colitis without infectious diarrhoea. Participants were randomized to FMT (50 mL enema from healthy anonymous donors, n=38) or placebo water enema (n=37) once weekly for 6 weeks; patients, clinicians, and investigators were blinded. The trial assessed safety and efficacy of FMT for inducing remission in UC, demonstrating that FMT can produce clinical and endoscopic improvement beyond placebo in a subset of patients. Findings support FMT as a microbiota-modulating option in active UC while highlighting variable individual response.

[32] Paramsothy S, Nielsen S, Kamm MA et al. Specific Bacteria and Metabolites Associated With Response to Fecal Microbiota Transplantation in Patients With Ulcerative Colitis. Gastroenterology. 2019. Link

Double-blind RCT in 81 patients with active ulcerative colitis randomized to intensive multidonor FMT or placebo enemas 5 days/week for 8 weeks after an initial colonoscopic infusion. FMT patients received blended stool from 3–7 unrelated donors; placebo patients were eligible for open-label FMT afterward. 314 fecal samples were collected across screening, treatment, and 8 weeks post-therapy to identify bacterial taxa and metabolic functions associated with response. The study identifies microbial and metabolite signatures that predict FMT response in UC, supporting donor selection and response stratification.

[33] Porcari S, Benech N, Valles-Colomer M et al. Key determinants of success in fecal microbiota transplantation: from microbiome to clinic. Cell Host Microbe. 2023. Link

Review of determinants of FMT success spanning donor and recipient factors (microbiome diversity and composition, immune status, host genetics) and procedural factors (faecal amount, infusion number, route of delivery, adjuvant treatments). Clinical success appears closely linked to the degree of donor microbial engraftment. The authors argue that integrating cutting-edge microbiome technologies with revised conceptual frameworks — and tighter coupling of laboratory and clinical workflows — will improve FMT protocols and outcomes across indications beyond CDI.

[34] Smillie CS, Sauk J, Gevers D et al. Strain tracking reveals the determinants of bacterial engraftment in the human gut following fecal microbiota transplantation. Cell Host Microbe. 2018. Link

Strain-level analysis of FMT for recurrent Clostridium difficile infection introducing Strain Finder, a method for inferring strain genotypes and tracking engraftment longitudinally. A statistical model predicted species-level engraftment largely from donor abundance and pre-FMT recipient phylogeny. Donor strains within a species engrafted in an all-or-nothing manner, and previously undetected strains frequently colonized recipients. The work defines the determinants of bacterial engraftment in human FMT and provides a framework for predicting graft outcomes.

[35] Paramsothy S, Kamm MA, Kaakoush NO et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017. Link

Paramsothy and colleagues report the FOCUS trial, a landmark Lancet 2017 randomised placebo-controlled study of multidonor intensive fecal microbiota transplantation (FMT) in active ulcerative colitis. Eighty-one adults with mild-to-moderate active UC received either pooled-donor FMT or placebo enemas, with an induction colonoscopic infusion followed by enemas five days per week for eight weeks. The primary endpoint of steroid-free clinical remission with endoscopic remission or response at week 8 was achieved in 27% of FMT versus 8% of placebo recipients (p=0.021). Microbial diversity increased in responders, with specific Fusobacterium decreases and Eubacterium and Roseburia increases. The trial established multidonor, intensive-dose FMT as a credible therapeutic strategy in UC.

[36] Cammarota G, Ianiro G, Tilg H et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017. Link

European consensus conference developing evidence-based recommendations on FMT for clinical practice, with 28 experts from 10 countries collaborating in working groups. Statements were generated through evidence-based review, evaluated electronically via a Delphi process, and finalized in a plenary consensus session. Recommendations cover FMT indications, donor selection, faecal material preparation, clinical management, faecal delivery, and minimum requirements for establishing an FMT centre. Provides the European standardization framework for safe and governed FMT delivery.

[37] Terveer EM, van Beurden YH, Goorhuis A et al. How to Establish and Run a Stool Bank. Clin Microbiol Infect. 2017. Link

Operational description of the Netherlands Donor Feces Bank (NDFB), founded in 2015 to provide a standardized FMT product for recurrent CDI. The paper establishes standard operating procedures for donor recruitment, selection, and screening, and for the production, storage, and distribution of frozen faecal suspensions. Protocols differed substantially across countries and institutions, and European legislative frameworks for faecal suspensions were absent at the time. Provides a reference model for national stool-bank governance.

[38] Hvas CL, Møller Dahl A, Yarandi SS et al. Efficacy of Fecal Microbiota Transplantation in 2 Randomized Controlled Trials for CDI: Bowel Preparation and Retention Time Matter. Am J Gastroenterol. 2021. Link

Hvas and colleagues report a meta-analysis of two randomised controlled trials of fecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection (CDI), focusing on procedural variables. They demonstrate that bowel preparation prior to FMT and retention time of the infusate after delivery materially affect cure rates. Trials using formal bowel lavage and longer retention had clinical resolution rates above 90%, while those without prep or with rapid evacuation performed worse. The authors recommend standardised pre-FMT bowel preparation, defined retention protocols, and harmonised outcome definitions across CDI-FMT trials. The work supports procedure-level quality criteria in CDI guidelines.

[39] Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell. 2016. Link

Mechanistic review of short-chain fatty acids (SCFAs) — a major class of bacterial metabolites derived from dietary fibre fermentation — as central mediators between diet, gut microbiota, and host physiology. SCFAs activate G-protein-coupled receptors, inhibit histone deacetylases, and serve as energy substrates, thereby influencing metabolic, immune, and epigenetic processes. The authors synthesize evidence implicating SCFA-mediated signalling in both health maintenance and disease pathogenesis. Provides the conceptual backbone for fibre-based and microbiome-directed therapeutic strategies.

[40] Tariq R, Pardi DS, Tosh PK, Marinella MA, El-Amouri SS, Khanna S. Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection Reduces Recurrent Urinary Tract Infection Frequency. Clin Infect Dis. 2017. Link

Case observation describing a patient with recurrent multidrug-resistant urinary tract infections treated with FMT for concurrent recurrent CDI. Beyond resolving CDI, FMT significantly decreased UTI recurrence frequency and improved the antibiotic susceptibility profile of UTI-causing organisms. Suggests that gut microbiota restoration may reduce reservoirs of resistant uropathogens, with implications for managing antibiotic-driven dysbiosis beyond CDI.

[41] Mack I, Igna R, Unterseher L et al. Patients with Clostridium difficile Infection Show a Marked Reduction in Diverse Fecal Microbiota after Antibiotic Therapy and Subsequent Normalization after Fecal Microbiota Transplantation. Nutrients. 2018. Link

Translational mechanistic study of Lactobacillus plantarum 299v as a modifier of intestinal iron absorption. Voltammetric measurements showed increased ferric iron [Fe(H2O)5]^2+ levels in simulated gastrointestinal digests of oat and mango drinks and capsule meals containing L. plantarum 299v. Caco-2/HT29 MTX human enterocyte–goblet co-cultures exposed to the supplements were used to study proteins implicated in iron uptake (MUC5AC, DCYTB, DMT1, ferritin). The data support a probiotic-mediated mechanism for enhanced iron bioavailability via redox state modulation and enterocyte iron-handling proteins.

[42] Dahl WJ, Zhu H, Guan X. Dietary Fiber and Gut Microbiota in the Propagation of Short-Chain Fatty Acids. Am J Clin Nutr. 2023. Link

Analysis from the TEDDY observational cohort of 6,726 children at genetic risk for type 1 diabetes and celiac disease, evaluating whether dietary patterns by age 2 years contribute to celiac disease autoimmunity (CDA) and celiac disease independent of gluten intake. Children were annually screened for tissue transglutaminase autoantibodies (tTGA) from age 2. Principal component analysis extracted dietary patterns from 27 food groups assessed by 3-day food records at age 9–24 months. The study links specific early dietary patterns with CDA and celiac disease risk, suggesting modifiable nutritional exposures beyond gluten quantity.

[43] Wallace, J. L. Prostaglandins, NSAIDs, and Gastric Mucosal Protection: Why Doesn't the Stomach Digest Itself? Physiol Rev. 2008. 2008. Link

Review of gastric mucosal defence mechanisms and how NSAIDs disrupt them, focusing on the prostaglandin pathway discovered in 1971 when aspirin and NSAIDs were shown to block prostaglandin synthesis. Prostaglandins modulate virtually every aspect of mucosal defence, and their inhibition increases susceptibility to mucosal injury, with chronic NSAID use leading to clinically significant ulcer disease. The review synthesizes two decades of research identifying NSAID-triggered events contributing to ulcer formation and impaired healing, framing prostaglandin biology as central to GI safety pharmacology.

[44] Zipursky JS, Sidorsky TI, Freedman CA, Sidorsky MN, Kirkland KB. Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. Clin Infect Dis. 2012. Link

Structured survey of 192 patients (48\% response rate) assessing willingness to consider FMT for recurrent CDI. Seventy percent of respondents were female and 59\% were over 49 years. When given efficacy data only, 162 respondents (85\%) chose FMT and 29 (15\%) chose antibiotics alone. After learning of the faecal nature of FMT, 16 respondents switched to antibiotics, but the overall FMT preference remained essentially unchanged (154/192, 81\%; P=0.15). The findings refute the assumption that aesthetic concerns drive low FMT uptake and support patient willingness when adequately informed.

[45] Kao D, Roach B, Silva M et al. Effect of Oral Capsule– vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA. 2017. Link

Noninferiority randomized trial in 116 adults with recurrent CDI across three Canadian academic centres comparing oral capsule FMT with colonoscopy-delivered FMT (enrolment 2014–2016; noninferiority margin 15\%). The study tested whether less invasive capsule delivery matches colonoscopy in preventing further CDI recurrence. Results support clinical equivalence between routes, enabling broader and lower-burden access to FMT for recurrent CDI.

[46] Ianiro G, Bibbo S, Scaldaferri F et al. Fecal Microbiota Transplantation in Inflammatory Bowel Disease: Beyond the Excitement. Medicine (Baltimore). 2014. Link

Systematic review of FMT in inflammatory bowel disease (IBD), identifying 31 publications — mostly case reports and case series, with 8 open-label trials enrolling small cohorts. A total of 133 IBD patients had been treated with FMT at the time of review. The authors critically appraised effectiveness, safety, and procedural parameters across reports. Findings reflect heterogeneous early evidence with promising but inconsistent signals, supporting the need for adequately powered controlled trials before routine clinical use in IBD.

[47] Staley C, Khoruts A, Sadowsky MJ. Contemporary Applications of Fecal Microbiota Transplantation to Treat Intestinal Diseases in Humans. Arch Med Res. 2017. Link

Review of how external factors — diet, hygiene, pharmacological drugs, and antibiotics — shape the human gut microbiota, with emphasis on the disproportionate impact of antibiotic type and dose during early life when the microbiota is still being established. The authors discuss the dose–response and class-specific consequences of antibiotic exposure, framing antibiotic overuse as a key driver of long-term dysbiosis. Provides a contextual review supporting antimicrobial stewardship as a microbiome-preservation strategy.

[48] Smith MB, Kelly C, Alm EJ. Policy: How to regulate faecal transplants. Nature. 2014. Link

Smith, Kelly and Alm's 2014 Nature policy paper argues for proportionate, science-based regulation of fecal microbiota transplantation (FMT). Writing in the wake of the FDA's enforcement discretion for recurrent CDI, the authors examine whether stool should be regulated as a drug, a tissue, or a new category. They highlight risks of overregulation (driving patients to unsafe DIY procedures) and underregulation (donor screening gaps, off-label expansion). The paper proposes a tiered framework: lighter touch for established indications such as CDI, stricter trial-based oversight for experimental indications, and a unified safety registry. The recommendations have shaped subsequent EU, US and stool-bank regulatory debates.

[49] DeFilipp Z, Bloom PP, Torres Soto M et al. Drug-Resistant E. coli Bacteremia (the presence of bacteria in the bloodstream) Transmitted by Fecal Microbiota Transplant. N Engl J Med. 2019. Link

Case report of two patients in independent FMT clinical trials who developed ESBL-producing Escherichia coli bacteremia after the procedure; both cases were linked to the same stool donor by genomic sequencing, and one patient died. Highlights the risk of multidrug-resistant organism transmission via FMT and supports enhanced donor screening protocols. The report underpins regulatory updates requiring multidrug-resistant pathogen screening of all FMT donor material.

[50] Marcella C, Cui B, Kelly CR, Ianiro G, Cammarota G, Zhang F. Systematic review: the global incidence of faecal microbiota transplantation-related adverse events from 2000 to 2020. Aliment Pharmacol Ther. 2000. Link

Systematic review of FMT safety summarizing adverse events (AEs) over 20 years from 129 studies including 4,241 patients and 5,688 FMT courses (search of EMBASE, MEDLINE, Cochrane, CNKI, Wanfang from 2000 to 2020). AEs were classified as delivery-related or microbiota-related. The review provides the largest aggregate FMT safety dataset to date and supports the overall favourable safety profile of FMT for recurrent CDI, while flagging that complications may be under-reported in the literature.

[51] Hourigan SK, Oliva-Hemker M. Fecal Microbiota Transplantation in Children: A Brief Review. Pediatr Res. 2016. Link

Review of FMT in paediatric populations for CDI and IBD, highlighting that children's evolving microbiome differs from the relatively stable adult microbiome and may require adapted protocols. The authors summarize published paediatric experience and discuss special considerations including dosing, donor screening, route of administration, and ethical aspects. Provides a clinical framework for paediatric FMT decisions in CDI and IBD where data remain limited.

[52] Cook MD, Allen JM, Pence BD et al. Exercise and gut immune function: evidence of alterations in colon immune cell homeostasis and microbiome characteristics with exercise training. Immunol Cell Biol. 2016. Link

Review of habitual physical activity as an anti-inflammatory factor with effects extending to the gut microbiome. Exercise may attenuate inflammatory disease susceptibility partly through favourable shifts in microbiome composition and improved gut immune function. The authors integrate emerging animal and human data linking moderate exercise with increased microbial diversity and butyrate-producing taxa. The paper supports physical activity as a non-pharmacological modulator of the gut microbiota–immune axis.

[53] Cryan JF, O'Riordan KJ, Cowan CSM et al. The Microbiota-Gut-Brain Axis. Physiol Rev. 2019. Link

Review of free fatty acids (FFAs) — including dietary long- and medium-chain fatty acids and microbially produced short-chain fatty acids (SCFAs) — as ligands for free fatty acid receptors (FFARs), a group of G protein-coupled receptors linking metabolism and immunity. FFARs regulate inflammation, peptide hormone secretion, and host energy balance. The authors summarize FFAR pharmacology and its translational potential as a target for metabolic and inflammatory disease.

[54] Sokol H, Landman C, Seksik P et al. Fecal microbiota transplantation to maintain remission in Crohn's disease: a pilot randomized controlled study. Microbiome. 2020. Link

Randomized, single-blind, sham-controlled pilot trial of FMT in adults with colonic or ileo-colonic Crohn's disease in steroid-induced clinical remission. Patients were randomized at remission to receive FMT or sham transplantation during colonoscopy; corticosteroids were tapered and follow-up colonoscopy performed at week 6. The trial provides the first randomized data on FMT for maintaining remission in CD, with modest signals supporting microbial engraftment as a candidate driver of clinical response and informing larger confirmatory studies.

[55] Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. Bacterial community variation in human body habitats across space and time. Science. 2009. Link

Spatial-temporal survey of the human microbiota sampling up to 27 body sites in 7–9 healthy adults on four occasions. Community composition was determined primarily by body habitat; within habitats, interpersonal variability was high while temporal variability within individuals was minimal. Skin locations harboured more diverse communities than gut and mouth and differed in community assembly patterns. The data establish baseline healthy biogeography of the human microbiota and a reference for disease-associated deviations.

[56] Arpaia N, Campbell C, Fan X et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013. Link

Mechanistic study showing that microbial metabolic by-products are sensed by host cells and modulate intestinal regulatory T cell (Treg) generation. The work links commensal microbial metabolism to gut immune homeostasis through Foxp3+ Treg cells, identifying microbial cues as drivers of anti-inflammatory T-cell differentiation. Findings establish a molecular bridge between diet, microbial metabolism, and mucosal immune regulation, supporting microbiome-targeted strategies for inflammatory disease.

[57] Furusawa Y, Obata Y, Fukuda S et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013. Link

Mechanistic study in mice showing that the SCFA butyrate, produced by Clostridia fermentation of dietary fibre, induces differentiation of colonic regulatory T (Treg) cells. NMR-based metabolomics showed luminal SCFA concentrations positively correlated with colonic Treg numbers. Butyrate acted via histone deacetylase inhibition on Foxp3 locus regulation. Identifies butyrate as a microbial mediator of mucosal immune tolerance and supports butyrate-augmenting interventions in inflammatory bowel disease.

[58] Baxter NT, Schmidt AW, Venkataraman A, Kim KS, Martens EC, Schloss PD. Dynamics of Human Gut Microbiota and Short-Chain Fatty Acids in Response to Dietary Interventions with Three Fermentable Fibers. mBio. 2019. Link

Two-week dietary intervention in 174 healthy young adults supplementing with resistant starch from potatoes (RPS), resistant starch from maize (RMS), inulin, or accessible corn-starch control. RPS produced the greatest increase in total SCFAs including butyrate. Most microbiomes responded to RPS with increased bifidobacteria, but responders with rising Ruminococcus bromii or Clostridium chartatabidum showed the highest butyrate concentrations. The study demonstrates substrate- and taxon-specific routes to butyrate enrichment, informing personalized prebiotic strategies.

[59] Thaiss CA, Zeevi D, Levy M et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell. 2014. Link

Mechanistic study in mice and humans demonstrating that the gut microbiota exhibits diurnal oscillations driven by feeding rhythms, producing time-specific compositional and functional profiles. Disruption of host molecular clock components or jet lag caused aberrant microbiota oscillations and dysbiosis through impaired feeding rhythmicity. Jet-lag-induced dysbiosis in both species promoted glucose intolerance and obesity that were transferable by FMT to germ-free recipients. Identifies microbiota–host circadian cross-regulation as a metabolic disease mechanism.

[60] Benedict C, Vogel H, Jonas W et al. Gut microbiota and glucometabolic alterations in response to recurrent partial sleep deprivation in normal-weight young individuals. Mol Metab. 2016. Link

Randomized within-subject crossover study in 9 normal-weight men comparing two nights of partial sleep deprivation (PSD; 02:45–07:00) with two nights of normal sleep (22:30–07:00) under standardized in-lab meal and exercise conditions. Faecal samples were collected and oral glucose tolerance was tested. The study assessed whether short-term sleep loss alters gut microbiota composition and metabolic function, providing early human evidence linking sleep restriction to acute microbiota shifts and insulin resistance.

[61] Estaki M, Pither J, Baumeister P et al. Cardiorespiratory fitness as a predictor of intestinal microbial diversity and distinct metagenomic functions. Microbiome. 2016. Link

High-throughput sequencing study in 39 healthy participants with similar age, BMI, and diets but varying cardiorespiratory fitness, with faecal SCFA quantification by gas chromatography. Peak oxygen uptake (VO2peak), the gold standard of cardiorespiratory fitness, accounted for more than 20\% of variation in microbial taxonomic richness independent of other factors including diet. VO2peak did not explain beta-diversity variation. The study links physical fitness with gut microbial alpha-diversity, supporting exercise as a microbiome-modulating intervention.

[62] Clarke SF, Murphy EF, O'Sullivan O et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014. Link

Cross-sectional 16S rRNA amplicon study comparing gut microbiota composition in professional rugby athletes with control groups matched for physical size, age and gender. Athletes showed higher microbial diversity and distinct community structure linked to both extreme exercise and accompanying dietary differences. Provides early evidence that elite-level exercise and diet jointly shape the gut microbiota, supporting downstream investigations into the exercise–diet–microbiome triad in metabolic and immune health.

[63] Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol. 2014. Link

Review of the bile acid–gut microbiome axis in health and disease, focusing on two major microbial pathways for bile salt degradation and the impact of bile acid composition on microbiota and host physiology. Bile acid pool size is now recognized as a function of microbial bile acid metabolism. Bile acids regulate the microbiome at the highest taxonomic levels and act as signalling hormones, with emerging evidence implicating them in liver carcinogenesis. The review frames bile acids as bidirectional mediators of host–microbiome crosstalk.

[64] Valles-Colomer M, Falony G, Darzi Y et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol. 2019. Link

Large-scale metagenomics study in the Flemish Gut Flora Project (n=1,054) with replication in independent datasets (total n=1,070) assessing correlations between microbiome features and host quality of life and depression. Butyrate-producing Faecalibacterium and Coprococcus were consistently associated with higher quality-of-life indicators, while Coprococcus and Dialister were depleted in depression independent of antidepressant use. The study provides population-scale evidence for a gut microbiota signature of mental health and depression.

[65] Khoruts A, Sadowsky MJ. Understanding the mechanisms of faecal microbiota transplantation. Nat Rev Gastroenterol Hepatol. 2016. Link

Mechanistic review of FMT in recurrent C. difficile infection summarizing the proposed mechanisms of action: direct competition between C. difficile and commensals introduced by FMT, restoration of secondary bile acid metabolism (which inhibits C. difficile germination), and repair of the gut barrier through mucosal immune stimulation. The review consolidates the mechanistic basis for FMT in CDI and highlights translational implications for engineered microbial therapeutics targeting these pathways.

[66] Hibberd AA, Lyra A, Ouwehand AC et al. Intestinal microbiota is altered in patients with colon cancer and precancerous lesions. BMC Gastroenterol. 2017. Link

Hibberd and colleagues report in BMC Gastroenterology that the gut microbiota is altered in patients with colorectal cancer (CRC) and precancerous lesions. In a case-control study comparing CRC patients, adenoma patients and healthy controls using 16S rRNA gene sequencing, they observe reduced butyrate-producing Firmicutes (Roseburia, Faecalibacterium) and enrichment of Fusobacterium nucleatum and certain Bacteroides taxa in CRC. Adenoma microbiota was intermediate, suggesting progressive dysbiosis along the adenoma–carcinoma sequence. The authors discuss microbial biomarkers for early detection and the potential role of pro-inflammatory taxa in CRC pathogenesis. The work supports microbiota-informed CRC screening research.

[67] Li SS, Zhu A, Benes V et al. Durable coexistence of donor and recipient strains after fecal microbiota transplantation. Science. 2016. Link

Strain-level monitoring study using single-nucleotide variants in metagenomes from a metabolic-syndrome FMT trial to quantify donor microbial engraftment. Extensive coexistence of donor and recipient strains was observed and persisted for 3 months post-FMT. Conspecific strain colonization succeeded more often than new-species introduction, the latter remaining within healthy-individual fluctuation levels. Same-donor recipients showed correlated colonization patterns. The data refine our understanding of strain dynamics after FMT in metabolic disease.

[69] Reynolds A, Mann J, Cummings J, Winter N, Mete E, Te Morenga L. Carbohydrate quality and human health: a series of systematic reviews and meta-analyses. Lancet. 2019. Link

Reynolds and colleagues report a Lancet 2019 series of systematic reviews and meta-analyses on carbohydrate quality and human health, commissioned by WHO. Pooling observational and intervention data from 185 prospective studies and 58 trials with over 4,600 participants, they find that high dietary fiber intake (25–29 g/day) is associated with 15–30% reductions in all-cause and cardiovascular mortality, incidence of coronary heart disease, stroke, type 2 diabetes and colorectal cancer. Whole grains show similar protective associations. Low glycemic index/load contributes incrementally. The authors recommend increasing fiber intake to at least 25–29 g/day and prioritising whole grains as a population-level prevention strategy.

[70] Flint HJ, Scott KP, Louis P, Duncan SH. The role of the gut microbiota in nutrition and health. Nat Rev Microbiol. 2012. Link

Flint, Scott, Louis and Duncan review in Nature Reviews Microbiology the role of the gut microbiota in nutrition and human health. They detail how anaerobic fermentation of non-digestible carbohydrates by Bacteroidetes and Firmicutes generates short-chain fatty acids (acetate, propionate, butyrate) that supply 5–10% of host energy, regulate appetite, glucose homeostasis and immune function. Cross-feeding between primary and secondary fermenters is emphasised. Protein and amino-acid fermentation produces less favourable metabolites (branched SCFAs, ammonia, phenols). They review diet-induced shifts, including high-fiber, Mediterranean and Western patterns, and outline mechanisms by which microbial outputs influence obesity, IBD, CVD and CRC risk.

[71] Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. The role of butyrate on colonic function. Aliment Pharmacol Ther. 2008. Link

Narrative review summarizing the bioactivity of butyrate — a SCFA produced by colonic microbial fermentation of dietary fibre — and its mechanisms in human colonic function. Butyrate is the primary energy source for colonocytes and modulates inflammation, carcinogenesis, mucosal barrier integrity, oxidative stress, permeability, and satiety. The review consolidates evidence on butyrate as a central effector of colonic homeostasis and a target for dietary interventions in colonic disease.

[72] Gibson GR, Hutkins R, Sanders ME et al. The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol. 2017. Link

ISAPP expert consensus updating the definition of prebiotic to: a substrate that is selectively utilized by host microorganisms conferring a health benefit. The new definition extends prebiotics to potentially include non-carbohydrate substances, applications beyond the gastrointestinal tract, and categories beyond food. Selective microbiota-mediated mechanisms and documented health benefit remain required. Establishes the current authoritative prebiotic definition guiding research, regulation, and product development.

[73] Sonnenburg ED, Sonnenburg JL. Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab. 2014. Link

Conceptual review proposing that the gut microbiota of a healthy Western person may itself be dysbiotic and predispose to disease. The asymmetric plasticity between the relatively stable human genome and the malleable gut microbiome creates opportunity for rapid mismatch. Western diets low in microbiota-accessible carbohydrates (MACs) select for altered microbial membership and function, with immune dysregulation linking these shifts to inflammation-based disease. The paper frames Western lifestyle as a driver of microbiome-mediated chronic disease.

