Literature
The complete bibliography of "UltraBiome HandBook" — 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
[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.
[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.
[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.
[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.
[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.
[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.
[53] Cryan JF, O'Riordan KJ, Cowan CSM et al. The Microbiota-Gut-Brain Axis. Physiol Rev. 2019. Link
A comprehensive review (Cryan et al., Physiol Rev 2019) of the microbiota-gut-brain axis. It details the communication routes linking the gut microbiota and the brain, including the immune system, tryptophan metabolism, the vagus nerve and enteric nervous system, and microbial metabolites (short-chain fatty acids, branched-chain amino acids, peptidoglycans). The article surveys animal and human evidence for the axis's physiological and behavioral/neurological significance.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[330] Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiota, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci. 2015. Link
The gut-brain axis is positioned as a critical node in stress-related psychiatric disorders, with the gut microbiome modulating brain development, function and behavior through immune, endocrine and neural pathways. Preclinical evidence implicates impaired intestinal barrier function — the so-called leaky gut — as a key mediator linking dysbiosis to chronic low-grade inflammation and disorders such as depression. The gut microbiome regulates intestinal permeability via short-chain fatty acids, mucin production and tight-junction signaling. The review argues that targeting microbiota-driven barrier integrity may offer mechanistic and therapeutic insight into stress-related psychiatric disease.
[357] Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997. Link
The authors evaluated the responsiveness of the Bristol Stool Form Scale to changes in whole-gut transit time (WGTT). Sixty-six volunteers had WGTT measured with radiopaque markers and recorded stool form on a 7-point scale and defecation frequency; measurements were repeated under senna and loperamide. Baseline WGTT correlated with frequency (r=0.35, P=0.005) and stool output (r=-0.41, P=0.001), and best with stool form (r=-0.54, P<0.001). Senna (n=44) shortened WGTT and increased frequency, form score and output (all P<0.001); loperamide (n=43) lengthened WGTT and reduced frequency, form score and output (all P<0.001). The Bristol scale is a valid surrogate for intestinal transit time and is responsive to pharmacological alteration.
[381] Househam AM, Peterson CT, Mills PJ, Chopra D. The effects of stress and meditation on the immune system, human microbiota, and epigenetics. Adv Mind Body Med. 2017. Link
Househam, Peterson, Mills and Chopra's 2017 Advances in Mind-Body Medicine review examines effects of stress and meditation on the immune system, human microbiota and epigenetics. The authors synthesise evidence that chronic psychological stress activates HPA-axis cortisol release, autonomic dysregulation, and pro-inflammatory cytokine production, with documented dysbiotic shifts in gut microbiota (decreased Lactobacillus and Bifidobacterium, increased pathobionts). Conversely, meditation practices — mindfulness, yoga, transcendental meditation — show effects on telomere length, DNA methylation, inflammatory gene expression and microbiota composition. The review supports a gut-brain-immune-mind axis framework and motivates trials of mind-body interventions for stress-related microbiome dysfunction.
[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.
[454] Cussotto, S., Strain, C. R., Fouhy, F., et al. Differential effects of psychotropic drugs on microbiome composition and gastrointestinal function. Translational Psychiatry. 2019. Link
The authors examined chronic psychotropic treatment (fluoxetine, escitalopram, venlafaxine, lithium, valproate, aripiprazole) in rats and showed that several drugs -- notably SSRIs and lithium -- alter gut-microbiota composition and GI function and display antimicrobial activity against specific taxa.
[506] Sokol H, Pigneur B, Watterlot L et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA. 2008. Link
Mucosa-associated microbiota was profiled in Crohn's disease (CD) patients at surgical resection and 6 months later by FISH. A reduction of Faecalibacterium prausnitzii — a major Firmicutes member — was associated with higher risk of postoperative ileal CD recurrence; lower F. prausnitzii on resected ileal mucosa also correlated with endoscopic recurrence at 6 months. In vitro and in vivo (TNBS-induced colitis) experiments demonstrated anti-inflammatory effects of F. prausnitzii. The species is a potential biomarker for postoperative recurrence risk and a candidate therapeutic in CD.
