Mooradian, A. D. Dyslipidemia in type 2 diabetes mellitus. Nature Clin. Pract. Endocrinol. Metab. 5, 150–159 (2009).
Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).
The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).
Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).
Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).
Li, J. et al. An integrated catalog of reference genes in the human gut microbiome. Nature Biotechnol. 32, 834–841 (2014).
Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).
Bäckhed, F., Manchester, J. K., Semenkovich, C. F. & Gordon, J. I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl Acad. Sci. USA 104, 979–984 (2007).
Rabot, S. et al. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. FASEB J. 24, 4948–4959 (2010).
Ding, S. et al. High-fat diet: bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. PLoS ONE 5, e12191 (2010).
Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).
Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).
The first study to show that the microbiota from an obese mouse could confer increased weight gain to a germ-free recipient mouse.
Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).
Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013).
This study showed that a microbiota from a lean individual could invade the microbiota of an obese individual and provide protection from weight gain, but that the invasion and protection was dependent on diet.
Goodrich, J. K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014).
Tremaroli, V. et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab. 22, 228–238 (2015).
Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).
David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).
De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl Acad. Sci. USA 107, 14691–14696 (2010).
The first of several studies to show that the gut microbiota of a traditional rural population is more diverse than and contains distinct taxa in comparison to the microbiotas of Western populations.
Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).
Cotillard, A. et al. Dietary intervention impact on gut microbial gene richness. Nature 500, 585–588 (2013).
Kovatcheva-Datchary, P. et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of Prevotella. Cell Metab. 22, 971–982 (2015).
Walker, A. W. et al. Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J. 5, 220–230 (2011).
Ley, R. E. et al. Evolution of mammals and their gut microbes. Science 320, 1647–1651 (2008).
Muegge, B. D. et al. Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 332, 970–974 (2011).
Torrey, J. C. The regulation of the intestinal flora of dogs through diet. J. Med. Res. 39, 415–447 (1919).
Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Med. 19, 576–585 (2013).
Wu, G. D. et al. Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production. Gut 65, 63–72 (2016).
Hehemann, J. H. et al. Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature 464, 908–912 (2010).
Wexler, A. G. et al. Human symbionts inject and neutralize antibacterial toxins to persist in the gut. Proc. Natl Acad. Sci. USA 113, 3639–3644 (2016).
Chatzidaki-Livanis, M., Geva-Zatorsky, N. & Comstock, L. E. Bacteroides fragilis type VI secretion systems use novel effector and immunity proteins to antagonize human gut Bacteroidales species. Proc. Natl Acad. Sci. USA 113, 3627–3632 (2016).
Lee, S. M. et al. Bacterial colonization factors control specificity and stability of the gut microbiota. Nature 501, 426–429 (2013).
Reyes, A., Wu, M., McNulty, N. P., Rohwer, F. L. & Gordon, J. I. Gnotobiotic mouse model of phage–bacterial host dynamics in the human gut. Proc. Natl Acad. Sci. USA 110, 20236–20241 (2013).
Wostmann, B. S., Larkin, C., Moriarty, A. & Bruckner-Kardoss, E. Dietary intake, energy metabolism, and excretory losses of adult male germfree Wistar rats. Lab. Anim. Sci. 33, 46–50 (1983).
Lozupone, C. A. et al. The convergence of carbohydrate active gene repertoires in human gut microbes. Proc. Natl Acad. Sci. USA 105, 15076–15081 (2008).
El Kaoutari, A., Armougom, F., Gordon, J. I., Raoult, D. & Henrissat, B. The abundance and variety of carbohydrate-active enzymes in the human gut microbiota. Nature Rev. Microbiol. 11, 497–504 (2013).
McNeil, N. I. The contribution of the large intestine to energy supplies in man. Am. J. Clin. Nutr. 39, 338–342 (1984).
Bergman, E. N. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol. Rev. 70, 567–590 (1990).
Bingham, S. & Cummings, J. H. in Medical Aspects of Dietary Fiber (eds Spiller, G. A. & Kay, R. M.) 261–2884 (Plenum, 1980).
Schnorr, S. L. et al. Gut microbiome of the Hadza hunter–gatherers. Nature Commun. 5, 3654 (2014).
Sommer, F. et al. The gut microbiota modulates energy metabolism in the hibernating brown bear Ursus arctos. Cell Rep. 14, 1655–1661 (2016).
Koren, O. et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 150, 470–480 (2012).
Turnbaugh, P. J., Bäckhed, F., Fulton, L. & Gordon, J. I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213–223 (2008).
Caesar, R., Tremaroli, V., Kovatcheva-Datchary, P., Cani, P. D. & Backhed, F. Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab. 22, 658–668 (2015).