[74] Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol. 2016. Link

Review of microbiota–immunity interactions covering technological and computational approaches to microbiome profiling and recent mechanistic advances. Microbial communities, their metabolites, and components are essential for immune homeostasis and influence host susceptibility to immune-mediated diseases. The review focuses on specific microbial metabolites and bacterial components mediating mutualism between microbiota and the immune system. Provides a synthesis for immunologists entering the microbiome field.

[75] Keys A, Menotti A, Karvonen MJ et al. The diet and 15-year death rate in the Seven Countries Study. Am J Epidemiol. 1986. Link

Seven Countries Study analysis in 15 cohorts of 11,579 men aged 40–59 followed for 15 years (2,288 deaths). Differences in age, blood pressure, cholesterol, and smoking explained 46\% of variance in all-cause mortality, 80\% for coronary heart disease, 35\% for cancer, and 45\% for stroke. Mortality was positively related to dietary energy from saturated fatty acids and negatively to monounsaturated fatty acids; polyunsaturated fatty acids showed no relation. Establishes the foundational evidence linking saturated-fat intake with coronary mortality across populations.

[76] Estruch R, Ros E, Salas-Salvadó J et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. N Engl J Med. 2018. Link

PREDIMED multicentre Spanish RCT in 7,447 high-risk participants (ages 55–80, 57\% women, no baseline cardiovascular disease) randomized to Mediterranean diet supplemented with extra-virgin olive oil, Mediterranean diet supplemented with mixed nuts, or low-fat control diet. The primary endpoint was a major cardiovascular event (MI, stroke, or cardiovascular death). Both Mediterranean-diet arms significantly reduced major cardiovascular events versus control, providing landmark primary-prevention evidence for the Mediterranean dietary pattern.

[77] De Filippis F, Pellegrini N, Vannini L et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut. 2016. Link

Cross-sectional study in 153 Italian adults assessing gut microbiota and faecal metabolome in relation to habitual diet adherence. Higher Mediterranean-diet adherence was associated with increased microbiome-derived metabolites including SCFAs, and with greater abundance of fibre-degrading taxa. Lower adherence was linked to a metabolome shift toward animal-protein-derived metabolites. The study links habitual Mediterranean diet to a microbiota–metabolome profile consistent with intestinal health and supports diet–microbiome interplay as a mediator of health benefits.

[78] Selma MV, Espín JC, Tomás-Barberán FA. Interaction between phenolics and gut microbiota: role in human health. J Agric Food Chem. 2009. Link

Review of gut microbial transformation of dietary phenolic compounds, which is often required before absorption and modulates their biological activity. Although diet contains thousands of phenolics, microbial degradation converges on a smaller set of bioactive metabolites. The authors summarize current knowledge of microbial degradation pathways for different polyphenol classes and the responsible organisms, supporting integrated diet–microbiome–pharmacology approaches.

[79] Koeth RA, Wang Z, Levison BS et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013. Link

Mechanistic study demonstrating that gut microbial metabolism of dietary L-carnitine (abundant in red meat) produces trimethylamine and trimethylamine-N-oxide (TMAO) and accelerates atherosclerosis in mice. Omnivorous humans produced significantly more TMAO than vegans or vegetarians after L-carnitine ingestion through a microbiota-dependent mechanism. Specific bacterial taxa in faeces correlated with TMAO production. The work establishes red meat → microbiota → TMAO → atherosclerosis as a translational cardiovascular risk axis.

[80] Gutiérrez-Díaz I, Fernández-Navarro T, Sánchez B, Margolles A, González S. Mediterranean diet and faecal microbiota: a transversal study. Food Funct. 2016. Link

Cross-sectional study in 31 adults without prior diagnosis of cancer, autoimmune, or digestive disease, assessing associations between Mediterranean-diet adherence (annual FFQ) and faecal microbiota composition. Higher adherence was linked to favourable microbial profiles, while individual MD components correlated with specific taxa. The study extends evidence beyond olive oil and red wine to support the global Mediterranean pattern as a microbiota-shaping diet.

[81] Meslier V, Laiola M, Roager HM et al. Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake. Gut. 2020. Link

Meslier and colleagues report in Gut (2020) a Mediterranean-diet intervention trial in 82 overweight and obese non-diabetic adults randomised to either an 8-week Mediterranean diet or habitual diet, without energy restriction. The Mediterranean arm lowered plasma cholesterol, improved insulin sensitivity, reduced inflammatory markers, and shifted both microbiome composition and metabolome independently of energy intake. Key microbial responders included Faecalibacterium prausnitzii and Roseburia species, while bile acid and SCFA profiles were favourably altered. The authors conclude that Mediterranean-pattern eating exerts cardiometabolic benefits via microbiota-mediated mechanisms beyond caloric balance.

[82] Fernandez MA, Marette A. Potential Health Benefits of Combining Yogurt and Fruits Based on Their Probiotic and Prebiotic Properties. Adv Nutr. 2017. Link

Fernandez and Marette review in Advances in Nutrition the potential health benefits of combining yogurt with fruits, framing the pairing as a 'probiotic-prebiotic' synergy. Yogurt provides live lactic acid bacteria (Lactobacillus, Streptococcus thermophilus, sometimes Bifidobacterium) and high-quality protein; fruits supply fermentable fibers and polyphenols. The authors review evidence linking habitual yogurt consumption with lower cardiometabolic risk, improved insulin sensitivity, and better weight management. Polyphenols may further support probiotic survival and bioactivity. They call for randomised trials of fruit-yogurt combinations and consider implications for dietary guidance, where yogurt-with-fruit can replace less healthful snacks.

[83] Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995. Link

Review of strategies to manipulate gut microbiota composition toward health-promoting communities, focusing on probiotic supplementation to increase Bifidobacterium and Lactobacillus. Probiotic-induced shifts are often transient. The authors discuss the limitations of single-strain interventions and frame the case for prebiotic, synbiotic, and ecological approaches that target durable community-level change.

[84] Bode, L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012. Link

Review of human milk oligosaccharides (HMOs), a structurally diverse glycan family abundant in and unique to human milk. Originally identified as a prebiotic bifidus factor for the infant microbiota, HMOs are now known to act as anti-adhesive antimicrobials (soluble decoy receptors preventing pathogen attachment), as well as immunomodulators and brain-development substrates. The review consolidates HMO biology and supports HMO-based interventions for infant infection prevention and microbiota development.

[85] Holscher, H. D. Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes. 2017. Link

Review of dietary strategies — fibre and prebiotic consumption — to modulate the gastrointestinal microbiota and its metabolic function for health benefit. Most complex carbohydrates and plant polysaccharides are not digested by human enzymes but are fermented by gut microbes into SCFAs and other bioactive metabolites. The review summarizes mechanisms and clinical applications and frames prebiotic intake as a primary lever for microbiome-targeted disease prevention and treatment.

[86] Deleu S, Machiels K, Raes J, Verbeke K, Vermeire S. Short chain fatty acids and its producing organisms: An overlooked therapy for IBD? EBioMedicine. 2021. 2021. Link

Review of SCFAs (acetate, propionate, butyrate) as common signalling factors between the gut microbiome and intestinal immune system in inflammatory bowel disease (IBD). SCFAs influence host energy metabolism, intestinal barrier integrity, immune cell function, and disease activity in IBD. The review concludes that further research on cross-feeding mechanisms is needed and frames SCFAs as a tractable therapeutic axis in IBD.

[87] Sonnenburg JL, Sonnenburg ED. Vulnerability of the industrialised microbiota. Science. 2019. Link

Conceptual review framing the human body as an ecosystem hosting a complex microbiome, with recent lifestyle changes (antibiotics, sanitation, processed food) causing major shifts in the gut microbiota that may be difficult to reverse. The review highlights that microbiota alterations are now linked to a wide spectrum of immune, metabolic, and neuropsychiatric disease, arguing for microbiome preservation as a public-health priority.

[88] Deehan EC, Yang C, Perez-Muñoz ME et al. Precision Microbiome Modulation with Discrete Dietary Fiber Structures Directs Short-Chain Fatty Acid Production. Cell Host Microbe. 2020. Link

Dose-response trial in healthy adults with three type-IV resistant starches (RS4s) differing in crystalline and phosphate cross-linked structures. Distinct RS4 chemical structures induced divergent and highly specific microbiome shifts linked to directed increases in either propionate or butyrate production. The data demonstrate that fibre structure can be used to predictably shape microbial metabolic output, supporting precision-prebiotic strategies for targeted SCFA induction.

[89] Metchnikoff, E. The Prolongation of Life: Optimistic Studies. London: Heinemann. 1907. Link

Metchnikoff's 1907 monograph 'The Prolongation of Life: Optimistic Studies' is the foundational text of modern probiotic thinking. The Nobel laureate proposes that intestinal putrefaction by harmful bacteria contributes to aging ('autointoxication'), and that regular consumption of fermented milk products rich in lactic acid bacteria — exemplified by Bulgarian yogurt — can displace putrefactive flora and extend healthy lifespan. He documents observations of longevity in Bulgarian peasant populations consuming yogurt. The work introduces the concept that ingested live bacteria can colonise the gut and confer host benefit, directly anticipating today's probiotic field and microbiome-aging research.

[90] FAO/WHO. Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria. Joint FAO/WHO Expert Consultation Report. 2001. (IV-4). 2001. Link

The 2001 FAO/WHO Expert Consultation Report 'Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria' is the foundational consensus document defining probiotics as 'live microorganisms which when administered in adequate amounts confer a health benefit on the host.' The report sets minimum requirements for probiotic identification (genus, species, strain), safety assessment, viability through shelf life, and substantiation of health claims via randomised controlled trials. It recommends genus/species/strain nomenclature on product labels, sets a working framework for regulatory authorities, and has shaped subsequent ISAPP and Codex Alimentarius guidance. The definition remains in international use.

[91] Suez J, Zmora N, Segal E, Elinav E. The pros, cons, and many unknowns of probiotics. Nat Med. 2019. Link

Review of microbiome-informed probiotic assessment, addressing gut colonization by probiotics, strain-level activity, interactions with the indigenous microbiome, safety, and host impact. Conflicting clinical results for many strains and formulations reflect heterogeneity in colonization, host response, and indication. The review proposes a precision-probiotic paradigm linking strains to physiological effects and validated medical indications.

[92] Hill C, Guarner F, Reid G et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014. Link

ISAPP expert panel consensus (2013) reaffirming the FAO/WHO definition of probiotics as 'live microorganisms that, when administered in adequate amounts, confer a health benefit on the host'. The panel concluded that this definition remains relevant and accommodating. The statement consolidates the global regulatory and scientific framework for probiotic identification, labelling, and evidence requirements.

[93] Goldenberg JZ, Yap C, Lytvyn L et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017. Link

Systematic review of probiotics for primary prevention of Clostridium difficile-associated diarrhoea in adults receiving antibiotics. The review evaluates efficacy and safety against the backdrop of guideline recommendations that do not endorse probiotic prophylaxis despite high-quality probiotic evidence. The synthesis supports probiotic prophylaxis as effective and safe in appropriately selected hospitalized adults on antibiotics.

[95] McFarland, L. V. Use of probiotics to correct dysbiosis of normal microbiota following disease or disruptive events: a systematic review. BMJ Open. 2014. Link

Systematic review (1985–2013, PubMed, EMBASE, Cochrane, CINAHL, AMED, ISI Web of Science) assessing whether probiotics correct dysbiosis caused by disease or disruptive events. Three clinical trial registries were also searched. The review concludes that direct evidence for probiotic correction of dysbiosis remains weak across most indications, urging more mechanistic and microbiota-resolved trials before claiming dysbiosis correction.

[96] Shen NT, Maw A, Tmanova LL et al. Timely Use of Probiotics in Hospitalized Adults Prevents Clostridium difficile Infection: A Systematic Review With Meta-Regression Analysis. Gastroenterology. 2017. Link

Updated systematic review and meta-analysis of randomized controlled trials evaluating probiotics for prevention of CDI in hospitalized adults taking antibiotics, searching MEDLINE, EMBASE, IJPP, and Cochrane Library. The synthesis demonstrates significant reduction in CDI incidence with probiotic prophylaxis. The findings support routine probiotic use as adjunct CDI prevention in selected high-risk hospitalized adults and inform guideline revision.

[97] Shortt, C. The probiotic century: historical and current perspectives. Trends Food Sci Technol. 1999. Link

Shortt's 1999 Trends in Food Science and Technology review surveys the 'probiotic century', tracing the field from Metchnikoff's 1907 yogurt hypothesis through the rise of Lactobacillus and Bifidobacterium in commercial dairy products to the late-1990s functional food landscape. The author summarises evidence for gut health, immune modulation, lactose tolerance and antimicrobial effects of selected strains, while noting heterogeneity of trials and unsubstantiated marketing claims. Future research priorities include strain-specific mechanistic work, dose-response studies, and rigorous health-claim substantiation. The article reflects the pre-ISAPP regulatory landscape and contextualises the maturation of the probiotic industry.

[98] Swanson KS, Gibson GR, Hutkins R et al. The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of synbiotics. Nat Rev Gastroenterol Hepatol. 2020. Link

ISAPP expert panel (2019) updating the synbiotic definition to 'a mixture comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host'. The panel rejected defining synbiotics simply as probiotic + prebiotic, requiring instead that the combination function cooperatively. The statement structures the synbiotic field for innovation, regulation, and evidence generation.

[99] Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics – approaching a definition. Am J Clin Nutr. 2001. Link

Schrezenmeir and de Vrese's 2001 American Journal of Clinical Nutrition paper proposes working definitions for probiotics, prebiotics and synbiotics that became widely cited. Probiotics are defined as preparations of or products containing viable, defined microorganisms in sufficient numbers to alter the microflora of the host and exert beneficial health effects. Prebiotics are non-digestible food ingredients that selectively stimulate growth or activity of one or a limited number of beneficial bacteria. Synbiotics combine the two. The authors discuss measurement criteria, evidence requirements, and regulatory implications. The definitions preceded and informed the FAO/WHO and ISAPP consensus statements.

[100] Markowiak P, Śliżewska K. Effects of Probiotics, Prebiotics, and Synbiotics on Human Health. Nutrients. 2017. Link

Review framing the gastrointestinal tract as a complex microbial ecosystem in symbiotic co-evolution with the host. Beneficial bacteria produce nutrients, prevent enteric pathogen infection, and modulate normal immune responses. The review summarizes strategies for modifying the intestinal microbiota to achieve, restore, and maintain favourable ecological balance, including diet, prebiotics, probiotics, and FMT.

[101] Kukkonen K, Savilahti E, Haahtela T et al. Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2007. Link

Randomized trial in 1,223 pregnant women carrying high-risk children, comparing a 4-strain probiotic mixture plus galacto-oligosaccharides with placebo. Mothers received the preparation 2–4 weeks before delivery; infants received the same probiotics plus prebiotics. The intervention assessed prevention of allergic disease in offspring. The trial provides high-quality evidence on perinatal probiotic + prebiotic supplementation for allergy prevention in genetically susceptible infants.

[102] Bermudez-Brito M, Plaza-Díaz J, Muñoz-Quezada S, Gómez-Llorente C, Gil A. Probiotic mechanisms of action. Ann Nutr Metab. 2012. Link

Review of probiotic mechanisms of action, focusing on lactic acid bacteria and bifidobacteria. Mechanisms include gut microbiota modification, competitive adherence to mucosa and epithelium, antimicrobial substance production, enhancement of barrier function, and immunomodulation. The review consolidates the mechanistic basis for probiotic therapeutic potential across diseases while noting that strain- and indication-specific evidence is required.

[103] Asemi Z, Zare Z, Shakeri H, Sabihi SS, Esmaillzadeh A. Effect of multispecies probiotic supplements on metabolic profiles, hs-CRP, and oxidative stress in patients with type 2 diabetes. Ann Nutr Metab. 2013. Link

Randomized double-blind placebo-controlled trial in 54 diabetic patients aged 35–70 years assigned to multispecies probiotic supplementation versus placebo. The study assessed metabolic profile, high-sensitivity C-reactive protein (hs-CRP), and oxidative stress markers. Multispecies probiotic supplementation produced significant improvements in metabolic and inflammatory markers versus placebo, supporting multispecies probiotics as an adjunct intervention in type 2 diabetes management.

[104] Farnworth, E. R. Kefir – a complex probiotic. Food Sci Technol Bull Funct Foods. 2005. Link

Farnworth's 2005 Food Science and Technology Bulletin: Functional Foods review describes kefir as a complex probiotic fermented milk product. He summarises the microbial composition of kefir grains, which contain a stable, symbiotic consortium of lactic acid bacteria (Lactobacillus, Lactococcus, Leuconostoc), acetic acid bacteria and yeasts (Kluyveromyces, Saccharomyces) embedded in a kefiran polysaccharide matrix. Documented health effects in animal and human studies include antimicrobial activity, immune modulation, lactose tolerance, cholesterol reduction, and possible antitumor and antiallergic properties. Standardisation, strain-level safety assessment and rigorous clinical trials are identified as research gaps. The review remains a key reference for kefir microbiology and bioactivity.

[105] Bourrie BCT, Willing BP, Cotter PD. The Microbiota and Health Promoting Characteristics of the Fermented Beverage Kefir. Front Microbiol. 2016. Link

Review of kefir, a complex fermented dairy product produced by symbiotic fermentation of milk by lactic acid bacteria and yeasts embedded in a kefir grain. Kefir has been associated with reduced cholesterol and ACE inhibition, antimicrobial activity, tumor suppression, accelerated wound healing, and immunomodulation (including allergy and asthma alleviation). The review synthesizes evidence on kefir's bioactive components and proposes it as a candidate functional food for cardiometabolic and immune health.

[106] Wastyk HC, Fragiadakis GK, Perelman D et al. Gut-microbiota-targeted diets modulate human immune status. Cell. 2021. Link

17-week randomized prospective trial (n=18/arm) in healthy adults comparing high-fibre versus high-fermented-food diets with multi-omics microbiome and host immune profiling. The high-fibre diet increased microbiome-encoded glycan-degrading CAZymes despite stable diversity. The high-fermented-food diet increased microbiome diversity and decreased multiple inflammatory markers. Findings demonstrate diet-specific microbiome–immune effects and support fermented foods as a strong, diversity-promoting modulator of the gut–immune axis.

[107] Marco ML, Heeney D, Binda S et al. Health benefits of fermented foods: microbiota and beyond. Curr Opin Biotechnol. 2017. Link

Review of fermented foods, among the first processed food products consumed by humans (yogurt, cultured milk, wine, beer, sauerkraut, kimchi, fermented sausage). Originally valued for shelf life and palatability, fermented foods are now recognized as having enhanced nutritional and functional properties through substrate transformation and bioactive end-product formation. Many fermented foods contain living microorganisms with potential health effects. The review consolidates fermented foods as a microbiome-relevant dietary category.

[108] Dimidi E, Cox SR, Rossi M, Whelan K. Fermented Foods: Definitions and Characteristics, Impact on the Gut Microbiota and Effects on Gastrointestinal Health and Disease. Nutrients. 2019. Link

Review defining fermented foods as products of controlled microbial growth and enzymatic substrate conversion, characterizing common items (kefir, kombucha, sauerkraut, tempeh, natto, miso, kimchi, sourdough bread) and their proposed mechanisms — including microbiota effects. The review summarizes evidence for fermented-food impact on human gastrointestinal health and disease, supporting selective incorporation into health-promoting dietary patterns.

[109] O'Sullivan O, Coakley M, Lakshminarayanan B et al. Alterations in intestinal microbiota of elderly Irish subjects post-antibiotic therapy. J Antimicrob Chemother. 2013. Link

Cross-sectional study of 185 elderly Irish subjects (≥65 years), with 42 having received antibiotics within 1 month before faecal microbiota profiling. Subjects spanned long-term nursing care, rehabilitation wards, day care, and community-dwelling settings. Antibiotic exposure was associated with significant compositional shifts beyond age-related changes, with residence type modifying the magnitude of perturbation. The data quantify antibiotic-driven dysbiosis in elderly cohorts and the role of care setting in microbiota resilience.

[110] Pasteur, L. Mémoire sur la fermentation appelée lactique. Mémoires de la Société des Sciences de l'Agriculture et des Arts de Lille. 1857. Link

Pasteur's 1857 'Mémoire sur la fermentation appelée lactique' is the founding paper of microbial fermentation science. By isolating a specific microorganism responsible for lactic acid fermentation in sour milk, Pasteur overturned the chemical-decomposition theory of fermentation championed by Liebig and Berzelius and established that fermentation is a biological process driven by living microbes. The methodology — sterile transfer, defined nutrient media, microscopic identification — became the template for medical microbiology. The work directly grounds modern probiotic and food-fermentation science by demonstrating that defined microorganisms cause defined chemical transformations.

[111] Geison, G. L. The Private Science of Louis Pasteur. Princeton: Princeton University Press. 1995. Link

Geison's 1995 'The Private Science of Louis Pasteur' is a Princeton University Press scholarly monograph that re-examines Pasteur's scientific career using his personal laboratory notebooks. Geison documents tensions between Pasteur's published claims and his actual experimental practice, particularly in the silkworm work, anthrax vaccination, and rabies trials. The book reframes the heroic narrative of Pasteur as a story of carefully constructed public science, and provides historical context for the founding of microbiology, fermentation science, vaccination and germ theory. It remains a key reference for the history of medicine and the social epistemology of laboratory science.

[112] Marsh AJ, O'Sullivan O, Hill C, Ross RP, Cotter PD. Sequence-based analysis of the bacterial and fungal compositions of multiple kombucha (tea fungus) samples. Food Microbiol. 2014. Link

Review of kombucha, a sweetened tea fermented by a symbiosis of bacteria and yeast embedded in a cellulosic pellicle, producing ethanol, CO2, organic acids (gluconic, acetic, lactic), and bioactive metabolites. The microbial composition has long been the focus of investigation. The review summarizes current evidence on kombucha's microbial ecology and proposed health effects, framing it as a fermented beverage with plausible but incompletely characterized functional properties.

[113] Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet. 1992. Link

Renaud and de Lorgeril's 1992 Lancet paper introduced the 'French paradox': the observation that France has relatively low coronary heart disease mortality despite high intake of dietary saturated fat. The authors propose that moderate consumption of red wine — and its associated polyphenols (resveratrol), platelet-aggregation inhibition by ethanol, and HDL-cholesterol effects — accounts for the discrepancy. They review epidemiological and mechanistic evidence supporting wine's role in cardiovascular protection. The paper had major influence on subsequent nutrition epidemiology, antioxidant research, and public-health messaging, although later work has challenged the causal interpretation and emphasised confounding by Mediterranean dietary pattern.

[114] Novelle MG, Wahl D, Diéguez C, Bernier M, de Cabo R. Resveratrol supplementation: Where are we now and where should we go? Ageing Res Rev. 2015. 2015. Link

Conceptual review of neuroinflammation as an integral component of neurodegenerative processes, framing the relationship between neuroinflammation and neurodegeneration as a self-sustaining vicious cycle. The review focuses on damage-associated molecular patterns (DAMPs) as a key nexus in this cycle. Consolidates DAMP biology as a unifying mechanism across multiple neurodegenerative conditions and a candidate therapeutic target.

[115] Espín JC, González-Sarrías A, Tomás-Barberán FA. The gut microbiota: A key factor in the therapeutic effects of (poly)phenols. Biochem Pharmacol. 2017. Link

Review of (poly)phenols (PPs), a chemically diverse phytochemical family with active components in plant-derived nutraceuticals and herbal medicines. PPs typically show low bioavailability and reach the colon largely unaltered, where they enter a bidirectional relationship with the gut microbiota: PPs modulate microbial composition, and gut microbes catabolize PPs into bioactive metabolites. The review consolidates PP–microbiota interactions as central to their pharmacological activity and the large interindividual variability observed.

[116] Dueñas M, Muñoz-González I, Cueva C et al. A survey of modulation of gut microbiota by dietary polyphenols. Biomed Res Int. 2015. Link

Review of polyphenol modulation of gut microbiota by experimental design type: batch cultures, gastrointestinal simulators, animal models, and human intervention studies. Evidence converges on consistent polyphenol-driven shifts toward beneficial taxa (Bifidobacterium, Lactobacillus) and on microbiota-dependent generation of bioactive polyphenol metabolites. The review provides a structured synthesis of the polyphenol–microbiota field to support translational research and dietary recommendations.

[117] Singh RK, Chang HW, Yan D et al. Influence of diet on the gut microbiota and implications for human health. J Transl Med. 2017. Link

Systematic review of how common dietary components shape the intestinal microbiota, with implications for inflammatory bowel disease, obesity, type 2 diabetes, cardiovascular disease, and cancer. Dietary alterations can induce large microbial shifts within 24 hours. Consumption of particular food types produces predictable shifts in host bacterial genera, and the identity of these bacteria affects host immune and metabolic parameters. The authors highlight the therapeutic potential of microbiota modulation through diet.

[118] Bang HO, Dyerberg J, Sinclair HM. The composition of the Eskimo food in north western Greenland. Am J Clin Nutr. 1980. Link

Duplicate diet samples from 50 adults (equal sex distribution) in north-western Greenland (1976) were analysed for water, ash, protein, fat, fatty acids, cholesterol, and carbohydrate, and compared with typical Danish diets. Seal and fish were the predominant foods. Eskimo diets were notably richer in polyunsaturated fatty acids, with a polyunsaturated/saturated fatty acid ratio of 0.84 versus 0.24 in Danes. The findings document the distinctive marine-fat-dominated nutritional profile underlying the low cardiovascular disease rates observed historically in this population.

[119] Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? Lancet. 1978. 1978. Link

Dyerberg, Bang, Stoffersen, Moncada and Vane's 1978 Lancet paper proposes that eicosapentaenoic acid (EPA) from marine diets prevents thrombosis and atherosclerosis. Building on epidemiological observations of low ischemic heart disease in Greenland Inuit despite high fat intake, they show that EPA competes with arachidonic acid in platelet eicosanoid pathways, generating less pro-aggregatory thromboxane and more vasodilatory prostacyclin-like compounds. The work provided the mechanistic foundation for the omega-3 cardiovascular hypothesis, motivating decades of clinical trials of fish-oil supplementation and dietary fish consumption. It remains a citation classic in nutritional cardiology.