[515] Vrieze A, Van Nood E, Holleman F et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012. Link
Male recipients with metabolic syndrome were randomized to small-intestinal infusion of allogeneic (lean-donor) or autologous gut microbiota. Six weeks after lean-donor infusion, insulin sensitivity increased (median glucose disappearance rate: 26,2 → 45,3 μmol/kg/min; p<0,05), with parallel increase in butyrate-producing intestinal microbiota. The proof-of-concept study supports development of gut microbiota as a therapeutic agent to improve insulin sensitivity in humans.
[542] McDonald D, Hyde E, Debelius JW et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018. Link
The American Gut Project compared >10 000 citizen-scientist stool samples from the US, UK and Australia with environmental samples using Earth Microbiome Project standardized protocols. Human stool microbiomes showed unexpectedly wide beta-diversity compared with environmental samples. Open data integration enabled discovery of new molecules and untargeted-metabolomic associations with diverse plant intake (a stronger predictor than reductive categorical variables like veganism). The work demonstrates feasibility of mail-shipped, self-collected microbiome samples for reproducing known and revealing new associations, including psychiatric illness links and individual perturbations such as surgery.
[693] Kootte R, Levin E, Salojärvi J, Smits L, Hartstra A, Udayappan S, Hermes G, Bouter K, Koopen A, Holst J, Knop F, Blaak E, Zhao J, Smidt H, Harms A, Hankemeijer T, Bergman J, Romijn H, Schaap F, Olde Damink S, Ackermans M, Dallinga-Thie G, Zoetendal E, de Vos W, Serlie M, Stroes E, Groen A, Nieuwdorp M. Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition. Cell metabolism. 2017. Link
Baseline microbiota composition determines who responds favorably to FMT in metabolic syndrome — Allogenic FMT improved insulin sensitivity at 6 weeks; the effect did not persist at 18 weeks. Response correlates with baseline low microbiota diversity. Plasma metabolites (GABA) changed. Mechanism-revealing follow-up to the Vrieze 2012 trial.
[772] Costabile A et al. A double-blind, placebo-controlled, cross-over study to establish the bifidogenic effect of a very-long-chain inulin extracted from globe artichoke in healthy human subjects2010;104(7):1007–1017. Br J Nutr. Link
There is growing interest in the use of inulins as substrates for the selective growth of beneficial gut bacteria such as bifidobacteria and lactobacilli because recent studies have established that their prebiotic effect is linked to several health benefits. In the present study, the impact of a very-long-chain inulin (VLCI), derived from globe artichoke (Cynara scolymus), on the human intestinal microbiota compared with maltodextrin was determined. A double-blind, cross-over study was carried out in thirty-two healthy adults who were randomised into two groups and consumed 10 g/d of either VLCI or maltodextrin, for two 3-week study periods, separated by a 3-week washout period. Numbers of faecal bifidobacteria and lactobacilli were significantly higher upon VLCI ingestion compared with the placebo. Additionally, levels of Atopobium group significantly increased, while Bacteroides-Prevotella numbers were significantly reduced. No significant changes in faecal SCFA concentrations were observed.
[960] Petropoulou K et al. A high-protein high-fibre breakfast promotes ileal appetite-relevant peptide release and modulates short-chain fatty acid production 2024;131(8):1346–1358. Br J Nutr. 2024.
Br J Nutr study showing that a high-protein high-fibre breakfast promotes ileal appetite-relevant peptide release and modulates short-chain fatty acid production.
[1000] Tey SL et al. Long-term consumption of high energy-dense snack foods on sensory-specific satiety and intake 2013;109(2):320–328. Br J Nutr. 2013.
A Br J Nutr article on the effect of long-term consumption of high energy-dense snack foods on sensory-specific satiety and intake.