Fleissner, C. K. et al. Absence of intestinal microbiota does not protect mice from diet-induced obesity. Br. J. Nutr. 104, 919–929 (2010).
Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92–96 (2015).
Suez, J. et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181–186 (2014).
McGill, C. R., Fulgoni, V. L. III & Devareddy, L. Ten-year trends in fiber and whole grain intakes and food sources for the United States population: National Health and Nutrition Examination Survey 2001–2010. Nutrients 7, 1119–1130 (2015).
Costello, E. K., Stagaman, K., Dethlefsen, L., Bohannan, B. J. & Relman, D. A. The application of ecological theory toward an understanding of the human microbiome. Science 336, 1255–1262 (2012).
Cardinale, B. J. et al. Biodiversity loss and its impact on humanity. Nature 486, 59–67 (2012).
Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).
Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).
Obregon-Tito, A. J. et al. Subsistence strategies in traditional societies distinguish gut microbiomes. Nature Commun. 6, 6505 (2015).
Martínez, I. et al. The gut microbiota of rural Papua New Guineans: composition, diversity patterns, and ecological processes. Cell Rep. 11, 527–538 (2015).
Clemente, J. C. et al. The microbiome of uncontacted Amerindians. Sci. Adv. 1, e1500183 (2015).
Forslund, K. et al. Country-specific antibiotic use practices impact the human gut resistome. Genome Res. 23, 1163–1169 (2013).
Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013).
Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).
Srinivasan, S. et al. Bacterial communities in women with bacterial vaginosis: high resolution phylogenetic analyses reveal relationships of microbiota to clinical criteria. PLoS ONE 7, e37818 (2012).
Martens, E. C., Kelly, A. G., Tauzin, A. S. & Brumer, H. The devil lies in the details: how variations in polysaccharide fine-structure impact the physiology and evolution of gut microbes. J. Mol. Biol. 426, 3851–3865 (2014).
Sonnenburg, E. D. & Sonnenburg, J. L. Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab. 20, 779–786 (2014).
Rampelli, S. et al. Metagenome sequencing of the Hadza hunter-gatherer gut microbiota. Curr Biol. 25, 1682–1693 (2015).
Sonnenburg, E. D. et al. Diet-induced extinctions in the gut microbiota compound over generations. Nature 529, 212–215 (2016).
Donia, M. S. & Fischbach, M. A. Small molecules from the human microbiota. Science 349, 1254766 (2015).
Meyer, T. W. & Hostetter, T. H. Uremic solutes from colon microbes. Kidney Int. 81, 949–954 (2012).
Cho, I. et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488, 621–626 (2012).
This study demonstrated that the use of antibiotics in early life might cause metabolic disease in later life.
Schwiertz, A. et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity 18, 190–195 (2010).
De Vadder, F. et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156, 84–96 (2014).
Liou, A. P. et al. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl. Med. 5, 178ra41 (2013).
Chambers, E. S. et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut 64, 1744–1754 (2015).
Donohoe, D. R. et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 13, 517–526 (2011).
Donohoe, D. R., Wali, A., Brylawski, B. P. & Bultman, S. J. Microbial regulation of glucose metabolism and cell-cycle progression in mammalian colonocytes. PLoS ONE 7, e46589 (2012).
Wichmann, A. et al. Microbial modulation of energy availability in the colon regulates intestinal transit. Cell Host Microbe 14, 582–590 (2013).
Thorburn, A. N. et al. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nature Commun. 6, 7320 (2015).
Davie, J. R. Inhibition of histone deacetylase activity by butyrate. J. Nutr. 133, 2485S–2493S (2003).
Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).
Samuel, B. S. et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl Acad. Sci. USA 105, 16767–16772 (2008).
Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).
Tang, W. H. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013).
Sjöström, L. et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 357, 741–752 (2007).
Sjöström, L. et al. Bariatric surgery and long-term cardiovascular events. J. Am. Med. Assoc. 307, 56–65 (2012).
Russell, D. W. The enzymes, regulation, and genetics of bile acid synthesis. Annu. Rev. Biochem. 72, 137–174 (2003).
Midtvedt, T. Microbial bile acid transformation. Am. J. Clin. Nutr. 27, 1341–1347 (1974).
Thomas, C., Pellicciari, R., Pruzanski, M., Auwerx, J. & Schoonjans, K. Targeting bile-acid signalling for metabolic diseases. Nature Rev. Drug Discov. 7, 678–693 (2008).
Kawamata, Y. et al. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278, 9435–9440 (2003).
Sayin, S. I. et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR Antagonist. Cell Metab. 17, 225–235 (2013).