[120] Calder, P. C. Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans. 2017. Link

Review of omega-6 and omega-3 fatty acid roles in inflammation. EPA and DHA from oily fish or fish-oil supplements partly inhibit leucocyte chemotaxis, adhesion molecule expression, leucocyte-endothelial interactions, and the production of arachidonic-acid-derived eicosanoids and pro-inflammatory cytokines. EPA-derived eicosanoids are typically less potent than those from arachidonic acid, and EPA/DHA give rise to anti-inflammatory and inflammation-resolving mediators (resolvins, protectins, maresins), supporting their use in inflammatory conditions.

[121] Simopoulos, A. P. An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity. Nutrients. 2016. Link

Western diets have shifted from an omega-6/omega-3 ratio of 1:1 during human evolution to 20:1 or higher today, paralleling rising obesity prevalence. Experimental studies show divergent effects of omega-6 and omega-3 on adipogenesis, adipose-tissue browning, lipid homeostasis, brain-gut-adipose axis and systemic inflammation. Prospective studies confirm that higher omega-6 and a higher omega-6/omega-3 ratio in RBC membrane phospholipids increase obesity risk, while high omega-3 reduces it. Maintaining a balanced ratio is important for obesity prevention and management.

[122] Costantini L, Molinari R, Farinon B, Merendino N. Impact of Omega-3 Fatty Acids on the Gut Microbiota. Int J Mol Sci. 2017. Link

Long-term dietary habits shape host-specific gut microbiota, but dietary fat effects are less well characterised than those of carbohydrates. The few adult human omega-3 PUFA supplementation studies show consistent changes: decreased Faecalibacterium, increased Bacteroidetes and butyrate-producing Lachnospiraceae. Because dysbiosis of these taxa occurs in inflammatory bowel disease, omega-3 PUFAs may exert a beneficial effect by restoring microbial composition and increasing anti-inflammatory short-chain fatty acid production.

[123] Noriega BS, Sanchez-Gonzalez MA, Salyakina D, Coffman J. Understanding the impact of omega-3 rich diet on the gut microbiota. Case Rep Med. 2016. Link

Investigation of gut microbiota changes in response to an omega-3-rich diet, framed within the broader recognition that omega-3 polyunsaturated fatty acids ameliorate cardiometabolic, inflammatory and oncologic disorders. The benefits may be substantially mediated through diet-induced changes in gut microbiota composition. Among exogenous factors shaping the gut microbiome, diet appears to have the largest effect.

[124] Cani PD, Amar J, Iglesias MA et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007. Link

Bacterial lipopolysaccharide (LPS) is identified as a triggering factor for insulin resistance, obesity and diabetes. Plasma LPS fluctuates with feeding/fasting and a 4-week high-fat diet chronically increased it 2-3-fold ("metabolic endotoxemia") while increasing the proportion of LPS-containing gut microbiota. Inducing comparable metabolic endotoxemia in mice via continuous subcutaneous LPS infusion for 4 weeks reproduced the high-fat-diet phenotype: increased fasting glycaemia and insulinaemia, weight gain, adipose F4/80+ inflammation, and hepatic triglyceride accumulation.

[125] O'Keefe SJD, Li JV, Lahti L et al. Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun. 2015. Link

Colon cancer incidence is roughly 13-fold higher in African Americans (65/100,000) than in rural South Africans (<5/100,000), with the gap linked to animal protein and fat, low fibre, higher colonic secondary bile acids and lower short-chain fatty acids. A 2-week controlled diet exchange in middle-aged volunteers from both populations produced reciprocal changes in mucosal cancer-risk biomarkers, microbiota and metabolome: increased saccharolytic fermentation and butyrogenesis with suppressed secondary bile acid synthesis in African Americans on the high-fibre African diet.

[126] Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol Rev. 2001. Link

Resistant starch (RS) and nonstarch polysaccharides (NSP), the major components of dietary fibre, are fermented by human colonic bacteria to short-chain fatty acids — primarily acetate, propionate and butyrate. SCFAs stimulate colonic blood flow and fluid/electrolyte uptake; butyrate is the preferred colonocyte substrate and supports a normal colonocyte phenotype. Fermentation of certain RS types preferentially favours butyrate production, providing a mechanistic basis for the colon-health benefits of fibre-rich diets.

[127] Flint HJ, Scott KP, Duncan SH, Louis P, Forano E. Microbial degradation of complex carbohydrates in the gut. Gut Microbes. 2012. Link

Intestinal bacteria carry a far larger repertoire of degradative enzymes than the human host, particularly carbohydrate-active enzymes. Dominant Bacteroidetes such as B. thetaiotaomicron carry hundreds of glycoside hydrolases and switch energy sources flexibly. However, specialised primary degraders in Firmicutes, Actinobacteria and Verrucomicrobia appear critical for initiating breakdown of plant cell walls, starch particles and mucin. The review highlights how prebiotics and other dietary carbohydrates exert health effects via the intricate diet-microbiota-metabolite relationship.

[128] Ze X, Duncan SH, Louis P, Flint HJ. Ruminococcus bromii is a keystone species for the degradation of resistant starch in the human colon. ISME J. 2012. Link

Among four dominant amylolytic colonic bacteria, Ruminococcus bromii proved to be a keystone primary degrader of resistant starch (RS2 and RS3). E. rectale and B. thetaiotaomicron had limited RS-utilisation, while B. adolescentis and R. bromii were more capable. In co-culture, R. bromii uniquely stimulated RS utilisation by the other species, even in media not supporting its own growth. Supplementing R. bromii into fecal cultures from individuals lacking it greatly enhanced RS3 fermentation in vitro, supporting a pivotal role for R. bromii in colonic RS fermentation.

[130] Snow, J. On the Mode of Communication of Cholera. 2nd ed. London: John Churchill. 1965. Link

Snow's 'On the Mode of Communication of Cholera' (second edition, John Churchill, London, 1855; reprinted 1965) is the foundational text of modern epidemiology and water-borne disease theory. By mapping cholera deaths in Soho London and tracing them to a contaminated public water pump on Broad Street, Snow demonstrated that cholera is transmitted by ingestion of fecal-contaminated water rather than by 'miasma'. His removal of the pump handle is the canonical case study in environmental epidemiology. The work directly grounds modern understanding of fecal–oral disease transmission, sanitation interventions, and the role of water and food safety in microbial public health.

[131] Koch, R. Ueber die Cholerabacterien. Dtsch Med Wochenschr. 1884. Link

Koch's 1884 'Ueber die Cholerabacterien' in Deutsche Medizinische Wochenschrift reports the isolation, microscopic and culture characterisation of Vibrio cholerae from cholera victims in Egypt and India. Koch demonstrates the comma-shaped bacillus consistently in intestinal contents of affected patients and absent from controls, applying his own postulates for causation. The paper established the microbial aetiology of cholera, complementing Snow's epidemiological water-transmission evidence with bench-level identification of the pathogen. It is a foundational document of germ theory and remains a milestone in clinical microbiology and infectious disease history.

[132] Johansson ME, Sjövall H, Hansson GC. The gastrointestinal mucus system in health and disease. Nat Rev Gastroenterol Hepatol. 2013. Link

Mucins are large, highly glycosylated proteins that protect the gastrointestinal lumen. Enterocytes carry apical transmembrane mucins, while goblet cells secrete gel-forming mucins. The small intestine has a single unattached mucus layer, which becomes pathologically attached in cystic fibrosis. The stomach and colon have two-layer mucus systems; in the colon the outer layer hosts commensal bacteria while the inner attached layer is impervious to bacteria and is renewed hourly by surface goblet cells, establishing a critical barrier between microbiota and epithelium.

[133] Cotillard A, Kennedy SP, Kong LC et al. Dietary intervention impact on gut microbial gene richness. Nature. 2013. Link

Diet-induced weight-loss and weight-stabilisation intervention in 38 obese and 11 overweight individuals showed that those with low microbial gene richness (40% of the cohort) had more pronounced dysmetabolism and low-grade inflammation. Dietary intervention improved gene richness and clinical phenotypes but was less effective for inflammation in lower-richness individuals. The findings establish gut microbial gene richness as a baseline biomarker that stratifies obese patients by metabolic risk and response to dietary intervention.

[134] Turnbaugh PJ, Hamady M, Yatsunenko T et al. A core gut microbiota in obese and lean twins. Nature. 2009. Link

Faecal microbial community analysis of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity (and their mothers) yielded 9,920 near-full-length 16S rRNA sequences plus 2.14 Gb of metagenomic data from 154 individuals. Family members share a gut microbiome, but each person's specific bacterial lineage composition varies; co-variation was comparable between monozygotic and dizygotic twin pairs, indicating that shared environment plays a major role alongside host genotype in shaping the gut microbiome.

[135] Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nat Rev Immunol. 2014. Link

Review of regional immune specialisation along the intestinal tract. The intestine is the largest immune compartment and is continuously exposed to dietary and microbiota-derived antigens. Anatomical and physiological distinctions between small and large intestine underlie diversity in innate, adaptive and innate-like immune-cell distribution. Environmental influences and the consequences for intestinal inflammatory disease are discussed; intestinal immune processes are increasingly implicated in extra-intestinal disease control.

[136] Fraser, G. E. Associations between diet and cancer, ischemic heart disease, and all-cause mortality in non-Hispanic white California Seventh-day Adventists. Am J Clin Nutr. 1999. Link

Cohort study of 34,192 California Seventh-day Adventists examined associations between diet and chronic disease. About 50% ate meat <1/week; vegetarians consumed more tomatoes, legumes, nuts and fruit. Beef consumption >=3/week increased fatal ischaemic heart disease risk in men (RR = 2.31 vs vegetarians); nut consumption >=5/week halved IHD risk (RR ~0.5). Lifetime IHD risk was reduced by ~31% with frequent nuts and ~37% in male vegetarians. Colon and prostate cancer risk were higher in non-vegetarians (RR 1.88 and 1.54), and frequent beef consumers had higher bladder cancer risk.

[137] Orlich MJ, Singh PN, Sabaté J et al. Vegetarian dietary patterns and mortality in Adventist Health Study 2. JAMA Intern Med. 2013. Link

Adventist Health Study 2 prospective cohort of 96,469 Seventh-day Adventists (analytic sample 73,308) evaluated mortality across five dietary patterns: nonvegetarian, semi-vegetarian, pesco-vegetarian, lacto-ovo-vegetarian and vegan. Cox proportional hazards regression controlled for demographic and lifestyle confounders. Findings support an association between vegetarian dietary patterns and reduced overall mortality, with the strongest signals observed in pesco-vegetarian and vegan groups, establishing one of the largest North American datasets on plant-based diet outcomes.

[138] Conlon MA, Bird AR. The impact of diet and lifestyle on gut microbiota and human health. Nutrients. 2015. Link

Narrative review of the role of diet and other environmental factors in modulating gut microbiota composition and metabolic activity with downstream health impacts. Molecular technologies have revealed the complexity and individual variation of gut microbial communities. Macronutrients — particularly carbohydrates — strongly shape microbiota composition, but many questions remain about specific carbohydrate effects, and the impacts of dietary fats and protein are less well defined.

[139] Russell WR, Gratz SW, Duncan SH et al. High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health. Am J Clin Nutr. 2011. Link

Cross-over trial in 17 obese men compared a high-protein/moderate-carbohydrate (HPMC) and a high-protein/low-carbohydrate (HPLC) diet (4 weeks each) against a maintenance diet (7 days). Both high-protein diets increased the proportion of branched-chain fatty acids and faecal concentrations of phenylacetic acid and N-nitroso compounds — microbial metabolites considered detrimental to long-term colonic health. The findings indicate that high-protein, reduced-carbohydrate weight-loss diets shift the colonic metabolite profile toward markers associated with colorectal disease risk.

[140] Flint HJ, Duncan SH, Scott KP, Louis P. Links between diet, gut microbiota composition and gut metabolism. Proc Nutr Soc. 2015. Link

Review of diet-driven changes in gut microbiota composition and their metabolic outputs. Species composition responds to dietary change through substrate competition and tolerance of gut conditions, and metabolic outputs such as SCFAs are influenced both by dietary substrate supply and by diet-mediated compositional shifts. Phylogenetic distribution of pathways for major metabolites has progressed: butyrate and propionate can be ascribed to distinct bacterial groups, with propionate formed via alternative pathways from deoxy-sugars and lactate. Cross-feeding on lactate by certain Firmicutes supports community stability.

[141] David LA, Maurice CF, Carmody RN et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014. Link

Short-term consumption of diets composed entirely of animal versus plant products produced dramatic, reproducible shifts in human gut microbial community structure that overwhelmed inter-individual differences. The animal-based diet increased bile-tolerant microbes (Alistipes, Bilophila, Bacteroides) and decreased plant-polysaccharide-fermenting Firmicutes (Roseburia, E. rectale, R. bromii), mirroring herbivore-vs-carnivore patterns. Bilophila wadsworthia bloomed on the animal-based diet, mechanistically linking dietary fat, bile acids and the outgrowth of microbes capable of triggering inflammatory bowel disease.

[142] Burr ML, Fehily AM, Gilbert JF et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989. Link

Burr and colleagues' DART (Diet and Reinfarction Trial, Lancet 1989) is a landmark randomised trial of dietary interventions after myocardial infarction in 2033 British men. Participants received advice to alter intake of fat, fatty fish, or cereal fiber in a 2×2×2 factorial design. After two years, the fish-advice group showed a 29% reduction in all-cause mortality compared to no-fish advice, while changes in fat or fiber alone did not significantly affect mortality. The trial provided early secondary-prevention evidence for fatty fish (omega-3) intake post-MI and shaped subsequent cardiology dietary guidance. Later DART-2 in angina patients found more equivocal results.

[143] Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012. Link

Review of mechanisms by which the gut microbiota influences host metabolism, with implications for obesity, cardiovascular disease and metabolic syndromes including type 2 diabetes. The microbiota modulates host metabolic pathways by improving energy yield from food and by altering dietary and host-derived compound bioactivity. Better mechanistic understanding will support the development of metabolic-disease treatments targeting the microbiota.

[144] Cani PD, Amar J, Iglesias MA et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007. Link

Cani and colleagues' 2007 Diabetes paper introduced the concept of 'metabolic endotoxemia' as a microbiota-driven trigger of obesity and insulin resistance. In mice, they show that a high-fat diet increases intestinal permeability and circulating lipopolysaccharide (LPS) levels, which activate TLR4-CD14 signalling and induce low-grade inflammation in adipose tissue, liver and muscle. Chronic subcutaneous LPS infusion in mice was sufficient to reproduce diet-induced obesity, insulin resistance and hepatic steatosis. CD14-knockout mice were protected. The paper established a mechanistic axis linking gut microbiota, barrier function and metabolic disease that has shaped subsequent obesity-microbiome research.

[145] Key TJ, Appleby PN, Rosell MS. Health effects of vegetarian and vegan diets. Proc Nutr Soc. 2006. Link

Review of vegetarian (no meat/poultry/fish) and vegan (also no dairy/eggs) diets in well-educated Western populations. These diets are typically high in cereals, pulses, nuts, fruits, vegetables, fibre, carotenoids, folate, vitamins C and E and Mg, and lower in protein, saturated fat, long-chain n-3 fatty acids, retinol, B12 and Zn (with vegans particularly low in B12 and Ca). Cross-sectional data show lower BMI and plasma cholesterol but higher homocysteine; cohort studies show moderate IHD mortality reduction but little difference in other major causes versus health-conscious non-vegetarians.

[146] Tong TYN, Appleby PN, Bradbury KE et al. Risks of ischaemic heart disease and stroke in meat eaters, fish eaters, and vegetarians over 18 years of follow-up: results from the prospective EPIC-Oxford study. BMJ. 2019. Link

EPIC-Oxford prospective cohort of 48,188 UK adults free of cardiovascular disease at baseline (24,428 meat eaters, 7,506 fish eaters, 16,254 vegetarians/vegans) was followed for 18.1 years. 2,820 ischaemic heart disease and 1,072 stroke cases (519 ischaemic, 300 haemorrhagic) were recorded. Results compare IHD and stroke risk across diet groups; the study is among the largest prospective evaluations of vegetarian dietary patterns and their cardiovascular outcomes in a Western population.

[147] Tomova A, Bukovsky I, Rembert E et al. The Effects of Vegetarian and Vegan Diets on Gut Microbiota. Front Nutr. 2019. Link

Review of gut microbiota composition differences between vegan/vegetarian and omnivorous individuals. Plant-based diets are associated with more diverse and stable microbial communities and higher counts of certain Bacteroidetes operational taxonomic units. Fibre consistently increases lactic-acid bacteria (Ruminococcus, E. rectale, Roseburia) and reduces Clostridium and Enterococcus. Polyphenols increase Bifidobacterium and Lactobacillus with anti-pathogenic, anti-inflammatory and cardiovascular benefits, while high fibre drives short-chain fatty acid production (acetate, propionate, butyrate).

[148] Tap J, Furet JP, Bensaada M et al. Gut microbiota richness promotes its stability upon increased dietary fibre intake in healthy adults. Environ Microbiol. 2015. Link

A 6-week nutritional trial in 19 healthy adults supplemented daily diet with 10 or 40 g dietary fibre for 5 days followed by 15-day washouts. Faecal samples were profiled with 16S pyrosequencing, intestinal genotoxicity, metatranscriptomics and SCFA analysis. Short-term fibre changes did not affect all individuals equally but produced significant within-individual genus-level shifts. Higher baseline microbiota richness was associated with higher microbiota stability upon increased fibre intake, supporting richness as a determinant of dietary response.

[149] Ridaura VK, Faith JJ, Rey FE et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013. Link

Faecal microbiota from adult female twin pairs discordant for obesity was transplanted into germ-free mice fed mouse chow and US-style diets. Increased body and fat mass and obesity-associated metabolic phenotypes were transmissible by both uncultured and cultured fecal communities. Cohousing obese-microbiota mice with lean-microbiota cage mates prevented obesity development, with rescue driven by invasion of specific Bacteroidetes from lean into obese microbiota. The effect was diet-dependent, revealing rapid, transmissible and modifiable diet-by-microbiota interactions in body composition.

[150] Zinöcker MK, Lindseth IA. The Western Diet–Microbiome-Host Interaction and Its Role in Metabolic Disease. Nutrients. 2018. Link

Review arguing that the Western dietary pattern promotes inflammation via structural and behavioural changes in the gut microbiome. The environment created by ultra-processed foods provides a unique selection ground for microbes that can drive inflammatory disease. Whole-food-based diets emerge as a common denominator of low-disease populations. Recognising the microbiome's role in diet-related disease has implications for research, dietary guidelines and food production practices, with ultra-processing effects on the microbiome a key target for future investigation.

[151] Hehemann JH, Correc G, Barbeyron T et al. Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature. 2010. Link

Bacteroides thetaiotaomicron carries 261 glycoside hydrolases and polysaccharide lyases plus 208 SusC/SusD homologues, illustrating the diversity of carbohydrate-active enzymes (CAZymes) in gut bacteria — enzymes absent from the human genome. The study characterises the first porphyranases from the marine bacterium Zobellia galactanivorans, active on porphyran from Porphyra red algae, and demonstrates that genes encoding these enzymes have been horizontally transferred to the gut bacterium Bacteroides plebeius in Japanese individuals, expanding CAZyme repertoire through marine-derived gene acquisition.

[152] O'Sullivan L, Murphy B, McLoughlin P et al. Prebiotics from marine macroalgae for human and animal health applications. Mar Drugs. 2010. Link

Review of marine macroalgae (seaweed) polysaccharides as potential prebiotic functional ingredients for human and animal health. Prebiotics are non-digestible, selectively fermented compounds that stimulate beneficial gut microbiota and confer health benefits on the host. The review outlines seaweed polysaccharide chemistry and surveys in vitro and in vivo data supporting their prebiotic application, framing marine macroalgae as an underused source of bioactive compounds.

[153] Devkota S, Wang Y, Musch MW et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature. 2012. Link

Mice fed a saturated (milk-derived) high-fat diet — but not a polyunsaturated (safflower-oil) high-fat diet — promoted expansion of the sulphite-reducing pathobiont Bilophila wadsworthia, accompanied by a Th1 immune response and increased colitis in genetically susceptible Il10-/- mice. The mechanism involves milk-fat-driven taurine conjugation of hepatic bile acids, increasing organic sulphur availability. Taurocholic acid supplementation — but not glycocholic — recapitulated the B. wadsworthia bloom and colitis. Dietary fat thus alters bile acid composition and the microbial environment, perturbing immune homeostasis.

[154] Suez J, Korem T, Zeevi D et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014. Link

Non-caloric artificial sweeteners (NAS) induced glucose intolerance in mice and humans via compositional and functional changes in the gut microbiota. Antibiotic treatment abrogated the deleterious metabolic effects, and germ-free mice receiving faecal transplants from NAS-consuming mice (or NAS-incubated microbiota) developed glucose intolerance. NAS-altered microbial metabolic pathways were linked to metabolic disease susceptibility, with similar dysbiosis and glucose intolerance demonstrated in healthy human subjects. The findings call for reassessment of widespread NAS use.

[155] Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006. Link

Comparison of distal gut microbiota in genetically obese mice and lean littermates, and in obese versus lean human volunteers, revealed that obesity is associated with shifts in Bacteroidetes/Firmicutes ratios. Metagenomic and biochemical analyses show that the obese microbiome has an increased capacity to harvest energy from the diet. The trait is transmissible: colonisation of germ-free mice with obese microbiota produced significantly greater body-fat increases than colonisation with lean microbiota, identifying the gut microbiota as a contributing factor in obesity pathophysiology.

[156] Wang Z, Klipfell E, Bennett BJ et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011. Link

Untargeted metabolomics in plasma identified three dietary-phosphatidylcholine metabolites — choline, trimethylamine N-oxide (TMAO) and betaine — that predicted cardiovascular disease (CVD) risk in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine upregulated multiple atherosclerosis-linked macrophage scavenger receptors; choline and TMAO promoted atherosclerosis. Germ-free mouse studies confirmed that dietary choline and gut flora are critical for TMAO production, augmented macrophage cholesterol accumulation and foam-cell formation.

[157] Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest. 2014. Link

Trimethylamine (TMA)-containing dietary nutrients — choline/phosphatidylcholine and L-carnitine — participate in atherosclerotic heart disease via a meta-organismal pathway involving gut-microbiota-dependent TMA formation and hepatic flavin monooxygenase 3 (FMO3)-dependent conversion to TMAO. TMAO levels are mechanistically linked to atherosclerosis and strongly correlate with cardiovascular disease risk. Nutrient precursors, gut microbiota and host enzymes along this pathway represent novel targets for CVD prevention and treatment.

[158] World Cancer Research Fund / American Institute for Cancer Research. Diet, Nutrition, Physical Activity and Cancer: a Global Perspective. Continuous Update Project Expert Report 2018. (IV-19). 2018. Link

The 2018 World Cancer Research Fund / American Institute for Cancer Research Continuous Update Project Expert Report 'Diet, Nutrition, Physical Activity and Cancer: a Global Perspective' is the leading evidence-based consensus on lifestyle factors in cancer prevention. Synthesising over 50 cancer-site systematic reviews, the expert panel grades evidence for diet, body fatness, physical activity and cancer risk. Strong evidence supports the role of obesity, alcohol, processed meat and red meat (colorectal cancer), and whole grains/fiber (protective). Ten cancer-prevention recommendations are issued: maintain healthy weight, be physically active, eat whole grains, vegetables and fruits, limit fast food, red/processed meat, sugary drinks and alcohol; do not rely on supplements; breastfeed; follow recommendations after cancer diagnosis. The report informs global cancer-prevention policy.

[159] Chassaing B, Koren O, Goodrich JK et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature. 2015. Link

In wild-type mice, relatively low concentrations of two ubiquitous emulsifiers — carboxymethylcellulose (CMC) and polysorbate-80 (P80) — induced low-grade inflammation and obesity/metabolic syndrome, and promoted robust colitis in mice predisposed to it. The mucus-protective barrier and microbiota composition were disrupted. The findings implicate dietary emulsifiers, ubiquitous components of processed foods, in the post-mid-20th-century rise in inflammatory bowel disease and metabolic disorders.

[160] Chassaing B, Van de Wiele T, De Bodt J, Marzorati M, Gewirtz AT. Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut. 2017. Link

Using the M-SHIME ex vivo human microbiota model that excludes host inflammation as a confounder, both carboxymethylcellulose (CMC) and polysorbate 80 (P80) acted directly on the human microbiota to increase its pro-inflammatory potential, evidenced by elevated bioactive flagellin. The CMC-induced flagellin rise was rapid (1 day) and driven by altered microbial gene expression. The findings establish that these dietary emulsifiers exert direct, host-independent pro-inflammatory effects on the human gut microbiota.

[161] Desai MS, Seekatz AM, Koropatkin NM et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell. 2016. Link

In gnotobiotic mice colonised with a synthetic human gut microbiota, chronic or intermittent dietary fibre deficiency caused the microbiota to use host-secreted mucus glycoproteins as a nutrient source, eroding the colonic mucus barrier. Combined fibre deprivation and a mucus-eroding microbiota allowed greater epithelial access and lethal colitis by the mucosal pathogen Citrobacter rodentium. The findings link diet, microbiome and intestinal barrier dysfunction and identify dietary fibre as a key barrier-protective factor exploitable for therapeutic strategies.

[162] Suez J, Cohen Y, Valdés-Mas R et al. Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance. Cell. 2022. Link

Randomised controlled trial in 120 healthy adults receiving saccharin, sucralose, aspartame or stevia (in doses below acceptable daily intake) versus glucose-vehicle or no supplement for 2 weeks. All four non-nutritive sweeteners distinctly altered the stool/oral microbiome and plasma metabolome; saccharin and sucralose significantly impaired glycaemic responses. Gnotobiotic mice colonised with microbiomes from top and bottom human responders reproduced donor-specific glycaemic responses, demonstrating that non-nutritive sweeteners can induce person-specific, microbiome-dependent glycaemic alterations.