[2610] McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients. World J Gastroenterol 2010;16(18):2202–2222. . 2010. Link
This article reviews the evidence for efficacy and safety of Saccharomyces boulardii (S. boulardii) for various disease indications in adults based on the peer-reviewed, randomized clinical trials and pre-clinical studies from the published medical literature (Medline, Clinical Trial websites and meeting abstracts) between 1976 and 2009. For meta-analysis, only randomized, blinded controlled trials unrestricted by language were included. Pre-clinical studies, volunteer studies and uncontrolled studies were excluded from the review of efficacy and meta-analysis, but included in the systematic review. Of 31 randomized, placebo-controlled treatment arms in 27 trials (encompassing 5029 study patients), S. boulardii was found to be significantly efficacious and safe in 84\% of those treatment arms. A meta-analysis found a significant therapeutic efficacy for S. boulardii in the prevention of antibiotic-associated diarrhea (AAD) (RR = 0.47, 95\% CI: 0.35-0.63, P < 0.001). In adults, S. boulardii can be strongly recommended for the prevention of AAD and the traveler's diarrhea.
[2628] Schwartz MW, Seeley RJ, Zeltser LM, Drewnowski A, Ravussin E, Redman LM, Leibel RL. Obesity Pathogenesis: An Endocrine Society Scientific Statement. Endocrine Reviews. 2017. Link
Endocrine Society scientific statement on the pathogenesis of obesity. It details how hypothalamic inflammation, leptin resistance, and dysregulation of central energy homeostasis raise the biologically defended body-weight set-point, and why hunger is not simply a matter of willpower. It establishes the view of obesity as a chronic neuroendocrine regulatory disease.
[2629] Spiegel K, Tasali E, Penev P, Van Cauter E. Brief Communication: Sleep Curtailment in Healthy Young Men Is Associated with Decreased Leptin Levels, Elevated Ghrelin Levels, and Increased Hunger and Appetite. Annals of Internal Medicine. 2004. Link
Randomized crossover laboratory study in 12 healthy young men: two nights of 4-hour sleep restriction under controlled caloric intake decreased leptin, increased ghrelin, and intensified hunger and appetite — especially for high-carbohydrate, energy-dense foods. The study provides causal evidence that sleep loss directly distorts appetite-regulating hormones.
[2630] Taheri S, Lin L, Austin D, Young T, Mignot E. Short Sleep Duration Is Associated with Reduced Leptin, Elevated Ghrelin, and Increased Body Mass Index. PLoS Medicine. 2004. Link
Population-based (Wisconsin Sleep Cohort) cross-sectional study: short habitual sleep duration was associated with lower leptin (about 15.5% lower for 5 vs. 8 hours) and higher ghrelin (about 14.9% higher), as well as elevated body mass index. The findings support the sleep-loss–appetite-hormone–obesity link at the population level.
[2631] Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS. Adipocyte Death Defines Macrophage Localization and Function in Adipose Tissue of Obese Mice and Humans. Journal of Lipid Research. 2005. Link
Seminal histological study describing "crown-like" structures: in adipose tissue of obese mice and humans the vast majority of macrophages organize around dead, overdistended (hypertrophic) adipocytes and produce inflammatory cytokines (e.g., TNF-α). It provides the mechanistic basis for the chronic low-grade adipose-tissue inflammation of obesity and the associated insulin resistance.
[2632] Richter EA, Hargreaves M. Exercise, GLUT4, and Skeletal Muscle Glucose Uptake. Physiological Reviews. 2013. Link
Comprehensive physiological review of how muscle contraction increases skeletal-muscle glucose uptake independently of insulin signaling, via GLUT4 translocation to the cell surface (AMPK-, Ca2+-, and NO-mediated pathways). It explains why movement stabilizes blood glucose and improves insulin sensitivity even in the presence of insulin resistance.
[2633] Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, Proietto J. Long-Term Persistence of Hormonal Adaptations to Weight Loss. New England Journal of Medicine. 2011. Link
Clinical study in 50 overweight/obese patients: the hormonal adaptations following weight loss (elevated ghrelin, reduced leptin, PYY, CCK and other satiety hormones) and the increased sense of hunger persisted even one year after the diet. The work provides a biological explanation for post-diet weight regain and the yo-yo effect: the body actively defends its previous body weight.