Li, F. et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nature Commun. 4, 2384 (2013).
Jiang, C. et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J. Clin. Invest. 125, 386–402 (2015).
Parséus, A. et al. Microbiota-induced obesity requires farnesoid X receptor. Gut http://dx.doi.org/10.1136/gutjnl-2015-310283 (2016).
Ryan, K. K. et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509, 183–188 (2014).
Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013).
Venkatesh, M. et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity 41, 296–310 (2014).
Meijers, B. K. et al. p-Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin. J. Am. Soc. Nephrol. 5, 1182–1189 (2010).
Koppe, L. et al. p-Cresyl sulfate promotes insulin resistance associated with CKD. J. Am. Soc. Nephrol. 24, 88–99 (2013).
Barreto, F. C. et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin. J. Am. Soc. Nephrol. 4, 1551–1558 (2009).
Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).
Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).
Caesar, R. et al. Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Gut 61, 1701–1707 (2012).
Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nature Med. 15, 921–929 (2009).
Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nature Med. 15, 914–920 (2009).
Liu, J. et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nature Med. 15, 940–945 (2009).
Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nature Med. 15, 930–939 (2009).
Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nature Med. 20, 159–166 (2014).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).
Cani, P. D. et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 50, 2374–2383 (2007).
Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).
The first study to demonstrate that the presence of endotoxin is sufficient to alter glucose metabolism in mice.
Erridge, C., Attina, T., Spickett, C. M. & Webb, D. J. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am. J. Clin. Nutr. 86, 1286–1292 (2007).
Ghoshal, S., Witta, J., Zhong, J., de Villiers, W. & Eckhardt, E. Chylomicrons promote intestinal absorption of lipopolysaccharides. J. Lipid Res. 50, 90–97 (2009).
Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 487, 104–108 (2012).
Garidou, L. et al. The gut microbiota regulates intestinal CD4 T cells expressing RORγt and controls metabolic disease. Cell Metab. 22, 100–112 (2015).
Sano, T. et al. An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses. Cell 163, 381–393 (2015).
Zeevi, D. et al. Personalized nutrition by prediction of glycemic responses. Cell 163, 1079–1094 (2015).
This study used a machine-learning approach to mine personal health profiles that included microbiome data to predict the postprandial glycaemic response.
Smith, M. I. et al. Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science 339, 548–554 (2013).
van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013).
Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916 (2012).
This study demonstrated that sensitivity to insulin could be changed by directly altering the gut microbiota through faecal microbiota transplantation.
Earle, K. A. et al. Quantitative imaging of gut microbiota spatial organization. Cell Host Microbe 18, 478–488 (2015).
Lichtman, J. S. et al. The effect of microbial colonization on the host proteome varies by gastrointestinal location. ISME J. 10, 1170–1181 (2016).
Turnbaugh, P. J. et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 1, 6ra14 (2009).
Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015).
The first example of inhibiting microbial enzymes (or 'drugging the bug') to prevent atherosclerosis.
Ajslev, T. A., Andersen, C. S., Gamborg, M., Sorensen, T. I. & Jess, T. Childhood overweight after establishment of the gut microbiota: the role of delivery mode, pre-pregnancy weight and early administration of antibiotics. Int. J. Obes. 35, 522–529 (2011).
Kim, Y. & Je, Y. Dietary fiber intake and total mortality: a meta-analysis of prospective cohort studies. Am. J. Epidemiol. 180, 565–573 (2014).
Yang, Y., Zhao, L. G., Wu, Q. J., Ma, X. & Xiang, Y. B. Association between dietary fiber and lower risk of all-cause mortality: a meta-analysis of cohort studies. Am. J. Epidemiol. 181, 83–91 (2015).
Salonen, A. et al. Impact of diet and individual variation on intestinal microbiota composition and fermentation products in obese men. ISME J. 8, 2218–2230 (2014).
Walker, A. W., Duncan, S. H., McWilliam Leitch, E. C., Child, M. W. & Flint, H. J. pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon. Appl. Environ. Microbiol. 71, 3692–3700 (2005).
Chung, W. S. et al. Modulation of the human gut microbiota by dietary fibres occurs at the species level. BMC Biol. 14, 3 (2016).
Bown, R. L., Gibson, J. A., Sladen, G. E., Hicks, B. & Dawson, A. M. Effects of lactulose and other laxatives on ileal and colonic pH as measured by a radiotelemetry device. Gut 15, 999–1004 (1974).
Kettle, H., Louis, P., Holtrop, G., Duncan, S. H. & Flint, H. J. Modelling the emergent dynamics and major metabolites of the human colonic microbiota. Environ. Microbiol. 17, 1615–1630 (2015).