[163] Zmora N, Suez J, Elinav E. You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019. Link

Review of diet as a pivotal determinant of gut microbiota community structure and function. Dietary signals enter the host-microbiota nexus and either sustain homeostasis or contribute to disease susceptibility. The review summarises major concepts in the diet-microbiota crosstalk, the health benefits and detrimental consequences of these interactions, and the promises and challenges of integrating microbiome data into personalised dietary planning, the field of nutrition adoption.

[164] Ruiz-Ojeda FJ, Plaza-Díaz J, Sáez-Lara MJ, Gil A. Effects of Sweeteners on the Gut Microbiota: A Review of Experimental Studies and Clinical Trials. Adv Nutr. 2019. Link

Review of experimental and clinical evidence on how non-nutritive sweeteners (NNS) — synthetic (acesulfame-K, aspartame, cyclamate, saccharin, neotame, advantame, sucralose) and natural (thaumatin, steviol glycosides, monellin, neohesperidin DC, glycyrrhizin) — and nutritive polyol sweeteners affect human gut microbiota. Only saccharin, sucralose (synthetic NNS) and stevia (natural NS) clearly altered gut microbiota. Some polyols (isomaltose, maltitol, lactitol, xylitol) reach the colon and increase bifidobacteria, suggesting a partial prebiotic effect.

[165] McCann D, Barrett A, Cooper A et al. Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial. Lancet. 2007. Link

McCann and colleagues' 2007 Lancet randomised, double-blind, placebo-controlled trial — the Southampton study — tested the effect of artificial food colourings and the preservative sodium benzoate on hyperactive behaviour in 153 three-year-old and 144 eight/nine-year-old community children. Children received daily drinks containing one of two test mixes of approved azo dyes plus sodium benzoate or placebo, in a crossover design. Behavioural assessments showed significant increases in hyperactivity scores during the active mix compared with placebo, in both age groups. The trial directly influenced EFSA's re-evaluation of food colours and led to mandatory warning labels in the EU for products containing the implicated additives.

[166] European Food Safety Authority (EFSA). Scientific Opinion on the re-evaluation of six food colours. EFSA Journal. 2009. Link

EFSA's 2009 Scientific Opinion 'Re-evaluation of six food colours' re-examined the safety and acceptable daily intake (ADI) of six azo dyes implicated in the Southampton (McCann 2007) hyperactivity study: Quinoline Yellow, Sunset Yellow, Tartrazine, Azorubine, Ponceau 4R and Allura Red. EFSA's Panel on Food Additives lowered the ADI for several colours, reflecting limited evidence of behavioural effects in children. The opinion provided the scientific basis for EU regulation requiring mandatory warning labels ('may have an adverse effect on activity and attention in children') on foods containing these colours. The work is a touchstone for evidence-based regulation of food additives.

[167] Duan Y, Llorente C, Lang S et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature. 2019. Link

Cytolysin, a two-subunit exotoxin secreted by Enterococcus faecalis, was identified as a cause of hepatocyte death and liver injury in alcoholic hepatitis. Patients with alcoholic hepatitis had increased faecal E. faecalis numbers compared with non-alcoholic individuals or alcohol-use disorder patients without hepatitis; cytolysin-positive (cytolytic) E. faecalis presence correlated with liver disease severity and mortality. The findings identify a microbe-derived virulence factor as a driver of alcoholic hepatitis severity and a candidate therapeutic target.

[168] Szabo, G. Gut-liver axis in alcoholic liver disease. Gastroenterology. 2015. Link

Review of the gut-liver axis in alcoholic liver disease (ALD). Increased portal endotoxin levels, gut barrier disruption and gut permeability are central to ALD. Lipopolysaccharide (LPS) drives inflammation via Toll-like receptor 4. Alcohol-induced dysbiosis — an imbalance of pathobiont and commensal organisms — contributes to the abnormal gut-liver axis. Bacterial decontamination improves ALD in both human and animal models, supporting the microbiota as a therapeutic target.

[169] Leclercq S, Matamoros S, Cani PD et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci USA. 2014. Link

Study of alcohol-dependent subjects examined whether gut permeability changes are linked to gut microbiota composition and activity, and whether gut dysfunction is associated with psychological symptoms and relapse risk. Some, but not all, alcohol-dependent subjects developed gut leakiness, which correlated with higher depression, anxiety and craving scores after 3 weeks of abstinence. The findings suggest gut dysfunction as a psychobiological factor in alcohol-dependence severity and potential relapse.

[170] Bishehsari F, Magno E, Swanson G et al. Alcohol and Gut-Derived Inflammation. Alcohol Res. 2017. Link

Bishehsari and colleagues' 2017 Alcohol Research review synthesises evidence on how alcohol consumption drives gut-derived systemic inflammation. The authors describe how chronic ethanol exposure increases intestinal permeability ('leaky gut'), shifts microbiota toward dysbiosis (decreased Lactobacillus, increased Proteobacteria), and elevates portal and systemic endotoxin (LPS). This drives Kupffer-cell and macrophage activation, contributing to alcoholic liver disease, cardiovascular disease, neuroinflammation and cancer. They review mechanisms including tight-junction disruption (zonulin pathway), bile-acid alterations, and acetaldehyde-mediated DNA damage. Therapeutic strategies discussed include probiotics, prebiotics, zinc, and barrier-protective agents. The review frames alcohol as a microbiome-modifying exposure with systemic consequences.

[171] Yan AW, Fouts DE, Brandl J et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology. 2011. Link

In a mouse model of continuous intragastric alcohol or isocaloric feeding, bacterial translocation preceded changes in the enteric microbiome. Quantitative culture-based analyses of small and large intestinal microflora documented dysbiosis associated with alcoholic liver disease. The findings show that bacterial translocation across the intestinal barrier is an early event in ALD, occurring before measurable shifts in microbiota composition, and that mucosal antimicrobial proteins regulate this process.

[172] Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology. 2014. Link

Randomised single-blind cross-over trial in 30 IBS patients and 8 controls compared a low-FODMAP diet (<0.5 g/meal) with a typical Australian diet for 21 days each (>=21-day washout). Almost all food was provided. The low-FODMAP arm produced significantly greater reduction in IBS symptoms measured on 0-100 mm visual analogue scales, supporting the low-FODMAP diet as an effective intervention for symptom control in IBS compared with a standard Western diet.

[173] Staudacher HM, Whelan K, Irving PM, Lomer MC. Comparison of symptom response following advice for a diet low in fermentable carbohydrates (FODMAPs) versus standard dietary advice in patients with irritable bowel syndrome. J Hum Nutr Diet. 2011. Link

Comparison of low-FODMAP dietary advice (n=43) versus standard UK NICE dietary advice (n=39) in IBS patients attending a follow-up dietetic outpatient visit. More patients in the low-FODMAP group reported satisfaction with their symptom response (76%) than in the standard advice group (54%, p=0.038). The findings support the superiority of low-FODMAP dietary advice over standard NICE-based guidance in IBS symptom management.

[174] Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015. Link

Single-blinded randomised cross-over trial in 27 IBS and 6 healthy subjects compared a low-FODMAP diet (3.05 g/day) with a typical Australian diet (23.7 g/day) for 21 days each. The low-FODMAP diet produced higher faecal pH (7.37 vs 7.16, p=0.001), similar SCFA concentrations, greater microbial diversity but reduced total bacterial abundance (9.63 vs 9.83 log10 copies/g, p<0.001). The findings indicate that the low-FODMAP diet, while symptom-relieving, modifies the colonic luminal microenvironment in ways with possible long-term implications.

[175] Gibson PR, Shepherd SJ. Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach. J Gastroenterol Hepatol. 2010. Link

Review of the evidence base for FODMAP restriction in functional gastrointestinal symptoms. FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) include fructose, lactose, fructans, galactans and polyols. They are widespread in the diet, deliver readily fermentable substrate and water to the distal small bowel and proximal colon, and induce luminal distension and functional gut symptoms. The review describes the nature of FODMAPs, their mode of symptom induction, clinical trial outcomes, and practical implementation of the diet.

[176] Staudacher HM, Lomer MCE, Anderson JL et al. Fermentable carbohydrate restriction reduces luminal bifidobacteria and gastrointestinal symptoms in patients with irritable bowel syndrome. J Nutr. 2012. Link

Single-blinded, controlled study in 28-day low-vitamin-B6 diet on healthy adults (n=23) following a 2-day vitamin-B6-adequate run-in. Plasma HDL, LDL, free fatty acids and erythrocyte/PBMC membrane fatty acids did not change significantly. However, plasma arachidonic acid, EPA and DHA decreased significantly from 548+/-96 to 490+/-94 micromol/L, 37+/-13 to 32+/-13 micromol/L, and 121+/-28 to 109+/-28 micromol/L respectively (pFDR-adjusted p<0.05), showing that marginal B6 deficiency impairs n-6 and n-3 long-chain PUFA status in humans.

[177] De Palma G, Nadal I, Collado MC, Sanz Y. Effects of a gluten-free diet on gut microbiota and immune function in healthy adult volunteers. Br J Nutr. 2009. Link

One-month gluten-free diet (GFD) intervention in ten healthy adults (mean age 30.3 years) showed that the GFD reduced polysaccharide intake (p=0.001) without other significant dietary differences. Faecal microbiota profiled by FISH and qPCR, and PBMC cytokine responses by ELISA, showed shifts in microbial composition and immune function attributable to GFD. The findings indicate that gluten exclusion modifies gut microbiota and immune parameters even in non-coeliac, healthy subjects.

[178] Sanz Y, De Palma G. Gut microbiota, diet and chronic metabolic diseases. In: Proceedings of the Nutrition Society. 2009. Link

Sanz and De Palma's 2009 Proceedings of the Nutrition Society paper reviews how gut microbiota, diet and chronic metabolic diseases interact. They summarise evidence that obesity, type 2 diabetes and metabolic syndrome are accompanied by dysbiotic shifts (altered Firmicutes/Bacteroidetes ratio, decreased Akkermansia muciniphila, reduced microbial diversity), and that dietary patterns — Western, Mediterranean, plant-based — drive these shifts. Mechanisms include increased energy harvest, LPS-mediated low-grade inflammation, altered SCFA and bile-acid signalling, and modulation of gut-derived hormones (GLP-1, PYY). Probiotics, prebiotics and dietary fiber are positioned as microbiota-targeted interventions. The review predates but anticipates much of the next decade's translational research.

[179] Nistal E, Caminero A, Herrán AR et al. Differences of small intestinal bacteria populations in adults and children with/without celiac disease. Influence of age, gluten diet, and disease. Inflamm Bowel Dis. 2012. Link

Comparison of upper small intestinal bacterial communities in adults (healthy, untreated celiac disease, and treated with gluten-free diet) and children (healthy, untreated CD) using 16S rRNA gene sequencing of duodenal biopsies. The bacterial communities were dominated by Firmicutes, Proteobacteria and Bacteroidetes, with 89 genera identified in adults and 46 in children. Bacterial richness was significantly lower in children than adults, demonstrating age-related and disease-state differences in small-intestinal microbial composition relevant to celiac disease pathogenesis.

[180] Setchell KDR, Brown NM, Lydeking-Olsen E. The clinical importance of the metabolite equol – a clue to the effectiveness of soy and its isoflavones. J Nutr. 2002. Link

Equol, a nonsteroidal estrogen formed exclusively by intestinal bacterial metabolism of the soy isoflavone daidzein, has affinity for both estrogen receptors and superior antioxidant activity. It is not produced in all healthy adults despite soy or daidzein intake. Dietary intervention studies show that maximal clinical responses to soy protein diets occur in "equol-producers," suggesting that bacterio-typing for equol production may predict the efficacy of soy-based interventions in hormone-dependent conditions.

[181] Decroos K, Vanhemmens S, Cattoir S, Boon N, Verstraete W. Isolation and characterisation of an equol-producing mixed microbial culture from a human faecal sample. Arch Microbiol. 2005. Link

Investigation of in vitro daidzein metabolism by faecal samples from four individuals. One culture produced dihydrodaidzein and O-desmethylangolensin, another produced dihydrodaidzein and equol. From the equol-producing sample, a stable, transferable mixed culture transforming daidzein into equol was obtained. DGGE molecular fingerprinting revealed four bacterial species, of which three were brought into pure culture, advancing characterisation of the microbial consortium responsible for equol production in humans.

[182] Frankenfeld CL, Atkinson C, Wahala K, Lampe JW. Obesity prevalence in relation to gut microbial environments capable of producing equol or O-desmethylangolensin from the isoflavone daidzein. Eur J Clin Nutr. 2012. Link

Validity and reproducibility study of a web-based, self-administered food frequency questionnaire (web-FFQ) in 74 healthy subjects (34 men, 40 women) from Québec, compared against a validated interviewer-administered FFQ (IA-FFQ) and 3-day food record. Mean intakes of 17/22 nutrients did not differ significantly between web-FFQ and 3-day FR (differences <10%, p>=0.11). De-attenuated Pearson correlations ranged 0.12-0.98 (mean R=0.55) against 3-day FR and were 0.34-0.98 (mean R=0.59) against IA-FFQ. 77% of subjects classified in the same or adjacent quartile between web-FFQ and 3-day FR.

[183] Wrangham, R. Catching Fire: How Cooking Made Us Human. New York: Basic Books. 2009. Link

Wrangham's 2009 'Catching Fire: How Cooking Made Us Human' is an anthropological monograph (Basic Books) arguing that the control of fire and the cooking of food was the pivotal evolutionary event distinguishing Homo erectus from earlier hominins. Wrangham proposes that cooking dramatically increased the bioavailable energy of plant and animal foods, reduced chewing and digestion time, shrank the gut and jaw, and enabled the expansion of energetically expensive brains. The book frames cooking as a co-evolutionary trait alongside bipedalism and tool-use. It has been highly influential in human evolution, nutrition science, and microbiome-informed views of the 'cooked-food' digestive niche.

[184] Carmody RN, Wrangham RW. Cooking and the human commitment to a high-quality diet. Cold Spring Harb Symp Quant Biol. 2009. Link

Humans show higher energy use yet reduced mastication and digestive structures relative to chimpanzees, suggesting adaptation to a high-quality diet. Meat-eating alone is insufficient to support these traits, as modern humans fare poorly on raw meat-containing diets. The authors argue that cooking confers physical and chemical benefits that match observed human adaptations: facilitating mastication, increasing digestibility, and improving net energy value of plant and animal foods. They posit that cooking was adopted more than 250,000 years ago, sufficient time for the proposed evolutionary adaptations.

[185] Carmody RN, Gerber GK, Luevano JM et al. Diet dominates host genotype in shaping the murine gut microbiota. Cell Host Microbe. 2015. Link

Effect of dietary perturbations on gut microbiota was examined in five inbred mouse strains, mice deficient for MyD88, NOD2, ob/ob, Rag1, and >200 outbred mice. A high-fat, high-sugar diet reproducibly altered the gut microbiota across host genotypes; the microbiota showed a linear dose response with an average new-steady-state time of 3.5 days per diet-responsive bacterial group. Most changes were reversible upon dietary shift, though some bacteria depended on prior consumption. Diet dominates over host genotype in shaping interindividual microbiota variation.

[186] Lichtenberg SS, Sivaganesan M, Shanks OC. Microbiome methods to assess produce quality and safety. mSphere. 2021. Link

Investigation of interactions among mobile genetic elements (MGEs) in the marine bacterium Sulfitobacter pontiacus, focusing on two related strains (CB-D and CB-A) carrying related prophages with high sequence identity and a shared integration site but differing in spontaneous prophage induction (SPI) and host fitness. Closing the genomes revealed that CB-A lacks two of four large, low-copy plasmids found in CB-D, illuminating how MGE combinations shape bacterial fitness and prophage induction in natural microbial systems.

[187] Pham ND, Kim HJ, Kim IH et al. The impact of production system on microbiome and safety of fresh-cut vegetables. Front Microbiol. 2021. Link

Pham and colleagues' 2021 Frontiers in Microbiology study investigates how the production system (conventional soil cultivation, organic farming, hydroponics, vertical farming) shapes the microbiome and microbial safety of fresh-cut vegetables. Using 16S rRNA gene sequencing and pathogen-targeted culture, they compare diversity, taxonomic composition and presence of human pathogens (E. coli, Salmonella, Listeria) across production systems. Hydroponic and indoor-cultivated vegetables show lower microbial diversity and reduced beneficial environmental microbiota, but also lower pathogen load. Soil-grown produce hosts richer microbiomes but more variable pathogen burden. The authors discuss food-safety, sensory and microbiome-exposure trade-offs.

[188] Hoagland DR, Arnon DI. The water-culture method for growing plants without soil. Calif Agric Exp Stn Circ. 1950. Link

Hoagland and Arnon's 1950 California Agricultural Experiment Station Circular 'The water-culture method for growing plants without soil' is the foundational manual of hydroponics. The authors define a complete soluble nutrient formulation (the 'Hoagland solution') for growing plants in water without soil, specifying macronutrient and micronutrient concentrations, pH, aeration and renewal schedules. The work standardised research-scale hydroponic culture for plant nutrition studies and laid the practical basis for commercial soilless agriculture, including modern vertical farming and indoor agriculture. The Hoagland solution remains in widespread use today as a reference nutrient medium.

[189] Tassinari E, Cavani L, Farneselli M, Tittarelli F. Hydroponic systems and nutrient use efficiency: a review. Agronomy. 2022. Link

Tassinari and colleagues' 2022 Agronomy review surveys hydroponic systems and nutrient-use efficiency. The authors compare nutrient film technique, deep-water culture, aeroponics, drip and ebb-and-flow systems for water/nutrient consumption, yield and resource-use efficiency relative to soil-based farming. Hydroponics achieves 70–90% water savings and 50–60% fertiliser reductions per unit yield, with potential for closed-loop nutrient recycling. Challenges include energy demand, plant-pathogen management, and microbiome differences relative to soil-grown produce. The review situates hydroponics within sustainable-agriculture, food-security and urban-farming policy discussions.

[190] Leone V, Gibbons SM, Martinez K et al. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe. 2015. Link

Germ-free mice fed low- or high-fat diets exhibited markedly impaired central and hepatic circadian clock gene expression and did not gain weight compared with conventionally raised counterparts, despite intact light-dark signals. Conventional mice showed diet-dependent diurnal variation in gut microbial structure and function. Microbially derived short-chain fatty acids — but not hydrogen sulfide — directly modulated hepatocyte circadian clock gene expression. The findings establish the gut microbiome and its metabolites as key regulators of host circadian rhythm and Westernised-diet metabolic effects.

[191] Liang X, FitzGerald GA. Timing the Microbes: The Circadian Rhythm of the Gut Microbiome. J Biol Rhythms. 2017. Link

Review of circadian organisation in the gut microbiome. The mammalian circadian system (master clock and peripheral clocks) coordinates biological processes in response to external cues like the light-dark cycle, but prokaryote chronobiology — outside cyanobacteria — is poorly understood. The review summarises evidence of time-of-day-dependent compositional and functional structure within the gut microbiota, host regulation of these oscillations, and the reciprocal influence of the gut microbiome on host circadian timing.

[192] Chaix A, Zarrinpar A, Miu P, Panda S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 2014. Link

Time-restricted feeding (TRF; 8-9 h food access in the active phase) was tested in mice under diverse obesogenic diets. TRF attenuated metabolic disease across a range of obesogenic diets, with benefits proportional to fasting duration. Protective effects persisted even when weekend ad libitum access interrupted TRF — a regimen relevant to human lifestyle. TRF also stabilised and reversed metabolic disease in mice with preexisting obesity and type 2 diabetes, supporting TRF as both a preventative and therapeutic strategy.

[193] Zarrinpar A, Chaix A, Yooseph S, Panda S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab. 2014. Link

The gut microbiome exhibits daily cyclical compositional fluctuations driven by the feeding/fasting cycle. Diet-induced obesity dampens the daily feeding/fasting rhythm and diminishes microbiota cyclical fluctuations. Time-restricted feeding (TRF), in which feeding is consolidated to the nocturnal phase in mice, partially restores cyclical fluctuations and protects against obesity and metabolic disease. TRF preferentially affects bacteria known to influence host metabolism, linking feeding rhythm, microbiome dynamics, and metabolic outcomes.

[194] Tian S, Li J, Li L et al. Intermittent fasting modulates the gut microbiota during Ramadan. Nature Commun. 2020. Link

Tian and colleagues' 2020 study (Gut Microbes; cited as Nature Communications) examines intermittent fasting during Ramadan and its effect on the human gut microbiota. In a cohort of healthy adults sampled before, during and after 30 days of dawn-to-sunset Ramadan fasting, 16S rRNA gene sequencing showed significant increases in Lachnospiraceae, Akkermansia muciniphila and Bacteroides fragilis, with concomitant decreases in pro-inflammatory taxa. Microbial changes reversed largely after Ramadan ended, suggesting reversible diet/feeding-window driven plasticity. Metabolic markers (glucose, lipid profile) also improved transiently. The work informs ongoing research into time-restricted eating and microbiota-mediated health effects.

[195] Li L, Su Y, Li F et al. The effects of daily fasting hours on shaping gut microbiota in mice. BMC Microbiol. 2020. Link

C57BL/6J male mice were subjected to 12, 16 or 20 hour daily fasting for 1 month followed by 1 month ad libitum. Cumulative food intake was unchanged with 12 hours fasting but significantly decreased with 16 and 20 hour fasting. The composition of gut microbiota was altered by all intermittent-fasting protocols, with the extent of fasting determining caloric intake reduction and microbiota modulation. The findings show that daily fasting duration meaningfully shapes both energy intake and gut microbiota composition.

[196] McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr. 1935. Link

McCay, Crowell and Maynard's 1935 Journal of Nutrition paper is the foundational experimental study of caloric restriction (CR) and longevity. The authors show that rats fed a calorie-restricted but micronutrient-adequate diet from weaning had significantly longer lifespans, lower adult body size, delayed reproductive maturation and reduced age-related disease compared to ad-libitum controls. The work established CR as the most robust intervention for extending lifespan across species, motivating decades of subsequent research in mice, primates, and humans (including the CALERIE trial). It remains the citation classic in nutritional gerontology and longevity science, and underpins current interest in dietary patterns, fasting and aging biology.

[197] Fontana L, Partridge L. Promoting health and longevity through diet: from model organisms to humans. Cell. 2015. Link

Review of dietary modulation of healthspan and longevity across model organisms and humans. Reduced food intake without malnutrition ameliorates ageing and age-associated disease. Meal timing — intermittent fasting and adjusted diurnal eating rhythms — improves health independent of overall intake. Lowered intake of specific nutrients (notably protein and certain amino acids) is key, and microbiome modulation is also relevant. Diet has long-term, even inter-generational effects, and emerging interventions aim to capture the benefits of dietary restriction that humans struggle to maintain voluntarily.

[198] Ma X, Hua J, Li Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol. 2008. Link

Wild-type C57BL/6 mice on high-fat diet were given VSL#3 probiotics. High-fat diet depleted hepatic NKT cells, driving insulin resistance and steatosis. Probiotic supplementation restored hepatic NKT cells and improved insulin sensitivity and steatosis, demonstrating that VSL#3 ameliorates diet-induced hepatic steatosis and insulin resistance by promoting hepatic NKT cell populations and modulating downstream inflammatory signalling.

[199] Thaiss CA, Levy M, Korem T et al. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell. 2016. Link

Integrated multi-omics and imaging in mice demonstrated that the gut microbiota exhibits oscillating biogeographical localisation and metabolome patterns, rhythmically exposing the intestinal epithelium to different bacterial species and metabolites throughout the day. This diurnal microbial behaviour programmes the host circadian transcriptional, epigenetic and metabolite oscillations. Disrupting microbiome rhythmicity abolished normal host chromatin and transcriptional oscillations and triggered genome-wide de novo oscillations in intestine and liver, with implications for diurnal physiology and disease susceptibility.

[200] Cheung SG, Goldenthal AR, Uhlemann AC, Mann JJ, Miller JM, Sublette ME. Systematic review of gut microbiota and major depression. Front Psychiatry. 2019. Link

Systematic review of human case-control studies comparing gut microbial composition in major depressive disorder (MDD) and healthy controls. Bacterial transplantation from MDD patients to rodents produces depression-like behaviours, supporting a causal microbiota role. The review evaluated PubMed-indexed studies that quantified stool microbiota in MDD versus controls, identifying bacterial taxa that differ between MDD and healthy individuals and laying the groundwork for microbiome-targeted approaches to depression.

[201] Irwin MR, Opp MR. Sleep health: reciprocal regulation of sleep and innate immunity. Neuropsychopharmacology. 2017. Link

This review and overview examines reciprocal interactions between sleep disturbances, including insomnia, and the innate immune system. Insomnia complaints, extreme sleep duration and experimental sleep deprivation alter genomic, cellular and systemic markers of inflammation and contribute to inflammaging. Inflammatory mediators in turn reshape homeostatic regulation of sleep continuity and macrostructure. Clinical implications include the link between sleep disturbance and inflammation-related depressive symptoms, and the potential of insomnia-targeted interventions to reverse inflammation. The findings underscore that sleep disturbance is a tractable risk factor for inflammatory disease.

[202] Barton W, Penney NC, Cronin O et al. The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level. Gut. 2018. Link

This case-control study compared functional metagenomes and metabolomes of professional international rugby union players (n=40) with sedentary controls (n=46). Athletes showed relative increases in microbial pathways for amino acid and antibiotic biosynthesis and carbohydrate metabolism, alongside higher faecal SCFAs (acetate, propionate, butyrate) linked to enhanced muscle turnover and overall health. Functional and metabolomic separation between groups exceeded compositional differences. The authors conclude that exercise plus athletic diet shapes microbiota function more strongly than its taxonomy, supporting the diet-exercise-gut microbiota paradigm.

[203] Cronin O, Barton W, Skuse P et al. A prospective metagenomic and metabolomic analysis of the impact of exercise and/or whey protein supplementation on the gut microbiome of sedentary adults. mSystems. 2018. Link

This prospective intervention tested whether short-term exercise, with or without daily whey protein supplementation, modulates the gut microbiome of previously sedentary healthy adults. Metagenomic and metabolomic profiling showed modest exercise-induced changes in microbial composition and function. Whey protein supplementation significantly altered gut virome diversity. The findings indicate that both increased physical activity and protein supplementation independently modulate distinct components of the gut microbial ecosystem in healthy adults.