[2634] Chambers ES, Viardot A, Psichas A, Morrison DJ, Murphy KG, Zac-Varghese SEK, MacDougall K, Preston T, Tedford C, Finlayson GS, Blundell JE, Bell JD, Thomas EL, Mt-Isa S, Ashby D, Gibson GR, Kolida S, Dhillo WS, Bloom SR, Morley W, Clegg S, Frost G. Effects of Targeted Delivery of Propionate to the Human Colon on Appetite Regulation, Body Weight Maintenance and Adiposity in Overweight Adults. Gut. 2015. Link
Human intervention study: propionate delivered directly to the colon (inulin-propionate ester) increased PYY and GLP-1 secretion, reduced acute energy intake, and over 24 weeks attenuated weight gain, abdominal and hepatic fat accumulation, and prevented deterioration in insulin sensitivity. Direct human evidence for the SCFA–L-cell–appetite axis.
[2635] Mongraw-Chaffin M, Foster MC, Anderson CAM, Burke GL, Haq N, Kalyani RR, Ouyang P, Sibley CT, Tracy R, Woodward M, Vaidya D. Metabolically Healthy Obesity, Transition to Metabolic Syndrome, and Cardiovascular Risk. Journal of the American College of Cardiology. 2018. Link
Prospective cohort study (MESA) that longitudinally followed the "metabolically healthy obese" phenotype. A substantial proportion of patients transitioned to metabolic syndrome over time, and even sustained metabolically healthy obesity carried elevated cardiovascular risk. It confirms that metabolically healthy obesity is an unstable, transient state and not durably safe.
[2636] Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, et al.; STEP 4 Investigators. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021. Link
The STEP-4 trial, after a 20-week semaglutide run-in, randomized patients to continue treatment or switch to placebo. From weeks 20-68 those switched to placebo regained 6.9% body weight while continuers lost a further 7.9%—demonstrating the biological reality of weight regain after discontinuation and the rationale for continued treatment.
[2637] Fothergill E, Guo J, Howard L, Kerns JC, Knuth ND, Brychta R, Chen KY, Skarulis MC, Walter M, Walter PJ, Hall KD. Persistent metabolic adaptation 6 years after "The Biggest Loser" competition. Obesity. 2016. Link
Fourteen "The Biggest Loser" contestants were followed for 6 years. Resting metabolic rate (RMR) fell substantially by the end of the competition and remained persistently low 6 years later, despite substantial weight regain. Metabolic adaptation (lower-than-expected energy expenditure for a given body weight) proved to be a persistent phenomenon, helping explain the tendency to regain weight after dieting.
[2638] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985. Link
The original paper introducing the HOMA model to estimate insulin resistance and beta-cell function from fasting glucose and insulin concentrations. HOMA-IR is derived from the product of the two basal values (insulin × glucose divided by a constant) and is a widely used, inexpensive metabolic marker for estimating insulin sensitivity.
[2639] Malagelada C, Azpiroz F. Gastrocolonic Response. Current Gastroenterology Reports. 2022. Link
Review of the gastrocolonic response: a physiologic increase in colonic motor activity following meal ingestion. It is provoked by gastric distension, caloric intake and meal fat content, mediated via the vagus nerve and neurohumoral mechanisms; it appears within minutes of eating and can last for hours in healthy subjects. The reflex is clinically relevant in constipation, IBS and other motility disorders.
[2640] Zeevi D, Korem T, Zmora N et al. Personalized Nutrition by Prediction of Glycemic Responses. Cell. 2015. Link
Zeevi and colleagues (Weizmann Institute) measured 46,898 postprandial glycemic responses with continuous glucose monitors in an 800-person cohort. They showed that individuals produce markedly different blood glucose responses to the same food, and an algorithm integrating clinical and microbiome features accurately predicts the personalized response, validated in an independent 100-person cohort. Algorithm-guided dietary intervention produced lower postprandial responses and consistent gut microbiota alterations.
[2641] Tuomi T, Nagorny CLF, Singh P et al. Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes. Cell Metabolism. 2016. Link
Tuomi and colleagues showed that the MTNR1B rs10830963 risk variant is an eQTL conferring increased MTNR1B mRNA expression in human pancreatic islets. Melatonin lowers cAMP in beta-cells and inhibits insulin release; increased melatonin signalling in G-allele carriers reduces insulin secretion and raises diabetes risk. In a clinical study, evening melatonin sensitivity rose with the risk genotype, providing the mechanism for the genotype-dependent glucose impact of late-evening carbohydrate loads.