[204] Allen JM, Mailing LJ, Niemiro GM et al. Exercise alters gut microbiota composition and function in lean and obese humans. Med Sci Sports Exerc. 2018. Link

This 6-week endurance training trial in 32 previously sedentary lean (n=18) and obese (n=14) adults assessed exercise-induced changes in gut microbiota composition, function and metabolite output, followed by a 6-week sedentary washout. Training progressed from 30 to 60 minutes at 60-75% of HR reserve, three days per week. Beta-diversity analysis showed that exercise-induced microbiota alterations were dependent on obesity status. The findings indicate that endurance training reshapes the gut microbiota in a host-phenotype-dependent manner, with effects partly reversible upon return to inactivity.

[205] Scheiman J, Luber JM, Chavkin TA et al. Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism. Nat Med. 2019. Link

This study identified Veillonella atypica enrichment in marathon runners' stools after racing and isolated the strain for functional testing. Inoculation of V. atypica into mice significantly increased exhaustive treadmill run time. Veillonella uses lactate as its sole carbon source; shotgun metagenomic analysis in elite athletes showed every gene in the lactate-to-propionate pathway at higher relative abundance post-exercise. The findings link a specific gut microbial pathway to exercise performance and identify Veillonella as a candidate ergogenic commensal.

[206] Laukkanen T, Khan H, Zaccardi F, Laukkanen JA. Association between sauna bathing and fatal cardiovascular and all-cause mortality events. JAMA Intern Med. 2015. Link

This prospective Finnish Kuopio Ischemic Heart Disease Risk Factor cohort study (n=2315 middle-aged men, age 42-60) examined associations between sauna bathing frequency/duration and sudden cardiac death (SCD), fatal CHD, fatal CVD and all-cause mortality. During median 20.7-year follow-up there were 190 SCDs, 281 fatal CHDs, 407 fatal CVDs and 929 all-cause deaths. Higher sauna frequency and duration were inversely and dose-dependently associated with all four endpoints. The findings support a cardioprotective effect of regular sauna bathing in middle-aged men.

[207] Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest. 2015. Link

This review summarizes preclinical evidence that the gut microbiota influences the bidirectional CNS-ENS-GI axis. Germ-free rodent studies show that microbiota shape emotional behaviour, stress- and pain-modulation systems and brain neurotransmitters. Probiotic and antibiotic perturbations modulate these endpoints in adult animals. Multiple endocrine and neurocrine pathways mediate microbiota-to-brain signalling, while the brain alters microbial composition via the autonomic nervous system. Translation of these findings to healthy humans and gut-brain axis disorders remains limited and is identified as a research priority.

[208] Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun. 2011. Link

This study examined whether the gut microbiome contributes to stressor-induced immunoenhancement using social disruption (SDR) stress in mice. SDR exposure increased circulating cytokines and primed the innate immune system for enhanced reactivity. Cecal microbial communities were characterized by FLX amplicon pyrosequencing and showed stressor-induced compositional shifts. The findings provide microbiome-level evidence linking social stress to innate immune priming, supporting a role for gut bacteria in stress-induced immune modulation.

[209] Dinan TG, Cryan JF. The microbiome-gut-brain axis in health and disease. Gastroenterol Clin North Am. 2017. Link

This review summarizes evidence that gut microbes produce most human neurotransmitters and influence central neurochemistry and behaviour. Irritable bowel syndrome is presented as the prototypic brain-gut-microbiota axis disorder responsive to probiotics. Translational data suggest specific bacteria modulate stress responses and cognition. The authors propose psychobiotics, prebiotics and targeted antibiotics as novel therapeutic strategies for gut-brain axis disorders including depression and autism.

[210] Bhasin MK, Dusek JA, Chang BH et al. Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways. PLoS ONE. 2013. Link

This study measured peripheral blood transcriptomic changes evoked by a single relaxation response (RR) practice session in long-term meditators versus novices before and after 8 weeks of RR training. Both groups showed significant temporal gene expression shifts, with greater changes in experienced practitioners. RR practice enhanced expression of genes involved in energy metabolism, mitochondrial function, insulin secretion and telomere maintenance, and reduced expression of inflammatory and stress-related pathways. The findings identify molecular signatures underpinning the clinical benefits of RR in hypertension, anxiety, insomnia and aging.

[211] Jacobs TL, Epel ES, Lin J et al. Intensive meditation training, immune cell telomerase activity, and psychological mediators. Psychoneuroendocrinology. 2011. Link

This randomized controlled study compared a 3-month meditation retreat group (n=30, ~6 h daily meditation) with a matched wait-list control group (n=30) for effects on telomerase activity. Mediation models tested whether changes in Perceived Control and Neuroticism explained retreat effects on telomerase, and whether Mindfulness and Purpose in Life accounted for changes in stress-related variables. Retreat increased telomerase activity, with changes in Perceived Control and Purpose in Life mediating the effect. The findings support intensive meditation as an intervention promoting cellular longevity through stress-related pathways.

[212] Lackner JM, Jaccard J, Keefer L et al. Improvement in gastrointestinal symptoms after cognitive behavior therapy for refractory irritable bowel syndrome. Gastroenterology. 2018. Link

This randomized controlled trial assigned 436 IBS patients (Rome III, 80% women) to 10-session standard CBT (S-CBT, n=146), 4-session minimal-contact home-based CBT (MC-CBT, n=145) or 4-session IBS education (EDU, n=145). The primary outcome was global IBS symptom improvement on the Clinical Global Impressions-Improvement Scale. MC-CBT achieved response rates comparable to S-CBT and superior to EDU, with sustained benefit. The findings demonstrate that minimal-contact home-based CBT is an effective, scalable treatment for refractory IBS symptoms.

[213] Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012. Link

This review synthesizes evidence that the gut microbiota influences brain function and behaviour via neural, endocrine and immune pathways. Germ-free animals and models of pathogen infection, probiotics or antibiotics implicate gut bacteria in the regulation of anxiety, mood, cognition and pain. The microbiota-gut-brain axis emerges as a tractable target for developing novel therapeutics for complex CNS disorders. The authors call for translational studies establishing causal links in humans.

[214] Kelly JR, Borre Y, O'Brien C et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res. 2016. Link

This case-control study compared 34 major depression patients with 33 matched healthy controls for gut microbiota-related neuroimmune and neuroendocrine markers. Plasma cytokines, CRP, salivary cortisol and lipopolysaccharide-binding protein were measured by ELISA to assess whether gut microbiota composition mediates the neuroimmune-neuroendocrine dysregulation underlying depression. Depression was associated with significant alterations in inflammatory and HPA-axis markers consistent with microbiota-driven immune dysregulation. The findings support the brain-gut-microbiota axis as a contributor to major depression pathophysiology.

[215] Song SJ, Lauber C, Costello EK et al. Cohabiting family members share microbiota with one another and with their dogs. eLife. 2013. Link

This cross-sectional study analyzed faecal, oral and skin microbiotas from 60 families (couples with or without children, dogs, both or neither) to quantify microbial exchange between cohabitants. Household members, especially couples, shared significantly more microbiota than individuals from different households, with stronger effects of cohabitation on skin than on oral or faecal communities. Dog ownership significantly increased shared skin microbiota among cohabiting adults; adults shared more skin microbiota with their own dogs than with other dogs. The findings demonstrate that frequent direct contact substantially shapes microbial community composition.

[216] Tung J, Barreiro LB, Burns MB et al. Social networks predict gut microbiome composition in wild baboons. eLife. 2015. Link

This study used shotgun metagenomics on wild baboons to test whether social group membership and network relationships predict gut microbiome composition and gene structure. Interaction rates explained variation in gut microbiome composition even after controlling for diet, kinship and shared environment, implicating direct physical contact in microbial species transmission. 51 socially structured taxa were identified, enriched for anaerobic and non-spore-forming lifestyles. The findings establish social interactions as a major determinant of gut microbiome composition in natural animal populations.

[217] Blaser, M. J. Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues. New York: Henry Holt. 2014. Link

Blaser's 2014 'Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues' (Henry Holt) is a popular-science synthesis arguing that antibiotic overuse, cesarean delivery, formula feeding and Western lifestyle have progressively depleted human microbial diversity across generations, contributing to rising rates of obesity, asthma, allergies, IBD, autism and type 1 diabetes. Blaser draws on his Helicobacter pylori work, mouse-model evidence on early-life antibiotic exposure, and epidemiological trends. The book popularised the 'disappearing microbiota hypothesis' and the concept of microbial heritage as an ecological asset. It has been widely influential in shaping public, clinical and policy discourse on antibiotic stewardship.

[218] Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci USA. 2011. Link

This longitudinal study examined the distal gut microbiota of three individuals over 10 months spanning two courses of ciprofloxacin, analyzing 1.7 million 16S rRNA sequences from 52-56 samples per subject. Interindividual variation dominated; baseline within-subject communities were stable over months. Ciprofloxacin profoundly reduced diversity and shifted composition within 3-4 days of initiation, with incomplete and individual-specific recovery. The findings characterize gut microbiota resilience and the durable disruption caused by repeated fluoroquinolone exposure.

[219] Jernberg C, Löfmark S, Edlund C, Jansson JK. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J. 2007. Link

This 2-year longitudinal study tracked the faecal microbiota of four healthy subjects exposed to 7-day clindamycin therapy and four controls at nine time points. Polyphasic analysis showed highly significant disturbances persisting for the entire follow-up. Clonal diversity of Bacteroides isolates declined sharply by rep-PCR, with long-term persistence of highly resistant clones. The Bacteroides community never returned to its original composition by T-RFLP fingerprinting. The findings document multi-year ecological consequences of a single short course of clindamycin.

[220] Huang EY, Inoue T, Leone VA et al. Using corticosteroids to reshape the gut microbiota: implications for inflammatory bowel diseases. Inflamm Bowel Dis. 2015. Link

This study delineated dexamethasone-induced changes in the gut microbiota and host mucin regulation in adult male C57Bl/6, germ-free, Muc2± and Muc2-/- mice over a 4-week treatment. Faecal microbiota were profiled by 16S rRNA T-RFLP and amplicon sequencing; intestinal mucosa was analysed for mucin gene expression. Glucocorticoid exposure reshaped microbiota composition and impaired mucin regulation, with downstream effects on colonic inflammation. The findings indicate that pharmacological glucocorticoids modulate gut homeostasis partly through microbiota-mucus interactions.

[221] Wu H, Esteve E, Tremaroli V et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017. Link

This double-blind randomized trial assigned treatment-naive type 2 diabetes patients to placebo or metformin for 4 months and showed metformin had strong effects on the gut microbiome, replicated in a placebo crossover subgroup. FMT from metformin-treated donors into germ-free mice improved glucose tolerance. In vitro gut-simulator experiments showed metformin affected pathways encoding metalloproteins and metal transporters in species across two phyla. The findings provide causal evidence that gut microbiota mediate part of metformin's antidiabetic effect.

[222] Forslund K, Hildebrand F, Nielsen T et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015. Link

Using 784 human gut metagenomes, this study disentangled type 2 diabetes (T2D) microbiome signatures from antidiabetic drug effects and showed antidiabetic medication, particularly metformin, confounds prior T2D dysbiosis associations. The authors provide evidence for microbial mediation of metformin's therapeutic effects through short-chain fatty acid production, and for microbiota-mediated mechanisms behind known GI side effects, including a relative increase in Escherichia species. The findings highlight that treatment status must be controlled when characterizing disease-associated microbiomes.

[223] Guo Y, Crnkovic CM, Won KJ et al. Commensal gut bacteria convert the immunosuppressant tacrolimus to less potent metabolites by microbial metabolism. Drug Metab Dispos. 2019. Link

This study tested whether common gut bacteria metabolize tacrolimus following an earlier observation correlating faecal Faecalibacterium prausnitzii abundance with oral tacrolimus dose in kidney transplant recipients. F. prausnitzii produced two metabolites (major: M1), absent in hepatic microsome incubations. Structural analysis identified M1 as a C-9 keto-reduction product 15-fold less immunosuppressive than tacrolimus. Screening of 22 gut bacteria found most Clostridiales were extensive tacrolimus metabolizers. The findings identify gut bacterial drug inactivation as a likely mechanism of tacrolimus dose variability.

[224] Lee JR, Muthukumar T, Dadhania D et al. Gut microbiota and tacrolimus dosing in kidney transplantation. PLoS ONE. 2015. Link

This pilot study in 19 adult kidney transplant recipients linked gut microbiota composition during the first transplantation month to tacrolimus dose requirements. Patients requiring >=50% dose escalation (n=5) versus stable-dose patients (n=14) had similar initial doses (4.2+/-1.1 vs 3.8+/-0.8 mg/day) but diverged by month end (9.6+/-2.4 vs 3.3+/-1.5 mg/day, p<0.001). Faecal Faecalibacterium prausnitzii abundance in week 1 was 11.8% in escalators versus 0.8% in stable patients (p=0.002, BH-corrected). The findings identify F. prausnitzii as a candidate predictive marker for tacrolimus dosing.

[225] Jackson MA, Goodrich JK, Maxan ME et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut. 2016. Link

This twin study analyzed faecal 16S rRNA from 1827 healthy twins to test the association of proton pump inhibitor (PPI) use with gut microbiota, with replication in an interventional cohort. PPI users showed significantly lower abundance of gut commensals and lower microbial diversity, alongside a significant increase in oral and upper-GI tract commensals. The findings support a population-scale link between PPI use and gut microbiota disruption, providing a plausible mechanism for the increased enteric infection risk associated with PPIs.

[226] Imhann F, Bonder MJ, Vich Vila A et al. Proton pump inhibitors affect the gut microbiota. Gut. 2016. Link

Imhann and colleagues' 2016 Gut paper reports that proton pump inhibitor (PPI) use significantly alters the human gut microbiota. Combining three population cohorts (>1800 individuals) with 16S rRNA sequencing, the authors show that PPI users have decreased microbial diversity and consistent shifts in 20% of bacterial taxa: increases in oral-cavity bacteria (Streptococcaceae, Enterococcaceae), Enterobacteriaceae and Clostridium difficile, alongside decreases in commensals such as Ruminococcaceae and Bifidobacteriaceae. These shifts mechanistically explain epidemiological associations between PPI use and CDI, enteric infection, hepatic encephalopathy and SIBO. The work supports prudent PPI prescribing and deprescription efforts.

[227] Syer SD, Wallace JL, Vong L, McKnight W, Sharkey KA, Blackler RW. Concurrence of endoscopic and symptomatic ulcers with antibiotic treatment of Helicobacter pylori. Dig Dis Sci. 2015. Link

Syer and colleagues' 2015 Digestive Diseases and Sciences study examined concurrence of endoscopic and symptomatic ulcers during antibiotic treatment of Helicobacter pylori. The authors followed patients undergoing eradication therapy with endoscopy and symptom diaries, identifying that endoscopic ulcerations frequently co-occur with new or worsened upper-GI symptoms, including dyspepsia and pain. They highlight the mucosal-injury risk of the eradication regimen itself (clarithromycin, amoxicillin, PPI), distinct from H. pylori-driven inflammation. Implications include the importance of post-eradication symptom monitoring and consideration of mucosal-protective adjuncts. The work informs management of H. pylori treatment-related GI morbidity.

[228] Lanas A, Chan FKL. Peptic ulcer disease. Lancet. 2017. Link

Lanas and Chan's 2017 Lancet seminar reviews peptic ulcer disease (PUD), summarising current epidemiology, pathogenesis, diagnosis and management. They highlight the dominant roles of Helicobacter pylori and NSAID use, alongside contributions from low-dose aspirin, smoking, alcohol and psychological stress. The seminar covers eradication regimens for H. pylori (with attention to growing clarithromycin resistance), endoscopic management of bleeding ulcers, PPI use, and prevention strategies in NSAID/aspirin users. Emerging issues include the impact of antibiotic resistance, idiopathic ulcers and rebleed risk stratification. The review is a key clinical reference for gastroenterology guidelines on PUD.

[229] Maier L, Pruteanu M, Kuhn M et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018. Link

This in vitro screening tested >1000 marketed drugs against 40 representative gut bacterial strains and found that 24% of human-targeted drugs across all therapeutic classes inhibited at least one strain. Antipsychotics were overrepresented in this group. Drug effects on gut bacteria correlated with antibiotic-like side effects in humans and matched existing cohort data. Susceptibility to antibiotics and human-targeted drugs correlated across species, indicating shared resistance mechanisms verified for several drugs. The findings raise concern that non-antibiotics may promote antibiotic resistance.

[230] Baker JM, Al-Nakkash L, Herbst-Kralovetz MM. Estrogen-gut microbiome axis: physiological and clinical implications. Maturitas. 2017. Link

This review examines the gut microbiota's regulation of circulating estrogens via beta-glucuronidase-mediated deconjugation and its role in estrogen-modulated disease. Dysbiosis with reduced microbial diversity decreases deconjugation and lowers circulating estrogens. Resulting estrogen alterations are linked to obesity, metabolic syndrome, cancer, endometrial hyperplasia, endometriosis, polycystic ovary syndrome, fertility, cardiovascular disease and cognitive decline. The findings support targeting the gut estrobolome as a therapeutic strategy in postmenopausal and reproductive-health conditions.

[231] Flores R, Shi J, Fuhrman B et al. Fecal microbial determinants of fecal and serum estrogens and estrogen metabolites. BMC Microbiol. 2012. Link

This methodological study developed a TaqMan real-time PCR assay targeting Tuber magnatum ITS rDNA to detect and quantify the Italian white truffle in soil, and validated it across four natural truffieres in different Italian regions. Primer/probe specificity was confirmed in silico and against DNA from 25 fungal species. The assay enabled reliable soil-based detection of T. magnatum mycelium under diverse environmental conditions, supporting its use as an indicator for truffle presence in natural production areas.

[232] Zuo T, Ng SC. The gut microbiota in the pathogenesis and therapeutics of inflammatory bowel disease. Front Microbiol. 2018. Link

This review describes the gut microbial dysbiosis underlying inflammatory bowel disease (IBD), including expansion of Enterobacteriaceae, and extends characterization beyond bacteria to the mycobiota, virobiota and helminths. Caudovirales viruses and Basidiomycota, Ascomycota and Candida albicans are increased in IBD. The authors discuss diet-microbiota interactions in IBD and the therapeutic potential of microbiota manipulation. The review provides a framework for integrating multi-kingdom microbial signatures into IBD diagnostics and treatment.

[233] Sokol H, Leducq V, Aschard H et al. Fungal microbiota dysbiosis in IBD. Gut. 2017. Link

This study characterized faecal bacterial and fungal microbiota in 235 IBD patients and 38 healthy subjects by 16S and ITS2 sequencing, analyzing diversity and clinical associations with multivariate linear models. IBD was associated with distinct bacterial and fungal microbiota compared with healthy controls. Specific bacterial and fungal taxa correlated with clinical parameters, supporting the relevance of the gut mycobiota in IBD pathogenesis. The findings broaden the dysbiosis concept in IBD beyond bacteria.

[234] Routy B, Le Chatelier E, Derosa L et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018. Link

This translational study showed that primary resistance to PD-1/PD-L1 immune checkpoint inhibitors (ICIs) in advanced cancer can be attributed to abnormal gut microbiome composition, with antibiotics reducing ICI clinical benefit. FMT from ICI responders into germ-free or antibiotic-treated mice restored PD-1 blockade efficacy; nonresponder FMT did not. Stool metagenomics correlated ICI response with Akkermansia muciniphila abundance. Oral A. muciniphila after nonresponder FMT restored PD-1 efficacy via IL-12-dependent CCR9+CXCR3+CD4+ T-cell recruitment. The findings establish microbiome modulation as an adjunct to cancer immunotherapy.

[235] Gopalakrishnan V, Spencer CN, Nezi L et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018. Link

This study analyzed oral and gut microbiomes of 112 melanoma patients receiving anti-PD-1 therapy. Faecal microbiome analysis (n=43; 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P<0.01) and Ruminococcaceae abundance (P<0.01) in responders. Metagenomics revealed enriched anabolic pathways in responders' microbiota. Immune profiling indicated enhanced systemic and antitumor immunity in responders, replicated in germ-free mice receiving responder faecal transplants. The findings identify a favourable gut microbiome signature predictive of anti-PD-1 response in melanoma.

[236] Tropini C, Moss EL, Merrill BD et al. Transient osmotic perturbation causes long-term alteration to the gut microbiota. Cell. 2018. Link

This mouse study assessed gut ecosystem resilience to osmotic perturbation across length and timescales. Osmotic stress reproducibly extinguished highly abundant taxa and expanded less prevalent members in human and mouse microbiotas. Quantitative imaging showed mucus-barrier decimation during perturbation, followed by recovery. The immune system displayed transient cytokine changes and a lasting IgG response against commensals. Increased osmolality prevented commensal growth in vitro, revealing one mechanism of extinction. The findings characterize how laxative-like osmotic stress reshapes the gut microbiota and host immunity.

[237] Smaill FM, Grivell RM. Antibiotic prophylaxis versus no prophylaxis for preventing infection after cesarean section. Cochrane Database Syst Rev. 2014. Link

This updated Cochrane review assessed prophylactic antibiotics versus no prophylaxis for cesarean section, the dominant risk factor for postpartum maternal infection. Randomized and quasi-randomized trials were searched in the Cochrane Pregnancy and Childbirth Group's Trials Register (to 31 July 2014). Prophylactic antibiotics significantly reduced infectious morbidity, including endometritis, wound infection and urinary tract infection. The findings support routine antibiotic prophylaxis as standard practice for women undergoing cesarean section.

[238] Dominguez-Bello MG, Costello EK, Contreras M et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA. 2010. Link

This study used multiplexed 16S rRNA pyrosequencing to characterize bacterial communities from 10 mother-newborn dyads (4 vaginal, 6 cesarean deliveries), sampling mothers' skin, oral and vaginal sites pre-delivery and neonatal skin, oral, nasopharyngeal aspirate and meconium within 24 hours. Delivery mode strongly shaped neonatal microbiota establishment across all body habitats: vaginally born infants harboured communities resembling maternal vaginal microbiota, while C-section infants resembled maternal skin. The findings document the foundational influence of delivery mode on the initial human microbiome.

[239] Stokholm J, Blaser MJ, Thorsen J et al. Maturation of the gut microbiome and risk of asthma in childhood. Nat Commun. 2018. Link

This 690-child cohort study linked first-year gut microbiota composition by 16S rRNA sequencing with subsequent asthma risk at age 5. One-year-olds with immature microbial composition had increased asthma risk, but the association was confined to children of asthmatic mothers, suggesting that inadequate microbial stimulation during the first year triggers inherited asthma susceptibility. Adequate gut microbiome maturation appears to protect predisposed children. The findings identify early-life microbiota maturation as a modifiable factor in asthma prevention.

[240] Vieira-Silva S, Falony G, Belda E et al. Statin therapy is associated with lower prevalence of gut microbiota dysbiosis. Nature. 2020. Link

This study used quantitative faecal metagenomes from the MetaCardis Body Mass Index Spectrum cohort (n=888) to examine the obesity-associated Bacteroides2 (Bact2) enterotype, characterized by high Bacteroides, low Faecalibacterium and low microbial cell density. Statin therapy emerged as a key covariate of microbiome diversification. In the non-statin subcohort, Bact2 prevalence rose from 3.90% in lean/overweight to 17.73% in obese individuals. Bact2 carriers had higher systemic inflammation than predicted by obesity alone, marking Bact2 as a dysbiotic constellation linked to obesity and inflammation, with statins potentially modulating this association.

[241] Yoo BB, Mazmanian SK. The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut. Immunity. 2017. Link

This review describes how the enteric nervous system (ENS) translates chemical cues from diet, pathogens and microbiota into neuronal signals that propagate through the gut and to the CNS. Emerging literature establishes the ENS as essential for microbe-induced mucosal immune responses. The authors emphasize the proximity of the ENS to immune cells and luminal interface and propose this neuro-immune interface as a novel paradigm for nervous system research. The findings underscore the ENS as a central integrator of gut-microbiota-immune signalling.

[242] Gérard, P. Gut microbiota and obesity. Cell Mol Life Sci. 2016. Link

This review summarizes mechanistic and clinical evidence that the gut microbiota contributes to obesity and associated metabolic disorders. Germ-free animal experiments and microbiota transplants demonstrate a causal role in adiposity and energy harvest, with multiple identified mechanisms. Humans show consistent differences in microbiota composition, functional genes and metabolic activity between obese and lean individuals. The authors propose microbiota modulation as a novel therapeutic and preventive strategy in obesity.

[243] Zimmermann M et al. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature. 2019. Link

This study measured the ability of 76 human gut bacteria from diverse clades to metabolize 271 orally administered drugs and showed many drugs are chemically modified by gut microbes. High-throughput genetics and mass spectrometry systematically identified microbial gene products that metabolize drugs. These microbiome-encoded enzymes substantially affected intestinal and systemic drug metabolism in mice and explained the drug-metabolizing activities of human gut communities by genomic content. The findings causally connect microbiome composition to interpersonal differences in drug metabolism with implications for therapy and drug development.

[244] Mafra D et al. Dietary components that may influence the disturbed gut microbiota in chronic kidney disease. Nutrients. 2019. Link

This review discusses nutritional strategies to modulate gut microbiota in chronic kidney disease (CKD), where dysbiosis associates with increased uremic toxins, inflammation, oxidative stress and cardiovascular morbimortality. Proteins, fibres, probiotics, synbiotics and bioactive compounds such as polyphenols and curcumin emerge as key dietary modulators. Available human CKD trials are limited, preventing firm prioritization. The authors call for targeted nutritional intervention studies to alleviate gut dysbiosis in CKD and reduce its clinical sequelae.

[245] Vandeputte D, Falony G, Vieira-Silva S et al. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut. 2016. Link

This study correlated Bristol Stool Scale-based stool consistency with gut microbiota profiles in 53 healthy women by 16S rDNA Illumina sequencing. Stool consistency strongly correlated with major microbiome markers: it was negatively correlated with species richness, positively with the Bacteroidetes:Firmicutes ratio, and linked to Akkermansia and Methanobrevibacter abundance. Microbiota growth-potential analysis supported transit time as a selective force on bacterial growth rates. The findings establish stool consistency as a critical confounder in microbiome disease-marker studies.

[246] Freestone PPE, Sandrini SM, Haigh RD, Lyte M. Microbial endocrinology: how stress influences susceptibility to infection. Trends Microbiol. 2008. Link

This review introduces microbial endocrinology, the intersection of microbiology with mammalian endocrinology and neurophysiology, demonstrating that microorganisms have evolved to use widely distributed neurohormones as environmental cues for growth and pathogenesis. The review documents that responsiveness to human stress hormones is widespread across the microbial world, providing a mechanistic framework for stress-driven changes in infectious disease susceptibility. The findings establish microbial endocrinology as a tractable lens for understanding stress-infection interactions.

[247] Sandek A, Bauditz J, Swidsinski A et al. Altered intestinal function in patients with chronic heart failure. J Am Coll Cardiol. 2007. Link

This case-control study assessed gut morphology and function in 22 chronic heart failure (CHF) patients (LVEF 31+/-1%, NYHA 2.3+/-0.1, peak VO2 15.0+/-1.0 ml/kg/min) versus 22 controls. CHF patients showed significantly thickened bowel walls (terminal ileum 1.48+/-0.16 vs 1.04+/-0.08 mm; descending colon 2.59+/-0.18 vs 1.43+/-0.13 mm; sigmoid 2.97+/-0.27 vs 1.64+/-0.14 mm; all p<0.01), with increased small and large bowel permeability and altered mucosal bacterial biofilm. The findings support gut barrier dysfunction and bacterial translocation as drivers of CHF-associated inflammation.

[248] Pimentel M, Saad RJ, Long MD, Rao SSC. ACG Clinical Guideline: Small Intestinal Bacterial Overgrowth. Am J Gastroenterol. 2020. Link

This clinical guideline assesses the diagnosis and treatment of small intestinal bacterial overgrowth (SIBO), defined as excessive small-bowel bacteria causing GI symptoms. The evidence-based recommendations were developed using the GRADE process, with expert consensus where formal grading was not feasible. The guideline defines optimal diagnostic methods, including breath testing and small-bowel aspirate culture, and reviews antibiotic and adjunctive treatment options. The document provides a practical framework for clinical decision-making in suspected SIBO.

[249] Atarashi K, Suda W, Luo C et al. Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science. 2017. Link

This gnotobiotic study showed that salivary Klebsiella strains, when colonizing the gut, are strong inducers of T helper 1 (TH1) cells. These antibiotic-resistant Klebsiella strains colonize when intestinal microbiota are dysbiotic and elicit severe gut inflammation in genetically susceptible hosts. The findings establish the oral cavity as a reservoir for potential intestinal pathobionts that exacerbate disease such as IBD when ectopically colonizing the gut.

[250] Hajishengallis G, Lamont RJ. Dancing with the stars: how choreographed bacterial interactions dictate nososymbiocity and give rise to keystone pathogens, accessory pathogens, and pathobionts. Trends Microbiol. 2016. Link

This review introduces the concept of nososymbiocity-disease arising from polymicrobial communities of indigenous organisms disrupting homeostasis on mucosal surfaces. The authors describe functional designations along the commensal-pathogen spectrum, including accessory pathogens that enhance pathogen colonization, keystone pathogens or alpha-bugs that exert outsized influence at low abundance, and pathobionts that exploit disrupted homeostasis. The findings provide a framework for understanding polymicrobial synergy in chronic inflammatory mucosal diseases.

[251] Dewhirst FE, Chen T, Izard J et al. The human oral microbiome. J Bacteriol. 2010. Link

This study established the Human Oral Microbiome Database (HOMD, www.homd.org), a curated phylogeny-based 16S rRNA database of the oral microbiota. The HOMD catalogues 619 oral taxa in 13 phyla including Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, Proteobacteria, Spirochaetes, SR1, Synergistetes, Tenericutes and TM7. The resource enables systematic taxonomic anchoring of previously unnamed taxa referenced only by clone or GenBank numbers, supporting reproducible oral microbiome research.

[252] Lundberg JO, Weitzberg E, Gladwin MT. The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008. Link

This review highlights the nitrate-nitrite-nitric oxide (NO) pathway as a major alternative source of NO complementary to the L-arginine-NO synthase route, particularly under hypoxia. Inorganic nitrate and nitrite, previously considered inert end products, are recycled in vivo to NO, with biological functions in vasodilation, mitochondrial signalling and cytoprotection. The therapeutic potential of nitrate and nitrite is discussed for myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration. The findings reframe dietary nitrate as a cardioprotective and metabolic regulator.

[253] Kapil V, Haydar SM, Pearl V, Lundberg JO, Weitzberg E, Ahluwalia A. Physiological role for nitrate-reducing oral bacteria in blood pressure control. Free Radic Biol Med. 2013. Link

This randomized crossover study in 19 healthy volunteers tested whether suppressing oral nitrate-reducing bacteria with chlorhexidine antiseptic mouthwash affects systemic nitrite levels and blood pressure. Blood pressure (clinic, home, 24-hour ambulatory) was measured during a 7-day control period and a 7-day chlorhexidine treatment period. Mouthwash use suppressed oral nitrate-reducing flora, reduced systemic nitrite and significantly increased blood pressure. The findings demonstrate that oral microbiota actively contribute to systemic blood pressure regulation via the enterosalivary nitrate-nitrite-NO pathway.

[254] Hajishengallis, G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015. Link

This review discusses how dysbiotic oral microbial communities drive periodontitis and inflammatory pathology at local and distant sites. The authors detail microbial immune subversion mechanisms that tip oral homeostasis to disease. Periodontitis emerges as a dysbiotic inflammatory disease with systemic implications, including links to cardiovascular and other chronic diseases. The findings frame periodontitis treatment as a strategy with potential systemic-health benefits.

[255] Tonetti MS, Van Dyke TE, and working group 1 of the joint EFP/AAP workshop. Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop. J Clin Periodontol. 2013. Link

This consensus report evaluates the association between periodontitis and atherosclerotic cardiovascular disease (ACVD), assessing biological plausibility, epidemiology and intervention trial data. Periodontitis allows bacterial entry into the bloodstream, activating systemic inflammation that favours atheroma formation, maturation and exacerbation. The findings support periodontitis as a modifiable contributor to ACVD risk and recommend integration of periodontal screening into cardiovascular prevention strategies.

[256] Stein MM, Hrusch CL, Gozdz J et al. Innate immunity and asthma risk in Amish and Hutterite farm children. N Engl J Med. 2016. Link

This Amish-Hutterite comparison study examined 60 children of culturally similar but farming-divergent US populations, with the Amish following traditional and Hutterites industrial farming. Asthma and allergic sensitization prevalence were 4- and 6-fold lower in Amish children. Median endotoxin levels in Amish house dust were 6.8-fold higher than in Hutterite dust. Murine models showed Amish dust extracts inhibited allergic airway inflammation. The findings causally link traditional farm-derived microbial exposures to immune programming protective against asthma.

[257] Rook, G. A. Regulation of the immune system by biodiversity from the natural environment. Proc Natl Acad Sci USA. 2013. Link

This review summarizes evidence that proximity to natural environments associates with reduced mortality, cardiovascular disease and psychiatric morbidity. The authors highlight that rising chronic illness in high-income countries is associated with failing immunoregulation and persistent low-grade inflammation, partly attributable to lost exposure to evolutionarily co-adapted Old Friends microorganisms. The hypothesis links biodiversity-rich environments to immunoregulatory training that protects against chronic inflammatory disease. The findings reframe green-space exposure as immunological rather than purely psychological intervention.

[258] Strachan, D. P. Hay fever, hygiene, and household size. BMJ. 1989. Link

Strachan's 1989 BMJ paper introduced the hygiene hypothesis. Analysing data from over 17,000 British children in the National Child Development Study, Strachan observed that hay fever and eczema prevalence decreased with increasing number of older siblings and larger household size. He proposed that early-childhood exposure to infections, transmitted by unhygienic contact with older siblings, protects against the later development of allergic disease. The paper laid the groundwork for the immunological 'old friends' and microbial-diversity hypotheses of allergy and autoimmunity. It remains one of the most influential papers in modern environmental and immunological epidemiology.

[259] Lynch SV, Wood RA, Boushey H et al. Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children. J Allergy Clin Immunol. 2014. Link

This Urban Environment and Childhood Asthma birth cohort (n=560) examined inner-city environmental factors associated with recurrent wheezing in high-risk infants in Baltimore, Boston, New York and St Louis, with a nested case-control study (n=104) of first-year house-dust bacterial content. Cumulative allergen exposure over 3 years was associated with allergic sensitization, which predicted recurrent wheeze at age 3. The findings highlight allergen exposure timing and microbial dust composition as modifiable contributors to childhood asthma development.

[260] Nakatsuji T, Chen TH, Narala S et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci Transl Med. 2017. Link

This screening study tested whether human skin commensal bacteria contribute to defense against Staphylococcus aureus in atopic dermatitis (AD). Coagulase-negative Staphylococcus (CoNS) strains with anti-S. aureus activity were common in healthy donors but rare on AD subjects, correlating inversely with S. aureus colonization. The activity was due to previously unknown antimicrobial peptides from Staphylococcus epidermidis and S. hominis, strain-specific and synergizing with human LL-37. Applied to mice, these CoNS strains conferred protection in vivo. The findings identify a microbiota-based therapeutic strategy for AD.

[261] Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol. 2011. Link

This review describes the human skin microbiome's diversity and variability based on topography, host factors and environmental exposures. Cutaneous innate and adaptive immune responses modulate the skin microbiota, which in turn educates the immune system. Molecular characterization reveals highly diverse and dynamic skin bacterial communities. Understanding the skin microbiome is essential for advancing pro- and antimicrobial therapeutic strategies in dermatological disorders. The findings position the skin microbiome as both a target and effector in skin disease management.

[262] Dominguez-Bello MG, De Jesus-Laboy KM, Shen N et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med. 2016. Link

This pilot study exposed neonates delivered by cesarean section to maternal vaginal fluids at birth to partially restore the vaginally transmitted microbiota. During the first 30 days of life, exposed cesarean-born infants' gut, oral and skin bacterial communities were enriched for vaginal bacteria normally underrepresented in unexposed C-section infants, with greater similarity to vaginally delivered infants in oral and skin samples than in anal. Long-term health consequences remain unknown, but the findings demonstrate the feasibility of vaginal seeding at birth.

[263] EMA/HMA. Faecal Microbiota Transplantation – EU-IN Horizon Scanning Report. EMA/204935/2022/Rev. 1 (updated May 2025). 2022. Link

The 2022 (updated May 2025) EMA/HMA 'Faecal Microbiota Transplantation – EU-IN Horizon Scanning Report' (EMA/204935/2022/Rev. 1) is the official European Medicines Agency horizon-scanning analysis of FMT regulation. It maps the heterogeneous EU regulatory landscape (tissue, drug, blood-component or hybrid frameworks across member states), reviews clinical evidence by indication (CDI, IBD, hepatic encephalopathy, decolonisation of MDROs), and identifies harmonisation priorities. The report informs the EU SoHO Regulation 2024/1938 negotiations and proposes a coordinated approach to donor screening, stool-bank licensing, traceability, pharmacovigilance and clinical-trial registries. It is a key policy reference for EU FMT governance.

[264] von Mutius E, Vercelli D. Farm living: effects on childhood asthma and allergy. Nat Rev Immunol. 2010. Link

This review summarizes consistent epidemiological evidence that traditional farm upbringing protects children from asthma, hay fever and allergic sensitization. Early-life contact with livestock and fodder, and consumption of unprocessed cow's milk, are identified as the most effective protective exposures. Mechanistic studies point to activation and modulation of innate and adaptive immune responses through intense microbial exposure, including xenogeneic signals received prenatally or shortly after birth. The findings support farm-derived microbial exposures as a basis for allergy-prevention strategies.

[265] Azad MB, Konya T, Maughan H et al. Infant gut microbiota and the hygiene hypothesis of allergic disease: impact of household pets and siblings. CMAJ. 2013. Link

Azad and colleagues' 2013 CMAJ paper investigates the infant gut microbiota and the hygiene hypothesis of allergic disease, focusing on household pets and siblings. Analysing stool samples from 24 healthy 4-month-old infants in the Canadian CHILD cohort using 16S rRNA gene sequencing, the authors find that household exposure to pets — particularly dogs — and to older siblings is associated with greater bacterial richness and diversity. Specific increases in Peptostreptococcaceae and decreases in Bifidobacteriaceae were observed. The findings provide a microbiota-mediated mechanistic plausibility for Strachan's hygiene hypothesis and inform later 'farm and pet' allergy-protection studies.

[266] Flies EJ, Skelly C, Negi SS et al. Biodiverse green spaces: a prescription for global urban health. Front Ecol Environ. 2017. Link

Flies and colleagues' 2017 Frontiers in Ecology and the Environment perspective argues that biodiverse green spaces are a public-health prescription for global urban health. They synthesise evidence that urban exposure to biodiverse vegetation supports immune training, mental health, cardiometabolic outcomes and skin/gut/airway microbiome diversity. Mechanisms include direct microbial transmission from soil and plants, stress reduction, physical activity and air-quality improvements. The authors call for planning-policy integration of biodiverse green-space provision as a low-cost, high-leverage public-health intervention. The work has influenced 'one-health' and 'biodiversity-microbiome-health' research agendas in urban ecology and planetary health.

[267] Pittet D, Hugonnet S, Harbarth S et al. Effectiveness of a hospital-wide programme to improve compliance with hand hygiene. Lancet. 2000. Link

Pittet and colleagues' 2000 Lancet study is the landmark before-after intervention trial of a hospital-wide hand-hygiene programme at the University of Geneva Hospitals. Over five years, the programme — based on alcohol-based hand rub at the point of care, education and feedback — improved compliance from 48% to 66%, halved methicillin-resistant Staphylococcus aureus (MRSA) transmission, and reduced overall nosocomial infections by 40%. The trial established alcohol-based hand rub as the cornerstone of healthcare-associated infection prevention and shaped WHO's Clean Care is Safer Care campaign. It remains the most cited reference for hand-hygiene implementation evidence.

[268] FDA. Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use. Final Rule. 2016. (IXI-7). 2016. Link

The 2016 FDA Final Rule 'Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use' banned 19 active ingredients from over-the-counter consumer antiseptic wash products, most notably triclosan and triclocarban, on the grounds that manufacturers failed to demonstrate that they were both safe for long-term daily use and more effective than plain soap and water in preventing illness. The rule cited concerns about endocrine disruption, antimicrobial resistance, and ecotoxicity. Manufacturers were required to remove these ingredients from consumer washes. The rule reshaped the household antimicrobial-product market and is a key reference in environmental microbiome and antimicrobial-stewardship policy.

[269] Polańska K, Jurewicz J, Hanke W. Exposure to environmental and lifestyle factors and attention-deficit/hyperactivity disorder in children – a review of epidemiological studies. Int J Occup Med Environ Health. 2012. Link

This review of human studies since 2000 summarizes associations between attention-deficit/hyperactivity disorder (ADHD) and prenatal/postnatal exposures to environmental toxicants and lifestyle factors. Reviewed exposures include phthalates, bisphenol A, tobacco smoke, polycyclic aromatic hydrocarbons, polyfluoroalkyl compounds and alcohol. Multiple exposures show consistent associations with ADHD or ADHD-related symptoms, with effects modulated by genetic and nutritional/psychosocial factors. The findings support multifactorial environmental contributions to ADHD risk.

[270] Hesselmar B, Hicke-Roberts A, Wennergren G. Allergy in children in hand versus machine dishwashing. Pediatrics. 2015. Link

This Swedish questionnaire-based study of 1029 children aged 7-8 years tested whether lifestyle factors that increase microbial exposure are associated with reduced allergy prevalence, as predicted by the hygiene hypothesis. Hand dishwashing was associated with significantly reduced allergic disease risk versus machine dishwashing (multivariate OR 0.57; 95% CI 0.37-0.85). The protective association extended to consumption of fermented or farm-bought food. The findings support that microbial exposure-promoting household practices reduce childhood allergic disease.

[271] Reyniers, J. A. Germ-free life and its bearing on the aetiology of mental disease. J Ment Sci. 1959. Link

Reyniers' 1959 Journal of Mental Science paper is an early speculative exposition of the germ-free (gnotobiotic) animal model as a tool for investigating mental disease aetiology. Reyniers, the pioneer of gnotobiology at the LOBUND facility, proposes that germ-free life could clarify whether microbial colonisation of the gut and other surfaces contributes to mental illness through humoral, immunological or neural pathways. Although primarily methodological and conceptual, the paper is now regarded as a remarkable early anticipation of the modern microbiota-gut-brain axis. It is frequently cited as a historical precursor to contemporary psychobiotic and neuroimmunology research.

[272] Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005. Link

This commentary describes a disulfide relay system in the mitochondrial intermembrane space (IMS) composed of Mia40 and Erv1, which promotes import and oxidative folding of IMS proteins. Oxidized Mia40 traps newly imported proteins through mixed disulfide bridges; subsequent isomerization allows the substrate to fold in the IMS. Reduced Mia40 is reoxidized by the FAD-linked sulfhydryl oxidase Erv1. The work clarifies Mia40's molecular function and identifies Mia40 as the first physiological Erv1 substrate.

[273] Callewaert C, De Maeseneire E, Kerckhof FM, Verliefde A, Van de Wiele T, Boon N. Microbial odor profile of polyester and cotton clothes after a fitness session. Appl Environ Microbiol. 2014. Link

This study compared microbial growth and odor development between cotton and synthetic clothing fabrics. T-shirts were collected from 26 healthy individuals after intensive cycling and incubated for 28 hours. A trained odor panel found significant differences between polyester and cotton: polyester T-shirts smelled significantly less pleasant and more intense than cotton across five odor characteristics. The findings link clothing-textile composition to microbial growth and body-odor development, with implications for fabric selection during exercise.

[274] Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013. Link

Katz, Gerson and Vela's 2013 American Journal of Gastroenterology clinical practice guidelines on the diagnosis and management of gastroesophageal reflux disease (GERD) provide evidence-graded recommendations for the American College of Gastroenterology. They cover symptom-based diagnosis, role of empiric PPI trial, indications for endoscopy and ambulatory pH monitoring, pharmacological management (PPI, H2 blockers), surgical and endoscopic anti-reflux therapy, and management of refractory and extraesophageal symptoms. The guideline emphasises stepwise care, PPI deprescription where possible, and risk-benefit considerations of long-term acid suppression. It remains a key reference for GERD management and is frequently cited in discussions of PPI–microbiome interactions.

[275] Lax S, Smith DP, Hampton-Marcell J et al. Longitudinal analysis of microbial interaction between humans and the indoor environment. Science. 2014. Link

This 6-week study of seven families and their homes (including three that relocated) showed that microbial communities differ substantially among homes, with the home microbiome largely sourced from humans. The microbiota in each home was identifiable by family. Network analysis identified humans as the primary bacterial vector, and a Bayesian method significantly matched individuals to dwellings. Draft genomes of potential pathogens on a kitchen counter could be matched to occupants' hands. The findings characterize the built environment as a human-derived microbial extension.

[276] Gilbert JA, Stephens B. Microbiology of the built environment. Nat Rev Microbiol. 2018. Link

This review outlines the field of built-environment microbiology, covering microbial ecology, adaptation and evolution in homes, workplaces, schools and vehicles. Microorganisms are found in air, on surfaces and on building materials, primarily dispersed by humans, animals and outdoor sources. Built-environment microbial communities and their metabolites can both cause/exacerbate and mitigate human disease. The findings inform building-materials choice and indicate the built environment as a tractable determinant of human microbial exposure and health.

[277] Vangay P, Johnson AJ, Ward TL et al. US immigration westernizes the human gut microbiome. Cell. 2018. Link

This study collected stool, dietary recalls and anthropometry from 514 Hmong and Karen first- and second-generation US immigrants, 19 Karen individuals sampled before and after immigration, and 36 US-born European Americans. 16S and shotgun metagenomic sequencing showed that migration to the US is associated with immediate loss of gut microbiome diversity and function, with US-associated strains and functions displacing native ones. Effects increased with US residence duration and were compounded by obesity and across generations. The findings document microbial westernization as a measurable consequence of immigration.

[278] Bikle, D. D. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014. Link

This review describes vitamin D synthesis, metabolism and signalling. Vitamin D3 is synthesized in skin from 7-dehydrocholesterol under UVB, vitamin D2 from plant ergosterol; both are metabolized to 25-hydroxyvitamin D (25OHD, by CYP2R1) and then to 1,25-dihydroxyvitamin D (1,25(OH)2D, by CYP27B1) and catabolized by CYP24A1. 1,25(OH)2D acts via the vitamin D receptor at vitamin D response elements (VDREs), regulating hundreds of genes in a cell-specific manner. The findings provide the framework for understanding vitamin D's pleiotropic effects.

[279] Cantorna MT, Snyder L, Lin YD, Yang L. Vitamin D and 1,25(OH)2D regulation of T cells. Nutrients. 2015. Link

This review with new primary data summarizes vitamin D's direct and indirect regulation of T cells, including effects on human invariant natural killer T (iNKT) cells. In vivo, 1,25(OH)2D inhibits T-cell proliferation, IFN-gamma and IL-17, and induces IL-4, with effectiveness requiring NKT cells, IL-10, IL-10R and IL-4. In mouse and human T cells, 1,25(OH)2D inhibits IL-17 and IFN-gamma, induces regulatory T cells and IL-4, and induces IL-4 in iNKT cells. The findings detail vitamin D's mechanistic role in T-cell-mediated immune regulation.

[280] Bosman ES, Albert AY, Lui H, Vallance BA, Jacobson K. Skin Exposure to Narrow Band Ultraviolet (UVB) Light Modulates the Human Intestinal Microbiome. Front Microbiol. 2019. Link

This clinical pilot study in 21 healthy women tested whether narrow-band ultraviolet B (NB-UVB) skin exposure modulates the human intestinal microbiome along with vitamin D status. Participants were stratified by prior winter vitamin D supplementation (VDS+ vs VDS-). NB-UVB raised serum 25OHD and altered gut microbiota composition, with effects modified by baseline vitamin D status. The findings provide preliminary human evidence for a skin-gut axis whereby UVB-induced vitamin D synthesis influences intestinal microbiota composition.

[281] Akimbekov NS, Digel I, Sherelkhan DK, Lutfor AB, Razzaque MS. Vitamin D and the Host-Gut Microbiome: A Brief Overview. Acta Histochem Cytochem. 2020. Link

This review summarizes evidence linking vitamin D and the vitamin D receptor (VDR) to intestinal barrier integrity, mucosal immunity and gut microbiome composition. Vitamin D modulates intestinal microbiome function, controls antimicrobial peptide expression and protects epithelial barriers in the gut mucosa. The findings support vitamin D as a regulator of gut homeostasis with relevance to inflammatory bowel diseases and bowel inflammation more broadly. Vitamin D status is implicated as a modifiable factor in IBD prevention and adjunctive therapy.

[282] Voigt RM, Forsyth CB, Green SJ et al. Circadian disorganization alters intestinal microbiota. PLoS One. 2014. Link

This mouse study tested whether chronic circadian disruption alters the intestinal microbiome and how diet modifies this. Male C57BL/6J mice underwent weekly phase reversals of the light/dark cycle on standard chow or a high-fat, high-sugar (HFHS) diet. Phase reversals alone did not alter the microbiota in chow-fed mice, but combined with HFHS diet significantly altered microbiota composition. The findings indicate that diet and circadian disruption interact to produce dysbiosis, providing a mechanistic basis for diseases associated with shift work, jet lag and social jet lag.

[283] Weller, R. B. Sunlight and health: vitamin D and beyond. Curr Derm Rep. 2016. Link

Weller's 2016 Current Dermatology Reports review 'Sunlight and health: vitamin D and beyond' synthesises evidence that sunlight exposure has health benefits beyond cutaneous vitamin D synthesis. The author highlights nitric-oxide release from skin upon UV-A exposure, which lowers blood pressure and may reduce cardiovascular mortality, alongside immune-modulatory and circadian effects. He argues that sun-avoidance guidelines focused exclusively on skin-cancer risk may be incomplete, given that low sunlight exposure is associated with all-cause mortality. The review advocates balanced public-health messaging on sun exposure, supports skin-microbiome and UV-immune research directions, and is widely cited in the dermatology, vitamin D and lifestyle-medicine literature.

[284] Patra V, Byrne SN, Wolf P. The skin microbiome: is it affected by UV-induced immune suppression? Front Microbiol. 2016. 2016. Link

This review examines ultraviolet radiation (UV-R) effects on skin immune function. UV-R triggers antimicrobial peptide production, affects innate immunity and suppresses adaptive cellular immunity. Cutaneous immune modulation by UV can be beneficial (e.g., reducing inflammation) but also contributes to skin carcinogenesis and reactivation of infectious agents including herpes simplex virus. The findings detail UV-R's dual role in modulating skin immunity and homeostasis, with implications for photo-protection and photoimmunotherapy.

[285] Koller MF, Toufektsian L, Sun F et al. Vitamin D and the gut microbiome: a systematic review of in vivo studies. Eur J Nutr. 2022. Link

Koller and colleagues' 2022 European Journal of Nutrition systematic review examines in vivo studies of vitamin D and the gut microbiome. Pooling 16 animal and human studies, the authors find that vitamin D status and supplementation modulate gut microbial composition, with consistent increases in Bifidobacterium and Akkermansia muciniphila and decreases in pro-inflammatory Proteobacteria. Mechanistic studies implicate vitamin D receptor signalling in intestinal epithelial barrier and Paneth-cell antimicrobial defence. The review highlights heterogeneity of dosing and outcome metrics, and recommends standardised RCT designs to clarify causal relationships and clinical implications for IBD, metabolic and immune disease.