[2642] Hevener AL, Clegg DJ, Mauvais-Jarvis F. Impaired estrogen receptor action in the pathogenesis of the metabolic syndrome. Molecular and Cellular Endocrinology. 2015. Link
Review of how impaired estrogen receptor action contributes to the pathogenesis of metabolic syndrome. Estrogen is a key regulator of insulin action and mitochondrial function; declining estrogen levels (e.g. menopause) impair insulin sensitivity, increase visceral/abdominal fat accumulation, and predispose to metabolic syndrome.
[2643] Wood W, Neal DT. A new look at habits and the habit-goal interface. Psychological Review. 2007. Link
Theoretical review of the nature of habits and the habit-goal interface. Habits are context-cued, automatized responses (cue-routine-reward) that operate without mediation by conscious goal states. The model explains the mechanisms of habit formation and change and distinguishes habits from goal-directed automaticity; a foundational source for the behavioral-science basis of the keystone-habit concept.
[2644] Lyssenko V, Nagorny CLF, Erdos MR et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nature Genetics. 2009. Link
Lyssenko and colleagues, in a genome-wide association study, identified a common variant in the MTNR1B (melatonin receptor 1B) gene (rs10830963) associated with elevated fasting glucose, impaired early (first-phase) insulin secretion and prospectively increased risk of type 2 diabetes. The risk variant links melatonin signalling to pancreatic beta-cell insulin output and helps explain individual sensitivity to evening carbohydrate loads.
[2645] Youm YH, Nguyen KY, Grant RW et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nature Medicine. 2015. Link
Youm and colleagues showed that beta-hydroxybutyrate (βHB), a ketone elevated by fasting, ketogenic diet or high-intensity exercise, specifically inhibits the NLRP3 inflammasome and is anti-inflammatory in vivo, attenuating NLRP3-mediated inflammatory disease. βHB acts by directly reducing inflammasome activation rather than via short-chain fatty acid receptors or HDAC inhibition, providing a documented mechanism for the signalling/neuromodulatory effects of ketones.
[2646] Wyatt P, Berry SE, Finlayson G et al. Postprandial glycaemic dips predict appetite and energy intake in healthy individuals. Nature Metabolism. 2021. Link
Wyatt and colleagues analysed 1,070 participants (PREDICT UK exploratory and US validation cohorts) across 8,624 standardised and 71,715 ad libitum meals using continuous glucose monitors. The 2-3 h postprandial glucose dip predicted hunger and subsequent energy intake better than the 0-2 h glucose peak or incremental area under the curve. Larger dips were associated with greater hunger, shorter time to next meal and higher 24 h energy intake, establishing a physiological (non-volitional) driver of overeating.
[2647] O'Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, O'Sullivan GC, Kiely B, Collins JK, Shanahan F, Quigley EMM. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005. Link
Double-blind, placebo-controlled trial in 77 IBS patients showing that Bifidobacterium infantis 35624 (10^10 cells) significantly relieved symptoms, with improvement associated with normalization of the anti- to pro-inflammatory cytokine ratio, suggesting an immune-modulating role. Lactobacillus salivarius UCC4331 showed no comparable effect, demonstrating strain specificity of probiotic action.
[2648] Pilz S, Frisch S, Koertke H, Kuhn J, Dreier J, Obermayer-Pietsch B, Wehr E, Zittermann A. Effect of Vitamin D Supplementation on Testosterone Levels in Men. Hormone and Metabolic Research. 2011. Link
Randomized controlled trial showing vitamin D supplementation (~3332 IU/day for 1 year) significantly increased total, bioactive, and free testosterone levels in overweight men compared with placebo. It supports the link between vitamin D deficiency and lower testosterone and the potential benefit of targeted supplementation.
[2649] Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine. 2021. Link
The STEP-1 phase 3 trial (n=1961) assessed once-weekly 2.4 mg semaglutide plus lifestyle intervention in adults with overweight/obesity without diabetes. Over 68 weeks mean weight loss was 14.9%, with 86% achieving ≥5% loss. Body-composition substudy showed a substantial fraction of lost mass was lean mass, underscoring the importance of muscle preservation.
[2650] Weghuber D, Barrett T, Barrientos-Pérez M, Gies I, Hesse D, Jeppesen OK, et al.; STEP TEENS Investigators. Once-Weekly Semaglutide in Adolescents with Obesity. New England Journal of Medicine. 2022. Link
The STEP-TEENS trial randomized adolescents aged 12-18 with obesity to weekly 2.4 mg semaglutide or placebo for 68 weeks with lifestyle intervention. The BMI reduction difference versus placebo was -16.7%. The trial supported pediatric approval of semaglutide from age 12 for severe obesity.
[2651] Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al.; SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. New England Journal of Medicine. 2023. Link
The SELECT trial randomized 17,604 patients with obesity (BMI ≥27) and established cardiovascular disease without diabetes to weekly 2.4 mg semaglutide or placebo, median follow-up 39.8 months. Semaglutide reduced major adverse cardiovascular events (CV death, nonfatal MI or stroke) by 20% (HR 0.80; 95% CI 0.72-0.90), an effect extending beyond weight loss.
[2652] Perkovic V TuttleKR,RossingP,MahaffeyKW,MannJFE,BakrisG,etal;FLOWTrialCommittees, Investigators. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. New England Journal of Medicine. 2024. Link
The FLOW trial in patients with type 2 diabetes and chronic kidney disease showed weekly semaglutide reduced major kidney outcomes by 24% (HR 0.76; 95% CI 0.66-0.88). The primary composite endpoint combined kidney function decline, kidney death, and cardiovascular death; the trial was stopped early for efficacy.
[2653] Malhotra A, Grunstein RR, Fietze I, Weaver TE, Redline S, Azarbarzin A, et al.; SURMOUNT-OSA Investigators. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. New England Journal of Medicine. 2024. Link
The SURMOUNT-OSA trial in patients with moderate-to-severe obstructive sleep apnea (OSA) and obesity showed tirzepatide significantly reduced the apnea-hypopnea index (AHI), body weight, hypoxic burden, hsCRP, and blood pressure. It is the first drug to gain an indication through structural improvement of OSA.
[2654] van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in healthy men. New England Journal of Medicine. 2009. Link
Twenty-four men were studied with 18F-FDG PET-CT under cold and thermoneutral conditions. Cold-activated brown adipose tissue (BAT) was detected in 96% (23 of 24) of subjects, absent under thermoneutral conditions. BAT activity was significantly lower in overweight/obese than in lean subjects; the authors concluded BAT is metabolically significant and a potential target for obesity treatment.
[2655] De Schryver AM, Keulemans YC, Peters HP, Akkermans LM, Smout AJ, De Vries WR. Effects of regular physical activity on defecation pattern in middle-aged patients complaining of chronic constipation. Scandinavian Journal of Gastroenterology. 2005. Link
Randomized study in middle-aged, inactive patients with chronic idiopathic constipation: a 12-week regular physical-activity programme (including walking) significantly reduced rectosigmoid and total colonic transit time and improved defecation pattern. The work provides direct clinical evidence that regular movement accelerates gut transit.
[2656] Simpson SJ, Raubenheimer D. Obesity: the protein leverage hypothesis. Obesity Reviews. 2005. Link
Foundational paper proposing the protein leverage hypothesis: because protein intake is regulated more tightly than fat or carbohydrate intake, dietary protein dilution (a fall in the protein-to-energy ratio) drives increased total energy intake until the protein requirement is met. The authors argue this mechanism may contribute to the obesity epidemic.
[2657] Sze MA, Schloss PD. Looking for a Signal in the Noise: Revisiting Obesity and the Microbiome. mBio. 2016. Link
Meta-analysis re-processing 16S rRNA data from ten human studies, showing that the previously proposed link between the Firmicutes/Bacteroidetes ratio and obesity is weak, inconsistent and study-dependent. The authors conclude that microbiota composition alone is not a reliable biomarker of body-weight status and caution against clinical over-interpretation of the F/B ratio.