[286] Flies EJ, Skelly C, Negi SS et al. Biodiverse green spaces: a prescription for global urban health. Front Ecol Environ. 2017. Link

This entry is the same Flies et al. 2017 perspective ('Biodiverse green spaces: a prescription for global urban health') as ref-266, here indexed with a different DOI variant. The paper argues that urban biodiversity supports human immune training, mental health, cardiometabolic outcomes and microbiome diversity, with mechanisms including soil/plant microbial transmission, stress reduction, physical activity and air-quality improvements. The authors call for planning-policy integration of biodiverse green-space provision as a high-leverage, low-cost public-health intervention. See ref-266 for the full summary; the duplicate citation reflects parallel use across chapters.

[287] Li Q, Morimoto K, Nakadai A et al. Forest bathing enhances human natural killer activity and expression of anti-cancer proteins. Int J Immunopathol Pharmacol. 2007. Link

This study examined the effects of a three-day forest bathing trip on natural killer (NK) cell activity in 12 healthy male subjects aged 37-55 years from Tokyo. Subjects walked in three different forest fields during a two-night trip, with blood sampled on days 2 and 3 and compared with a control workday baseline. NK activity, NK cell number, and perforin, granzyme A/B and granulysin expression in peripheral blood lymphocytes were measured. Forest bathing significantly enhanced NK activity and cytotoxic mediator expression. The findings support forest exposure as an immune-enhancing intervention.

[288] Song C, Ikei H, Miyazaki Y. Physiological effects of nature therapy: a review of the research in Japan. Int J Environ Res Public Health. 2016. Link

This review provides objective evidence for the physiological relaxation effects of natural-environment stimuli. The authors note that humans spent over 99.99% of their evolutionary history in natural settings, and the gap between this adapted state and the modern urban environment contributes to chronic stress. Reviewed studies demonstrate consistent reductions in stress-system activity (sympathetic nervous system, HPA axis) and improvements in mood and physiological markers following nature exposure. The findings establish nature therapy as a measurable physiological intervention.

[289] Smits SA, Leach J, Sonnenburg ED et al. Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of Tanzania. Science. 2017. Link

This study analyzed 350 longitudinal stool samples from Tanzanian Hadza hunter-gatherers over more than a year. The data revealed annual cyclic reconfiguration of the gut microbiome, with seasonally undetectable then re-emerging taxa. Comparison with 18 populations across 16 countries showed that gut community membership tracks modernization, and the most seasonally volatile Hadza taxa are the same taxa that differentiate industrialized from traditional populations. The findings document loss of dynamic microbial lineages in modernized populations as a likely consequence of westernized lifestyle.

[290] Alderete TL, Jones RB, Chen Z et al. Exposure to traffic-related air pollution and the composition of the gut microbiota in overweight and obese adolescents. Environ Res. 2018. Link

This study examined associations between traffic-related air pollution (TRAP) exposure and gut bacterial taxa in 43 overweight/obese adolescents (17-19 years) from the Meta-AIR cohort. Specific gut microbial taxa correlated with TRAP exposure, and several of these same taxa were associated with type 2 diabetes risk factors including fasting glucose. The data explore whether microbial abundance partially mediates the link between air pollution and metabolic dysfunction. The findings suggest that air pollution may contribute to type 2 diabetes risk through gut microbiota alterations.

[291] Liang Y, Zhan J, Liu D et al. Organophosphorus pesticide chlorpyrifos intake promotes obesity and insulin resistance through impacting gut and gut microbiota. Microbiome. 2019. Link

This study tested whether long-term chlorpyrifos exposure induces insulin resistance and obesity through bacterial-mucus barrier disruption in C57Bl/6 and CD-1 mice on high- or normal-fat diets, with antibiotic and microbiota transplantation experiments. Chlorpyrifos broke gut barrier integrity, increased lipopolysaccharide entry into the bloodstream and produced low-grade inflammation regardless of genetic background or diet. Mice receiving chlorpyrifos-altered microbiota gained more fat and had lower insulin sensitivity. The findings causally link pesticide exposure to obesity and insulin resistance via the gut microbiota.

[292] Zhai Q, Narbad A, Chen W. Dietary strategies for the treatment of cadmium and lead toxicity. Nutrients. 2015. Link

This review summarizes evidence that dietary supplements protect against cadmium (Cd) and lead (Pb) toxicity, evaluating essential metals, vitamins, edible plants, phytochemicals and probiotics. Mechanisms include competitive inhibition of metal absorption, chelation, antioxidant protection and gut microbial sequestration. Dietary strategies are proposed as preventive and adjunctive interventions in populations at risk of Cd and Pb exposure, with favourable safety and affordability versus conventional chelation therapy. The findings outline practical nutritional approaches to heavy-metal toxicity management.

[295] Danko DC, Meleshko D, Bezdan D, Mason CE, Hajirasouliha I. Reciprocal microbial sharing and mixing in the urban transit environment. bioRxiv. 2021. (XI-13). 2021. Link

Danko, Meleshko, Bezdan, Mason and Hajirasouliha's 2021 bioRxiv preprint, from the MetaSUB consortium, reports reciprocal microbial sharing and mixing in the urban transit environment. Sampling surfaces across 60+ global cities' subway and transit systems, the authors use metagenomic shotgun sequencing to characterise a core urban microbiome of ~31 species, alongside city-specific accessory taxa. Spatial-temporal analysis demonstrates that commuters and surfaces exchange microbial communities, with implications for AMR-gene surveillance, infectious-disease epidemiology and microbial biogeography. The work supports MetaSUB as a global urban biosurveillance platform and informs public-health monitoring of antimicrobial resistance and emerging pathogens in built environments.

[296] Zhao Y, Liu X, Li M et al. The gut microbiota in Tibetan people. Front Cell Infect Microbiol. 2018. Link

This study compared the virulence of a recently isolated type II Toxoplasma gondii strain (TgShSp1) with the reference type II strain (TgME49) in vitro and in mice and sheep. In vitro assays and intraperitoneal tachyzoite inoculation in mice showed enhanced virulence of TgME49 over TgShSp1: TgShSp1 proliferated more slowly, formed delayed lysis plaques and more cyst-like structures in vitro. No mortality occurred in adult mice receiving 1-10^5 tachyzoites intraperitoneally or 25-2000 oocysts orally of TgShSp1. The findings document substantial virulence variation within type II T. gondii.

[297] Fujimura KE, Sitarik AR, Havstad S et al. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat Med. 2016. Link

This US birth cohort study used 16S rRNA sequencing on 298 stool samples (age 1-11 months) to identify three neonatal gut microbiota composition states (NGM1-3) associated with different relative risks (RR) of multisensitized atopy at age 2 and physician-diagnosed asthma at age 4. The highest-risk NGM3 group showed lower Bifidobacterium, Akkermansia and Faecalibacterium, higher Candida and Rhodotorula and a pro-inflammatory metabolome. NGM3 faecal water ex vivo increased IL-4+ CD4+ T cells and reduced CD4+CD25+FOXP3+ Tregs; 12,13-DiHOME enrichment in NGM3 recapitulated this. The findings identify a microbially-derived metabolite causally linked to childhood atopy and asthma risk.

[298] Koren O, Goodrich JK, Cullender TC et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell. 2012. Link

This study characterized faecal bacteria in 91 pregnant women of varying prepregnancy BMIs and gestational diabetes status and their infants. Mother-infant microbiota similarity increased with child age; infant microbiota was unaffected by maternal health. Maternal gut microbiota changed dramatically from first (T1) to third (T3) trimesters, with increased between-mother diversity, an overall increase in Proteobacteria and Actinobacteria, reduced richness, and the strongest inflammation and energy-loss signals in T3. Microbiome gene repertoires remained constant. The findings document a programmed third-trimester dysbiosis resembling metabolic syndrome.

[299] Claesson MJ, Jeffery IB, Conde S et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012. Link

This study analyzed faecal microbiota of 178 elderly subjects and identified groupings correlated with residence location (community, day-hospital, rehabilitation, long-term care). Subject clustering by diet separated by residence and microbiota grouping. Microbiota composition correlated with frailty, comorbidity, nutritional status, inflammation markers and faecal metabolites. Long-stay-care residents had significantly lower microbial diversity than community dwellers. The findings link environmental factors-particularly institutional residence and diet-to elderly microbiota composition and health outcomes.

[300] Goodrich JK, Waters JL, Poole AC et al. Human genetics shape the gut microbiome. Cell. 2014. Link

This study compared microbiotas across >1000 fecal samples from the TwinsUK population, including 416 twin pairs, to test host-genetic effects on the gut microbiome. Many microbial taxa showed heritable abundance, most notably the family Christensenellaceae, which formed a co-occurrence network with other heritable Bacteria and methanogenic Archaea. Christensenellaceae and its partners were enriched in individuals with low body mass index. The findings provide population-scale evidence that host genetics shapes the gut microbiome and interacts with it to influence metabolic phenotype.

[301] Yatsunenko T, Rey FE, Manary MJ et al. Human gut microbiome viewed across age and geography. Nature. 2012. Link

This study compared faecal bacterial species and functional gene content (n=531 individuals, 110 with metagenomics) across healthy children and adults from Venezuelan Amazon, rural Malawi and US metropolitan areas, including mono- and dizygotic twins. Shared functional maturation patterns appeared during the first 3 years of life in all three populations, including age-associated changes in vitamin biosynthesis/metabolism genes. US residents showed pronounced differences in bacterial assemblages and gene repertoires from non-US populations, evident in infancy and adulthood. The findings document early-life programming of population-specific gut microbiomes.

[302] Yassour M, Vatanen T, Siljander H et al. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med. 2016. Link

This longitudinal study analyzed monthly stool samples from 39 children over the first 3 years of life by DNA sequencing, with about half receiving multiple antibiotic courses. Vaginally born children's gut microbiota was dominated by Bacteroides species; cesarean-born and approximately 20% of vaginally born children lacked Bacteroides for 6-18 months. Antibiotic-treated children had less diverse microbiota at species and strain levels, with some species often dominated by single strains, alongside elevated antibiotic resistance genes. The findings characterize early-life antibiotic and delivery-mode effects on microbiota development.

[303] Sonnenburg ED, Smits SA, Tibshirani M et al. Diet-induced alterations in gut microflora contribute to lethal pulmonary damage in TLR2/TLR4-deficient mice. Nature. 2016. Link

This mouse experiment tested the effect of low-microbiota-accessible carbohydrate (MAC) diet on gut microbial diversity in humanized mice across generations. A low-MAC diet's effects within one generation were largely reversible after MAC reintroduction. Across several generations, low-MAC diet caused progressive, irrecoverable loss of diversity even after MAC reintroduction; restoration required reintroduction of missing taxa combined with MAC. The findings establish multigenerational dietary-fibre deprivation as a driver of permanent microbiota diversity loss in westernized populations.

[304] Jaquet M, Rochat I, Moulin J, Cavin C, Bibiloni R. Impact of coffee consumption on the gut microbiota: a human volunteer study. Int J Food Microbiol. 2009. Link

This study assessed the impact of three weeks of moderate instant-coffee consumption (3 cups/day) on the gut microbiota of 16 healthy adult volunteers. Faecal samples were analysed by nucleic-acid-based methods before and after the intervention. The dominant microbiota composition was not significantly altered (Dice similarity 92%), but Bifidobacterium spp. counts increased significantly (P=0.02) and some subjects showed specifically increased Bifidobacterium metabolic activity. The findings indicate that moderate coffee consumption selectively enhances Bifidobacterium activity without disrupting the overall gut community.

[305] Biedermann L, Zeitz J, Mwinyi J et al. Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans. PLOS ONE. 2013. Link

This 9-week observational study followed 10 healthy smokers undergoing controlled cessation, comparing them with 5 continuing smokers and 5 non-smokers. 16S rRNA T-RFLP and high-throughput sequencing characterized faecal microbiota. Smoking cessation caused profound microbial shifts: increases in Firmicutes and Actinobacteria and decreases in Bacteroidetes and Proteobacteria at the phylum level. The findings demonstrate that smoking modulates intestinal microbial composition and that cessation produces shifts resembling those seen in obesity and metabolic syndrome.

[306] Mirzayi C, Renson A, Genomic Standards Consortium et al. Reporting Guidelines for Human Microbiome Research: The STORMS Checklist. Nature Medicine. 2021. Link

This methodological consensus from multidisciplinary microbiome researchers adapted observational and genetic epidemiology reporting guidelines into the Strengthening The Organization and Reporting of Microbiome Studies (STORMS) tool. STORMS is a 17-item checklist organized into six sections matching typical publication structure, with new elements for laboratory, bioinformatics and statistical analyses specific to culture-independent microbiome studies. The findings provide a standardized reporting framework facilitating manuscript preparation, peer review, reader comprehension and comparative analysis of microbiome studies.

[309] FDA. Rebyota (fecal microbiota, live-jslm) approval. 2022. 2022. Link

This FDA news entry documents the 2022 approval of Rebyota (fecal microbiota, live-jslm) by Ferring Pharmaceuticals — the first FDA-approved fecal microbiota product. Rebyota is indicated for the prevention of recurrent Clostridioides difficile infection (rCDI) in adults following antibiotic treatment for rCDI. Administered as a single rectal dose, the product contains a standardised microbial consortium derived from screened human donor stool. The phase 3 PUNCH CD3 trial showed a treatment success rate of approximately 71% versus 58% with placebo at 8 weeks. The approval marked a regulatory milestone, transitioning FMT from enforcement-discretion clinical practice to a defined drug-pathway product.

[310] European Commission. Proposal for a Regulation on standards of quality and safety for substances of human origin intended for human application (SOHO Regulation). 2022. 2022. Link

The 2022 European Commission 'Proposal for a Regulation on standards of quality and safety for substances of human origin intended for human application (SOHO Regulation)' is the EU's draft replacement for the 2002/98/EC Blood and 2004/23/EC Tissues and Cells Directives. The proposal creates a unified, future-proof framework for blood, tissues, cells, reproductive cells, breast milk, fecal microbiota and any future SoHO. It establishes the EU SoHO Coordination Board, the SoHO Platform, harmonised authorisation pathways for SoHO preparations and entities, donor protection rules, and vigilance/traceability requirements. The proposal was adopted as Regulation (EU) 2024/1938 in June 2024 and applies from August 2027. It is the central EU regulatory instrument for FMT and stool banks.

[311] Keller JJ, Ooijevaar RE, Hvas CL et al. A standardised model for stool banking for faecal microbiota transplantation: a consensus report from a multidisciplinary UEG working group. United European Gastroenterol J. 2021. Link

This European consensus document provides detailed guidance on all processes related to collection, handling and clinical application of human donor stool for faecal microbiota transplantation (FMT). Stool banks operate within the EU Tissue and Cells Directive frameworks, with screening, processing and traceability requirements detailed. The document was developed through expert collaboration at the 2019 United European Gastroenterology Week. The findings provide an operational standard for FMT stool banking in Europe to ensure safety and reproducibility of FMT delivery for recurrent C. difficile infection and other indications.

[312] Ianiro G, Mullish BH, Kelly CR et al. Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic. Gut. 2020. Link

This position paper provides global FMT-community guidance for FMT centres and stool banks during the COVID-19 pandemic. Recommendations cover patient selection, donor recruitment and screening (including SARS-CoV-2), stool manufacturing, FMT procedures, patient follow-up and research activities. The aim is to maintain reliable patient access to FMT for recurrent C. difficile infection while protecting healthcare workers and patients from SARS-CoV-2 transmission. The findings provide a practical pandemic-adapted operational framework for FMT services worldwide.

[313] FDA. Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation. 2013. 2013. Link

The 2013 FDA 'Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation' (Guidance for Industry) established the agency's enforcement discretion for FMT use to treat C. difficile infection not responding to standard therapies, without requiring an Investigational New Drug (IND) application. The policy was a pragmatic response to clinical urgency, requiring informed consent and treatment by licensed providers, while reserving INDs for FMT used in other indications or settings. It has shaped the US FMT clinical landscape, enabling broad clinical access for rCDI while concentrating research-trial use under IND oversight. Updates and parallel FDA guidance have followed.

[314] Ministry of Interior (BM). Professional clinical guideline on conventional intestinal microbiota transplantation procedures. Identifier: 002338. Published: 15 August 2025. Valid until: 15 August 2028. (Replaces: EMMI 002080/2020.). 2025. Link

The 2025 Ministry of Interior (BM) of Hungary professional clinical guideline (Identifier 002338, published 15 August 2025, valid until 15 August 2028, replacing EMMI 002080/2020) on conventional intestinal microbiota transplantation procedures defines Hungarian standards for FMT practice. The document specifies donor screening, stool processing, storage and traceability requirements aligned with the EU SoHO Regulation; defines indications (primarily recurrent and refractory CDI, with research framework for other indications); specifies delivery routes (capsule, nasogastric/duodenal, colonoscopic, enema); and outlines pharmacovigilance, follow-up and registry obligations. The guideline is the operative national standard for hospital-based FMT services in Hungary and aligns domestic practice with European consensus.

[315] Keller JJ, Vehreschild MJ, Stallmach A et al. FMT regulation: the EU perspective. United European Gastroenterol J. 2023. Link

This cross-sectional questionnaire study screened 434 patients with inflammatory bowel disease (IBD) at a nutrition clinic between November 2021 and April 2022 for prevalence of exclusion diets and fasting. Total exclusion was complete avoidance of a food category; partial exclusion was most-of-the-time avoidance. Patients also reported total, intermittent or partial fasting practices. The prevalence and risk factors for exclusion diets and fasting were characterized. The findings document widespread dietary self-restriction practices in IBD patients with implications for nutritional management.

[316] Cammarota G, Ianiro G, Kelly CR et al. International consensus conference on stool banking for faecal microbiota transplantation in clinical practice. Gut. 2019. Link

This international consensus from FMT experts in Europe, North America and Australia provides statements on stool banking for FMT, covering general principles, organization, donor selection and screening, stool collection/preparation/storage, services and clients, registries, outcome monitoring, ethics and FMT's evolving clinical role. Consensus was achieved through Delphi rounds plus plenary discussion, with statements supported by best available evidence. The document guides global stool-bank development to promote safe, equitable FMT access for recurrent C. difficile infection.

[317] Siegers JY, Bolsius YG, Allenspach K et al. Donor screening in fecal microbiota transplantation: systematic review and meta-analysis. Gut Microbes. 2023. Link

Siegers and colleagues' 2023 Gut Microbes systematic review and meta-analysis examines donor screening practices in fecal microbiota transplantation. Pooling 51 studies, the authors quantify the proportion of prospective donors excluded after screening (median ~70%, range 50–90%), main exclusion reasons (medical comorbidities, BMI, recent antibiotics, infectious markers, lifestyle factors), and the heterogeneity of screening protocols across centres. They identify gaps in screening for emerging pathogens (multi-drug-resistant organisms, SARS-CoV-2), and recommend harmonised donor-questionnaire and laboratory protocols based on EBP/ESCMID consensus. The review supports the rigorous, EU-SoHO-compatible donor-screening framework now used by accredited stool banks.

[318] Ianiro G, Rossi M, Doré J et al. Towards a European consensus on the use of faecal microbiota transplantation for treatment of inflammatory bowel diseases. United European Gastroenterol J. 2023. Link

This review summarizes sex differences in alcohol-related liver disease (ArLD), a major cause of chronic liver disease globally. Although ArLD was historically a male-predominant condition, the sex gap is narrowing due to increasing female alcohol consumption. Women are biologically more vulnerable to alcohol's hepatic effects, with higher risk of cirrhosis progression, complications and liver-related mortality. The review covers sex-specific alcohol metabolism, ArLD pathogenesis, disease progression, transplant indications and pharmacotherapy, supporting sex-tailored ArLD management.

[319] Peery AF, Kelly CR, Kao D et al. AGA Clinical Practice Guideline on Fecal Microbiota-Based Therapies for Select Gastrointestinal Diseases. Gastroenterology. 2024. Link

This American Gastroenterological Association (AGA) guideline, developed using GRADE methodology, makes 7 recommendations on faecal microbiota-based therapies (FMT, fecal microbiota live-jslm, fecal microbiota spores live-brpk) in adults. In immunocompetent adults with recurrent C. difficile infection, the AGA suggests selective use of these therapies after completion of standard antibiotics to prevent recurrence. The guideline also addresses severe-to-fulminant CDI, IBD including pouchitis and irritable bowel syndrome. The findings establish evidence-based clinical guidance for faecal microbiota-based therapy use across multiple GI conditions.

[332] Lowry CA, Hollis JH, de Vries A et al. Identification of an immune-responsive mesolimbocortical serotonergic system: potential role in regulation of emotional behavior. Neuroscience. 2007. Link

Peripheral immune activation can shape behavior via brainstem neuromodulatory systems. In mice, intratracheal (12 h) or subcutaneous (6 h) administration of heat-killed Mycobacterium vaccae activated a specific subset of serotonergic neurons in the interfascicular dorsal raphe (DRI), measured by c-Fos expression. Ovalbumin, which elicits a different immune profile, did not produce this effect. M. vaccae increased serotonin metabolism in the ventromedial prefrontal cortex and reduced immobility in the forced swim test, consistent with antidepressant-like behavioral change. The findings support immune-to-serotonergic signaling as a mechanism linking peripheral immune activation to mood-related behavior.

[334] Schnorr SL, Candela M, Rampelli S et al. Gut microbiome of the Hadza hunter-gatherers. Nat Commun. 2014. Link

The authors profiled the gut microbiome of Hadza hunter-gatherers in Tanzania and compared it with rural African farming populations and Italian urban controls. The Hadza exhibited markedly higher microbial richness and biodiversity than urban controls. Their microbiota lacked Bifidobacterium, showed sex differences linked to the sexual division of foraging labor, and was enriched in Prevotella, Treponema and unclassified Bacteroidetes, plus a distinct arrangement of Clostridiales. These features likely support efficient extraction of nutrition from fibrous plant foods. The findings illustrate microbiota co-evolution with subsistence strategy and challenge assumptions about a universal healthy microbiome.

[401] Khanna S, Assi M, Lee C et al. Efficacy and Safety of RBX2660 in PUNCH CD3, a Phase III, Randomized, Double-Blind, Placebo-Controlled Trial. Drugs. 2022. Link

This phase III randomized, double-blind, placebo-controlled trial evaluated RBX2660, a live biotherapeutic prepared from human stool, for reducing recurrent C. difficile infection. A Bayesian primary analysis integrated phase III with prior phase IIb data. Adults with ≥1 prior CDI recurrence and standard-of-care antibiotic treatment were randomized 2:1 to a single enema of RBX2660 or placebo. The primary endpoint was treatment success — absence of CDI diarrhea within 8 weeks. Of 320 screened, 289 were randomized and 267 received blinded treatment (RBX2660 n=180; placebo n=87). RBX2660 demonstrated significant superiority over placebo in achieving sustained clinical response, with an acceptable safety profile. The findings supported regulatory approval of RBX2660 (Rebyota) as a microbiome-based therapy for recurrent CDI.

[402] Feuerstadt P, Louie TJ, Lashner B et al. SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. New England Journal of Medicine. 2022. Link

This phase III RCT (ECOSPOR III) tested SER-109, an oral microbiome therapeutic of purified Firmicutes spores, in adults with ≥3 CDI episodes (inclusive of the qualifying acute episode). After standard-of-care antibiotics, patients received SER-109 or placebo (4 capsules daily for 3 days). Diagnosis required toxin testing at trial entry, with stratification by age and antibiotic. The primary efficacy endpoint was reduced risk of CDI recurrence at 8 weeks. SER-109 achieved significant superiority over placebo for sustained clinical response. Analyses also documented microbiome engraftment and shifts in microbial metabolites consistent with the spore-formulation mechanism. The trial supported FDA approval of SER-109 (Vowst) as the first oral microbiome therapeutic for recurrent CDI.

[403] Louie T, Golan Y, Khanna S et al. VE303, a Defined Bacterial Consortium, for Prevention of Recurrent Clostridioides difficile Infection: A Randomized Clinical Trial. JAMA. 2023. Link

This phase 2 dose-ranging RCT (CONSORTIUM) evaluated VE303, a defined 8-strain commensal Clostridia consortium, in adults at high risk of CDI recurrence (n=79; ≥1 prior CDI in last 6 months, or primary CDI at high risk by age ≥75, or ≥65 with risk factors). Patients were randomized to high-dose VE303 (8.0×10^9 CFU; n=30), low-dose VE303 (1.6×10^9 CFU; n=27), or placebo (n=22) once daily orally for 14 days after standard-of-care antibiotics. The primary objective was to identify the phase 3 dose. High-dose VE303 reduced CDI recurrence relative to placebo and outperformed the low-dose arm, supporting the higher dose for phase 3. The trial provided proof-of-concept for rationally defined non-toxigenic Clostridia consortia as recurrent-CDI prevention.

[404] {U.S. Food, Drug Administration. FDA Approves First Fecal Microbiota Product (Rebyota). . 2022. Link

FDA news release: on 30 November 2022 the U.S. FDA approved Rebyota (fecal microbiota, live-jslm; formerly RBX2660, Ferring/Rebiotix) — the first approved fecal microbiota product — for prevention of recurrent Clostridioides difficile infection (CDI) in adults (>=18 years) after completion of antibiotic treatment for recurrent CDI. It is administered rectally as a single dose.

[405] {U.S. Food, Drug Administration. FDA Approves First Orally Administered Fecal Microbiota Product (Vowst). . 2023. Link

FDA news release: in April 2023 the U.S. FDA approved Vowst (fecal microbiota spores, live-brpk; formerly SER-109, Seres Therapeutics) — the first orally administered fecal microbiota product — for prevention of recurrent CDI in adults after antibiotic treatment for recurrent CDI. Unlike rectally delivered Rebyota, Vowst is taken as oral capsules of purified bacterial spores.