[2658] Myers MG, Cowley MA, Münzberg H. Mechanisms of leptin action and leptin resistance. Annual Review of Physiology. 2008. Link
Review of the mechanisms of leptin action and the development of leptin resistance. Adipose-derived leptin acts via the hypothalamic LRb receptor (mainly through STAT3 signaling) to regulate energy balance. In obesity, negative-feedback pathways (e.g. SOCS3, phosphorylation of Tyr985 on the leptin receptor) attenuate leptin signaling, producing cellular leptin resistance: the brain perceives a state of deficit despite high fat stores.
[2659] Kreider RB, Kalman DS, Antonio J, Ziegenfuss TN, Wildman R, Collins R, Candow DG, Kleiner SM, Almada AL, Lopez HL. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. Journal of the International Society of Sports Nutrition. 2017. Link
The 2017 ISSN position stand on the safety and efficacy of creatine supplementation. It concludes creatine monohydrate is safe long-term in healthy individuals, does not impair kidney function, and that any rise in serum creatinine reflects spontaneous creatine degradation rather than renal damage. A 3-5 g/day maintenance dose is well tolerated.
[2660] Ledochowski L, Ruedl G, Taylor AH, Kopp M. Acute Effects of Brisk Walking on Sugary Snack Cravings in Overweight People, Affect and Responses to a Manipulated Stress Situation and to a Sugary Snack Cue: A Crossover Study. PLoS ONE. 2015. Link
Crossover experiment in overweight sugary-snack consumers: a 15-minute brisk walk significantly reduced acute cravings for sugary snacks and attenuated urges triggered by a stress situation and a food cue. Evidence that a short walk acts as an immediate, non-willpower-based intervention that dampens cravings.
[2661] Monteiro CA, Levy RB, Claro RM, Castro IRR, Cannon G. A new classification of foods based on the extent and purpose of their processing. Cadernos de Saúde Pública. 2010. Link
The paper that established the NOVA classification: foods are grouped not by nutrient composition but by the extent and purpose of industrial processing (unprocessed/minimally processed, culinary ingredients, processed foods, ultra-processed products). This framework became the most widely applied food-processing classification in the scientific literature and the reference basis for the UPF concept.
[2662] Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K, Kawai Y, Tsujisaki M. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009. Link
In 56 healthy adults (aged 23–65) 18F-FDG PET-CT measured brown adipose tissue (BAT) glucose uptake during cold exposure and under thermoneutral conditions. Cold exposure revealed metabolically active BAT in a high proportion of subjects, absent under thermoneutral conditions. BAT activity correlated negatively with age and adiposity (BMI, visceral fat), suggesting a role in the control of body temperature and body fat.
[2663] Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J, Reimann F, Gribble FM. Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein-Coupled Receptor FFAR2. Diabetes. 2012. Link
Short-chain fatty acids (acetate, propionate, butyrate) trigger GLP-1 secretion via FFAR2 (GPR43) and FFAR3 (GPR41) receptors expressed on GLP-1-secreting L-cells. SCFAs raised cytosolic calcium in L-cells; mice lacking Ffar2 or Ffar3 showed reduced SCFA-triggered GLP-1 release and impaired glucose tolerance. This is the mechanistic basis of the fermentable fiber → SCFA → GLP-1 pathway.
[2664] DeFronzo RA, Tripathy D. Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes. Diabetes Care. 2009. Link
DeFronzo and Tripathy review evidence that under insulin-stimulated (euglycemic clamp) conditions roughly 80% of whole-body glucose uptake occurs in skeletal muscle, making muscle the principal determinant of glycemia. Skeletal muscle insulin resistance is the initiating, primary defect in type 2 diabetes, detectable decades before beta-cell failure and overt hyperglycemia, underscoring the metabolic importance of preserving muscle mass.
[2665] DiPietro L, Gribok A, Stevens MS, Hamm LF, Rumpler W. Three 15-min bouts of moderate postmeal walking significantly improves 24-h glycemic control in older people at risk for impaired glucose tolerance. Diabetes Care. 2013. Link
Randomized crossover study in older adults at risk for impaired glucose tolerance: three 15-minute bouts of moderate post-meal walking, measured with continuous glucose monitoring (CGM), significantly improved 24-hour glycemic control and notably blunted postprandial glucose excursions, most clearly after the evening meal. Demonstrates that short post-meal walking directly attenuates postprandial glucose rises.