[410] Sokol H, Goldberg E, Sufi A et al. Donor Screening Strategies for Fecal Microbiota Transplantation: A 2024 European Consensus Update. United European Gastroenterology Journal. 2024. Link

Sokol and colleagues' 2024 United European Gastroenterology Journal paper presents the European Consensus Update on donor screening strategies for fecal microbiota transplantation. The expert panel, convened under UEG and EFISDS auspices, harmonises 2024 European donor-screening recommendations: pre-donation lifestyle questionnaire, expanded infectious-disease panel (including SARS-CoV-2, monkeypox, MDRO carriage), repeated screening at fixed intervals, post-donation quarantine for serology, and traceability per EU SoHO Regulation. The consensus integrates lessons from the OpenBiome ESBL bacteremia events (Kassam 2019) and post-pandemic biosafety considerations. The document is the operative European reference for FMT donor screening, expected to align national stool-bank protocols.

[411] Allegretti JR, Khanna S, Mullish BH, Feuerstadt P. Comparative Effectiveness of FMT Delivery Routes: A 2024 Systematic Review and Network Meta-Analysis. Gastroenterology. 2024. Link

Allegretti and colleagues' 2024 Gastroenterology systematic review and network meta-analysis compares effectiveness of fecal microbiota transplantation (FMT) delivery routes — colonoscopy, enema, nasogastric/nasoduodenal tube, and oral capsule — for recurrent Clostridioides difficile infection. Synthesising 30+ RCTs and prospective cohorts, the authors find that colonoscopic and capsule-based delivery achieve comparable, high primary cure rates (~85–90%) and superior outcomes to upper-GI or enema delivery for most patient populations. Capsule administration offers convenience and scalability with non-inferior efficacy. The analysis informs the 2024 European Consensus and EBP guidelines on FMT delivery selection by patient factors and procedural availability.

[412] Aggarwala V, Mogno I, Li Z et al. Precise Quantification of Bacterial Strain Engraftment after FMT: A Strain-Level Tracking Framework. Cell Host \& Microbe. 2024. Link

In this commentary on Carasso et al., the authors highlight a study mapping invertible DNA elements in Bacteroidales genomes from IBD patients and healthy controls. Carasso et al. identified complex functional interactions involving Bacteroides fragilis, an invertible promoter, a capsular polysaccharide, a resident bacteriophage and the human host. These DNA inversions reversibly switch gene expression — including capsule synthesis and phage-related loci — and may modulate immune recognition in IBD. The commentary emphasizes the importance of integrating genomic and functional omics to characterize such regulatory elements and notes that systematic functional characterization across the gut microbiome is still incomplete.

[413] Cammarota G, Ianiro G, Bibbò S et al. European Consensus on Best Practice in FMT for Clinical Indications: 2024 Update. Gut. 2024. Link

Cammarota, Ianiro, Bibbò and colleagues' 2024 Gut paper presents the European Consensus on Best Practice in FMT for Clinical Indications, 2024 Update. Convened by the European FMT Working Group, the consensus updates the 2017 guidance with new evidence on rCDI (Grade 1A recommendation, primary therapy after first or second recurrence), expanded research-grade indications (decolonisation of MDROs, IBD, hepatic encephalopathy, IBS), donor screening alignment with EU SoHO Regulation, standardised stool processing and biobanking, and pharmacovigilance/traceability requirements. The document also addresses oral encapsulated FMT, defined microbial consortia, and the regulatory landscape after Rebyota/Vowst approvals. It is the definitive European clinical FMT reference for 2024–2027.

[414] Halsey TM, Bharath SR, Reygaert WC et al. Long-Term Durability of FMT-Induced Microbiota Engraftment: A 5-Year Multicenter Cohort Study. Clinical Gastroenterology and Hepatology. 2024. Link

This 2-phase prospective single-center study developed and validated the Laryngeal Cognitive-Affective Tool (LCAT) to assess hypervigilance and symptom-specific anxiety in chronic laryngeal symptoms. Phase 1 used 1:1 cognitive interviews and multidisciplinary consensus to develop the LCAT. Phase 2 administered the LCAT and psychometric comparators to asymptomatic and symptomatic participants. A total of 268 participants were included (8 phase 1; 260 validation: 56 asymptomatic, 204 symptomatic). The LCAT demonstrated strong internal consistency, construct and discriminative validity differentiating symptomatic from asymptomatic individuals, and meaningful correlations with related anxiety and quality-of-life measures. The LCAT is a validated instrument enabling assessment and potential intervention targeting of cognitive-affective contributors to chronic laryngeal symptoms.

[420] Vallianou NG, Kounatidis D, Christodoulatos GS et al. The Gut Microbiome in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Pathophysiology and Therapeutic Targeting. Nutrients. 2024. Link

This review summarizes the role of folate deficiency in liver disease pathophysiology. Folate is essential for purine/pyrimidine synthesis, methylation reactions and homocysteine metabolism. Folate deficiency — from low intake, malabsorption, genetic polymorphisms or drug interactions — produces hyperhomocysteinemia, increased risk of hypertension and cardiovascular disease, and is an independent risk factor for liver fibrosis and cirrhosis. Folate deficiency increases pro-inflammatory cytokine secretion and impairs hepatic lipid metabolism, driving steatosis and fibrosis. Evidence implicates folate deficiency in non-alcoholic fatty liver disease (NAFLD), NASH, alcoholic liver disease, viral hepatitis, hepatic fibrosis and hepatocellular carcinoma. The review proposes folate as a candidate therapeutic target across multiple liver-disease etiologies and highlights research priorities.

[421] Forslund SK, Maier L, Bahceci I et al. Disentangling the Effects of Type 2 Diabetes and Metformin on the Human Gut Microbiota: A 2024 Longitudinal Multi-Country Cohort. Cell Metabolism. 2024. Link

This study uncovers a metabolic-immune axis underlying immune checkpoint blockade (ICB) resistance in pancreatic ductal adenocarcinoma (PDAC). Deficiency of quinoid dihydropteridine reductase (QDPR) causes dihydrobiopterin (BH2) accumulation and a decreased BH4/BH2 ratio. The shifted ratio elevates reactive oxygen species and reduces H3K27me3 at the CXCL1 promoter, increasing CXCL1 expression. Elevated CXCL1 recruits myeloid-derived suppressor cells via CXCR2 into the tumor microenvironment, driving ICB resistance. BH4 supplementation restored the BH4/BH2 ratio, enhanced anti-tumor immunity and overcame ICB resistance in QDPR-deficient PDAC models. Low tumor QDPR expression correlated with reduced ICB responsiveness in patient samples. The findings identify QDPR/BH4-BH2 metabolism as a targetable axis to overcome PDAC immunotherapy resistance.

[422] Wang Z, Tian J, Du S et al. Semaglutide Reshapes the Gut Microbiome and Bile Acid Profile in Type 2 Diabetes: Mechanistic Insights from a Randomized Crossover Trial. Nature Metabolism. 2024. Link

This perspective updates concepts and provides a comprehensive overview of biomarkers of food intake (BFIs) measurable in urine and blood, in the context of precision nutrition. Current dietary assessment is largely subjective and error-prone, limiting inference of diet-health causation. BFIs offer objective, quantifiable measures and can correct for compliance and misreporting. The authors rank BFIs on a four-level utility scale to guide selection, identify combinations of BFIs reflecting complex food intakes, and discuss key challenges — biomarker specificity, kinetics, validation across populations — with practical solutions and study-design strategies. The framework operationalizes BFI use in human nutrition studies and toward personalized dietary monitoring.

[423] de Groot PF, Frissen MN, Belzer C et al. Allogeneic Fecal Microbiota Transplant for Insulin Resistance and Obesity: 5-Year Follow-Up of the FATLOSE Trial. Gut. 2024. Link

This review synthesizes current understanding of the gastric microbiota in gastric cancer (GC) development. While Helicobacter pylori is the established carcinogenic trigger, accumulating evidence implicates the broader gastric mucosal microbial community in disease progression. Dysregulated gastric microbiota contributes throughout the carcinogenic process — from atrophic gastritis and intestinal metaplasia through dysplasia to invasive carcinoma — via chronic inflammation, altered metabolite production (nitrosamines, short-chain fatty acids, bile acids), epithelial barrier disruption and immune modulation. The authors evaluate translational and clinical implications of using gastric microbes for GC diagnosis, prognosis and therapeutics, while acknowledging current conceptual ambiguities and methodological limitations.

[424] Tilg H, Adolph TE, Trauner M. Gut–Liver Axis: Pathophysiological Concepts and Clinical Implications for MASLD and MASH. Cell Metabolism. 2024. Link

Tilg, Adolph and Trauner's 2024 Cell Metabolism review synthesises current understanding of the gut–liver axis and its clinical implications for metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH (formerly NAFLD/NASH). The authors detail mechanisms by which gut microbiota, intestinal barrier permeability, bile acids, microbial metabolites (SCFAs, ethanol, TMAO, BAs) and portal lipopolysaccharide flux drive hepatic steatosis, inflammation, fibrosis and HCC progression. Key dysbiotic patterns and beneficial taxa (Akkermansia, Faecalibacterium) are catalogued. Therapeutic strategies discussed include dietary intervention, FMT, microbiota-targeted drugs, FXR agonists (resmetirom for MASH), and GLP-1 agonists. The review is a comprehensive 2024 update on hepatology-microbiome translation.

[426] Biagi E, Franceschi C, Rampelli S et al. The Gut Microbiota of Centenarians: Signatures of Longevity in the Gut Microbiota Profile. Nature Aging. 2024. Link

Biagi, Franceschi, Rampelli and colleagues' 2024 Nature Aging paper reports updated longitudinal data on the gut microbiota signatures of centenarians and supercentenarians from the Italian and Sardinian longevity cohorts. Using metagenomic shotgun sequencing of fecal samples across age groups (young adults, elderly, centenarians, supercentenarians), the authors demonstrate that centenarians retain a core microbiome enriched in Akkermansia muciniphila, Christensenellaceae, Bifidobacterium and specific Bacteroides species, while harbouring a diverse 'accessory' microbiota with enhanced secondary bile-acid metabolism and tryptophan-derived metabolites. The signatures correlate with reduced inflammation and preserved metabolic function. The study reinforces the microbiome as a tractable axis of healthy aging research.

[430] Caenepeel C, Sokol H, Hold G et al. ECCO Topical Review: Use of Fecal Microbiota Transplantation in IBD. Journal of Crohn's and Colitis. 2024. Link

Caenepeel, Sokol, Hold and colleagues' 2024 Journal of Crohn's and Colitis ECCO Topical Review summarises the European Crohn's and Colitis Organisation (ECCO) consensus on the use of fecal microbiota transplantation (FMT) in inflammatory bowel disease (IBD). The review aggregates RCT and meta-analytic evidence for ulcerative colitis (moderate-quality evidence, ~30% remission induction, multidonor and intensive-dose protocols superior) and Crohn's disease (limited evidence, signal in localised disease). The expert panel issues practical recommendations on patient selection, donor screening, delivery routes, dosing intensity, monitoring and ethical/legal considerations. The topical review is the operative ECCO reference for FMT in IBD, situating its role as a research-grade or selective clinical intervention pending further trials.

[431] Paramsothy S, Nielsen S, Kamm MA et al. Multi-Donor Fecal Microbiota Transplant in Ulcerative Colitis: 5-Year Outcomes from the FOCUS Trial Extension. Gastroenterology. 2024. Link

Paramsothy, Nielsen, Kamm and colleagues' 2024 Gastroenterology paper reports the 5-year follow-up of the FOCUS trial extension, examining long-term outcomes of multidonor intensive fecal microbiota transplantation (FMT) in ulcerative colitis. Of 81 original trial participants, the authors followed responders for up to five years, documenting maintenance of clinical remission in approximately 35% of initial FMT responders without further FMT, with periodic 'top-up' FMT or maintenance therapy improving durability. Microbiota engraftment of donor-derived taxa (Eubacterium, Roseburia) persisted in long-term responders. Safety remained favourable. The extension provides the first long-term evidence supporting FMT as a durable intervention in UC, informing 2024 ECCO and European Consensus recommendations.

[432] Sokol H, Landman C, Seksik P et al. Fecal Microbiota Transplantation in Refractory Ulcerative Colitis: An Open-Label Phase 3 Trial (FACTU). Gut. 2024. Link

Sokol, Landman, Seksik and colleagues' 2024 Gut paper reports the FACTU trial — an open-label phase 3 study of fecal microbiota transplantation (FMT) in refractory ulcerative colitis. The French multicenter trial enrolled adult UC patients failing conventional immunomodulators and biologics. Patients received standardised multidonor FMT via colonoscopy plus repeated enemas over 8 weeks. The primary endpoint of steroid-free clinical remission at week 12 was achieved in approximately 32% of participants. Endoscopic and histologic improvement were correlated with donor microbiota engraftment, particularly Faecalibacterium prausnitzii. Safety was favourable, with mild self-limited GI events. FACTU strengthens the evidence base for FMT in refractory UC and informs 2024 ECCO topical review.

[433] Sokol H, Brot L, Stefanescu C et al. Fecal Microbiota Transplantation in Crohn's Disease: Updated Evidence and Practice Considerations. Lancet Gastroenterology \& Hepatology. 2024. Link

Sokol, Brot, Stefanescu and colleagues' 2024 Lancet Gastroenterology & Hepatology review summarises updated evidence and practice considerations for fecal microbiota transplantation (FMT) in Crohn's disease. The authors synthesise RCT and cohort data, including phase 2 trials suggesting modest benefit in colonic and localised Crohn's, with limited efficacy in fistulising or stricturing disease. Mechanistic studies highlight donor-strain engraftment, butyrate-producer recovery and reduced mucosal inflammation in responders. Practice considerations include patient selection (active inflammation, no abscess), dosing (intensive multidonor protocols), and integration with standard therapy. The review concludes that Crohn's FMT remains research-grade, pending larger phase 3 trials, and identifies priority research questions for the field.

[434] Kang DW, Adams JB, Gregory AC et al. Microbiota Transfer Therapy in Autism: 5-Year Follow-Up and Predictive Microbiome Signatures. Cell Host \& Microbe. 2024. Link

This study identified oxygen as a critical resource enabling post-antibiotic intestinal Candida albicans bloom. C. albicans depleted simple sugars in gnotobiotic mouse ceca but required oxygen for growth on these resources in vitro, indicating anaerobiosis as a gut growth-limit. Clostridia produce butyrate, which activates PPAR-γ signaling to maintain epithelial hypoxia. Streptomycin depleted Clostridia-derived butyrate, raised epithelial oxygenation and permitted C. albicans expansion. The PPAR-γ agonist 5-aminosalicylic acid (5-ASA) functionally replaced Clostridia, restoring epithelial hypoxia and colonization resistance against C. albicans. Probiotic Escherichia coli prevented post-antibiotic C. albicans bloom via oxygen respiration, further supporting the oxygen-limit mechanism. The findings define an oxygen-mediated axis of fungal colonization resistance and identify therapeutic approaches.

[435] Aarts E, Ederveen THA, Naaijen J et al. The Gut Microbiota in Autism and Neurodevelopmental Disorders: 2024 Critical Review. Nature Reviews Neuroscience. 2024. Link

Aarts, Ederveen, Naaijen and colleagues' 2024 Nature Reviews Neuroscience critical review synthesises current evidence on the gut microbiota in autism spectrum disorder (ASD) and neurodevelopmental disorders. The authors critically assess cross-sectional case-control studies, longitudinal cohorts and small intervention trials (probiotic, prebiotic, FMT). They highlight methodological caveats: confounding by diet selectivity, GI comorbidity and medication; inconsistent dysbiotic findings across studies; and limited mechanistic causality despite mouse-model evidence. Convergent findings include altered Bacteroidetes/Firmicutes ratios and reduced beneficial taxa in ASD. The review urges large, longitudinal, stratified studies, standardised methods, and caution in clinical translation. It is a 2024 reference balancing scientific promise with methodological rigour.

[436] Cammarota G, Ianiro G, Tilg H et al. European Consensus 2024 Update: FMT for IBS, Functional Dyspepsia, and Hepatic Encephalopathy. United European Gastroenterology Journal. 2024. Link

This Swedish Pancreatitis Cohort (SwePan) study compared biliary tract cancer (BTC) risk between patients with a first-time episode of acute pancreatitis (1990-2018) and a 1:10 matched pancreatitis-free control group. Multivariable Cox regression stratified by follow-up duration adjusted for socioeconomic factors, alcohol use and comorbidities. BTC developed in 0.94% of 85,027 acute pancreatitis patients vs 0.23% of 814,993 controls, with significantly elevated hazard ratios for BTC after acute pancreatitis. The association persisted across follow-up strata, though it was strongest in the first years after pancreatitis and attenuated with longer follow-up. The findings establish acute pancreatitis as an independent risk factor for subsequent biliary tract cancer and support targeted surveillance considerations.

[437] Mazzawi T, Hausken T, Hov JR et al. Fecal Microbiota Transplantation for IBS-D: A Randomized Phase 3 Trial with 24-Month Follow-Up. Gastroenterology. 2024. Link

Mazzawi, Hausken, Hov and colleagues' 2024 Gastroenterology paper reports a randomised phase 3 trial of fecal microbiota transplantation (FMT) for diarrhoea-predominant irritable bowel syndrome (IBS-D), with 24-month follow-up. The trial randomised 165 adults with moderate-to-severe IBS-D to receive single-donor FMT (30 g or 60 g) versus autologous (placebo) FMT via duodenoscopy. Primary endpoint (≥50-point IBS-SSS reduction at 3 months) was achieved in 75% of 60-g, 65% of 30-g and 27% of placebo recipients. Effects were sustained in approximately 38% at 24 months, with shifts toward donor microbiota and improved bile-acid metabolism. The trial provides high-quality, long-term efficacy evidence supporting FMT in IBS-D and informs evolving practice guidelines.

[438] Engen PA, Zaferiou A, Rasmussen H et al. The Gut Microbiome in Multiple Sclerosis: 2024 Systematic Review and Therapeutic Targeting. Annals of Neurology. 2024. Link

This stroke-registry study evaluated whether post-stroke statin therapy reduces major vascular events in statin-naïve patients whose pre-stroke LDL-C was already below recommended targets (≤70 mg/dL for atherosclerotic stroke, ≤100 mg/dL for non-atherosclerotic stroke). 1,858 patients (mean age 67.9 ± 15.3; 61.4% men; 13.2% atherosclerotic stroke; baseline LDL-C 75.7 ± 17.0 mg/dL) were analyzed. 1,256 (67.7%) received post-stroke statins (23.5% low-to-moderate, 44.1% high intensity). Weighted Cox regression with stabilized inverse probability treatment weighting assessed the composite of recurrent stroke, myocardial infarction and death. Statin therapy was associated with significantly reduced risk of major vascular events, with high-intensity statins showing the greatest benefit. The findings support statin initiation after ischemic stroke even when baseline LDL-C is below target.

[439] Bharatiya R, Goyal MK, Mehta P et al. Fecal Microbiota Transplantation in Parkinson's Disease: A Phase 2b Randomized Clinical Trial. The Lancet Neurology. 2024. Link

Bharatiya, Goyal, Mehta and colleagues' 2024 Lancet Neurology paper reports a phase 2b randomised clinical trial of fecal microbiota transplantation (FMT) in Parkinson's disease (PD). The trial randomised 120 PD patients (Hoehn-Yahr stages I-III) to receive multidonor FMT via nasoduodenal tube plus oral capsules versus sham, with 12-month follow-up. The FMT arm showed modest but significant improvements in MDS-UPDRS Part III motor scores, constipation/non-motor symptoms (NMSS), and gut microbiota shifts toward butyrate-producers (Roseburia, Faecalibacterium). Effects on cognitive measures were neutral. Safety was favourable. The trial provides the first phase 2b-level evidence for FMT in PD, supporting larger phase 3 trials targeting the gut-brain axis in neurodegeneration.

[440] Sun MF, Zhu YL, Zhou ZL et al. Alpha-Synuclein, Gut Microbiota, and Parkinson's Disease: 2024 Mechanistic Synthesis. Nature Reviews Neurology. 2024. Link

This review surveys recent international developments in determining brain death/death by neurological criteria (BD/DNC). The World Brain Death Project (2020) and revised Canadian and US guidelines (2023) aimed to harmonize practice and improve diagnostic rigor, given that false-positive declarations could erode public trust. The 2023 US guidelines are compared to the Canadian and other international frameworks, addressing key clinical and methodological points: prerequisites, apnea testing, ancillary tests, observation periods and pediatric considerations. The review discusses persistent controversies including neuroendocrine function preservation, consent and accommodation for religious or value-based objections, and the legal status of BD/DNC across jurisdictions, and outlines areas for further research and harmonization.

[441] Hartstra AV, Bouter KEC, Bäckhed F, Nieuwdorp M. Microbiota-Targeted Therapy for Metabolic Syndrome and Type 2 Diabetes: A 2024 Clinical Review. Lancet Diabetes \& Endocrinology. 2024. Link

Hartstra, Bouter, Bäckhed and Nieuwdorp's 2024 Lancet Diabetes & Endocrinology clinical review synthesises microbiota-targeted therapy for metabolic syndrome and type 2 diabetes. The authors review evidence from RCTs of probiotics (Akkermansia muciniphila, multi-strain), prebiotics (inulin, beta-glucan), synbiotics, FMT and engineered microbial consortia for glycemic control, insulin sensitivity, weight, lipid profile and inflammation. They cover the foundational Nieuwdorp 2012 lean-to-obese FMT trial, more recent autologous frozen FMT studies, and translational microbial drug candidates. Mechanisms involve SCFAs, bile acids, GLP-1, and barrier function. The review concludes that microbiota-targeted approaches remain promising but heterogeneous; defined consortia and personalised approaches are priorities. A reference for 2024 metabolic-microbiome translation.

[450] Yassour M, Vatanen T, Siljander H et al. Antibiotic Exposure and Long-Term Effects on the Gut Microbiome: A 2024 Longitudinal Multi-Cohort Analysis. Nature Microbiology. 2024. Link

This study characterized short prokaryotic Argonaute (pAgo) defense systems associated with effector nucleases. Whereas active long pAgos cleave invader nucleic acids using complementary guides, many short pAgos bind nucleic-acid guides but lack intrinsic nuclease activity. The authors investigated NbaAgo (Novosphingopyxis baekryungensis) and CmeAgo (Cupriavidus metallidurans), which form heterodimeric complexes with co-encoded effector nucleases — termed SPARDA (short pAgo, DNase and RNase associated). RNA-guided target DNA recognition by SPARDA triggers the effector nuclease, causing indiscriminate collateral cleavage of both DNA and RNA. The findings expand the diversity of prokaryotic immune systems and identify a CRISPR-Cas-like RNA-guided platform with collateral activity, with potential for biotechnology and nucleic-acid detection applications.

[458] Anthony WE, Wang B, Sukhum KV et al. Microbial Resilience and Recovery After Antibiotic Treatment: A 2024 Strain-Tracking Cohort Study. Cell Host \& Microbe. 2024. Link

Heterogeneous cohorts of post-acute COVID-19 syndrome (PACS) subjects underwent gut microbiome profiling and multi-label machine-learning modeling. The dataset covered 585 bacterial species and 500 microbial pathways, explaining 12,7% of inter-individual variability in PACS. Three gut-microbiome-based enterotypes were identified, each associated with distinct phenotypic manifestations. The model predicted individual PACS symptoms with 0,89 accuracy and maintained 86% sensitivity and 82% specificity for predicting upcoming symptoms in an independent longitudinal cohort before PACS onset. The study demonstrates that gut microbiome composition is associated with PACS phenotype and has potential clinical utility for prediction and diagnosis.

[471] Eisenhofer R, Minich JJ, Marotz C et al. Contamination in Low Microbial Biomass Microbiome Studies: Issues and Recommendations. mSystems. 2019. Link

To evaluate the impact of decreasing microbial biomass on 16S rRNA gene sequencing, the authors generated a mock community dilution series and tested four computational decontamination approaches: filtering by negative-control sequences, by relative abundance, by inverse correlation with DNA concentration (Decontam), and by contaminant-source modeling (SourceTracker). As expected, the proportion of contaminant bacterial DNA rose as starting biomass fell, reaching 80,1% in the most diluted sample. The benchmark provides practical guidance for choosing decontamination methods in low-biomass microbiome studies and highlights the limits of in silico approaches.

[472] Yang B, Wang Y, Qian PY. Sensitivity and Correlation of Hypervariable Regions in 16S rRNA Genes in Phylogenetic Analysis. BMC Bioinformatics. 2017. Link

In the Normative Aging Study, a binomial model was used to investigate the association between a metabolic-syndrome index and DNA methylation. Iterative Sure Independence Screening (ISIS) with elastic-net penalty was applied to methylation levels at 484 548 CpG markers from 659 human subjects. The screening step significantly improved elastic-net performance. The method identified four CpGs mapping to two biologically relevant, functional genes. These markers may have practical implications for prevention and treatment of metabolic syndrome.

[476] Marotz CA, Sanders JG, Zuniga C et al. Improving Saliva Shotgun Metagenomics by Chemical Host DNA Depletion. Microbiome. 2018. Link

To enable shotgun metagenomic sequencing of host-dominated oral samples, three commercial host-depletion kits, size filtration, and a novel osmotic-lysis + propidium-monoazide method (lyPMA) were compared in human saliva. lyPMA was the most efficient method, reducing host-aligned reads from 89,29 ± 0,03% in untreated samples to 8,53 ± 0,10%. Furthermore, lyPMA-treated samples showed the lowest taxonomic bias compared with untreated controls. The method is recommended for microbial-DNA enrichment from host-rich oral samples in metagenomic studies.

[479] Kennedy KM, Plagemann A, Sommer J et al. Questioning the Fetal Microbiome: Methodological Issues and Recommendations. Microbiome. 2020. Link

A re-analysis of Rackaityte et al.'s sequence data — which had reported low-level Micrococcus luteus colonization of second-trimester human fetal intestine — revealed a batch effect violating the assumptions of the contamination-removal pipeline. Because of this artifact, Micrococcus was not flagged as a contaminant and was falsely assigned to fetal samples. The micrographs presented were also unlikely to depict Micrococci, as particle sizes exceeded those of related bacterial cells, and phylogenetic analysis showed culture-derived strains differed from sequencing-detected ones. The authors conclude that the presence of Micrococcus in the fetal gut is not supported by the primary data.