[2666] Shukla AP, Iliescu RG, Thomas CE, Aronne LJ. Food Order Has a Significant Impact on Postprandial Glucose and Insulin Levels. Diabetes Care. 2015. Link
Shukla and colleagues, in a crossover pilot in overweight adults with type 2 diabetes, gave an identical 628 kcal meal in two orders. When vegetables and protein were eaten before carbohydrate, postprandial glucose was 28.6%, 36.7% and 16.8% lower at 30, 60 and 120 min, the incremental area under the curve fell by 73%, and insulin excursions were attenuated versus the reverse order. Food order thus flattens the glucose curve without changing the food itself.
[2667] Rosenstock J, Ferrannini E. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care. 2015. Link
Rosenstock and Ferrannini review the 2015 FDA safety warning that all approved SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) carry an increased risk of euglycemic diabetic ketoacidosis (with mildly-to-moderately elevated or normal blood glucose). Triggers include intercurrent illness, reduced food/fluid intake and reduced insulin dose. The atypical, normoglycemic presentation can delay diagnosis, justifying caution especially with low-carbohydrate intake.
[2668] Shukla AP, Andono J, Touhamy SH et al. Carbohydrate-last meal pattern lowers postprandial glucose and insulin excursions in type 2 diabetes (Effect of Food Order on Ghrelin Suppression). Diabetes Care. 2018. Link
Shukla and colleagues, in a crossover study of 16 metformin-treated adults with overweight/obesity and type 2 diabetes, compared carbohydrate-first, carbohydrate-last and mixed (sandwich) meal orders. The carbohydrate-last order significantly reduced the incremental glucose area under the curve and peak (by 53-54%), attenuated insulin excursions, increased GLP-1, and more strongly suppressed ghrelin 3 h postmeal. Food order is thus relevant for appetite and weight management.
[2669] Carpentier AC, Blondin DP, Virtanen KA, Richard D, Haman F, Turcotte ÉE. Brown adipose tissue energy metabolism in humans. Frontiers in Endocrinology. 2018. Link
Review of human brown adipose tissue (BAT) energy metabolism. It summarizes 18F-FDG PET-CT-measured BAT volume and activity and the caloric contribution of cold-induced thermogenesis. Adult BAT energy expenditure is modest (typically ~100–300 kcal/day at peak cold exposure), and functional BAT amount is reduced in obesity and metabolic syndrome, limiting BAT as a stand-alone weight-loss tool.
[2670] Boyle RJ et al. (Lactobacillus Bacteremia, Probiotics review authors). Lactobacillus Bacteremia and Probiotics: A Review. Microorganisms. 2023. Link
Review of probiotic-associated Lactobacillus bacteremia and sepsis cases. Although population-level risk is low, in immunocompromised, critically ill, or central-catheter patients probiotic strains can cause bacteremia, fungemia, and sepsis. The authors recommend heightened vigilance in vulnerable populations (immunosuppression, malignancy, premature neonates).
[2671] Leidy HJ, Clifton PM, Astrup A et al. The role of protein in weight loss and maintenance. American Journal of Clinical Nutrition. 2015. Link
Leidy and colleagues review evidence that higher-protein diets (1.2-1.6 g protein/kg body weight/day), with at least ~25-30 g protein per meal, improve appetite control, body-weight management and cardiometabolic risk factors. Under energy restriction, higher protein intake helps preserve lean mass, which is key for maintaining basal metabolic rate and preventing weight regain.
[2672] Armstrong LE, Ganio MS, Casa DJ, Lee EC, McDermott BP, Klau JF, Jimenez L, Le Bellego L, Chevillotte E, Lieberman HR. Mild Dehydration Affects Mood in Healthy Young Women. Journal of Nutrition. 2012. Link
Placebo-controlled, repeated-measures study in 25 young women: mild dehydration (~1.36% body mass loss, induced by moderate exercise without hyperthermia) degraded mood, increased perceived task difficulty, lowered concentration, and produced headache symptoms. The findings support that even mild fluid deficit measurably affects cognition and well-being.