Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).
This article is the first catalogue of the human metagenome.
Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).
This paper reports that the diversity of the gut microbiota differs between lean and obese individuals.
Sjogren, K. et al. The gut microbiota regulates bone mass in mice. J. Bone Miner. Res. 27, 1357–1367 (2012).
Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).
This article reports a link between the gut microbiota and adiposity.
Reinhardt, C. et al. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 483, 627–631 (2012).
Stappenbeck, T. S., Hooper, L. V. & Gordon, J. I. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc. Natl Acad. Sci. USA 99, 15451–15455 (2002).
Larsson, E. et al. Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88. Gut 61, 1124–1131 (2011).
Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).
Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).
Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).
Furet, J. P. et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 59, 3049–3057 (2010).
Duncan, S. H. et al. Human colonic microbiota associated with diet, obesity and weight loss. Int. J. Obes. (Lond.) 32, 1720–1724 (2008).
Schwiertz, A. et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity 18, 190–195 (2010).
Zhang, H. et al. Human gut microbiota in obesity and after gastric bypass. Proc. Natl Acad. Sci. USA 106, 2365–2370 (2009).
Sjostrom, L. et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N. Engl. J. Med. 351, 2683–2693 (2004).
Sjostrom, L. et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 357, 741–752 (2007).
Cani, P. D. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008).
Membrez, M. et al. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J. 22, 2416–2426 (2008).
Caesar, R. et al. Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Gut http://dx.doi.org/10.1136/gutjnl-2011-301689 (25 April, 2012).
Bergman, E. N. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol. Rev. 70, 567–590 (1990).
Samuel, B. S. & Gordon, J. I. A humanized gnotobiotic mouse model of host–archaeal–bacterial mutualism. Proc. Natl Acad. Sci. USA 103, 10011–10016 (2006).
Hoverstad, T. & Midtvedt, T. Short-chain fatty acids in germfree mice and rats. J. Nutr. 116, 1772–1776 (1986).
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).
Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).
This article demonstrates that the microbiota of those who are obese is enriched in genes for energy harvest and that obesity can be transmitted by transplantation of microbiota.
Nair, S., Cope, K., Risby, T. H. & Diehl, A. M. Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am. J. Gastroenterol. 96, 1200–1204 (2001).
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).
This article demonstrates the affect of diet in shaping the gut microbiota.
Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011).
Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).
Ramirez-Farias, C. et al. Effect of inulin on the human gut microbiota: stimulation of Bifidobacterium adolescentis and Faecalibacterium prausnitzii. Br. J. Nutr. 101, 541–550 (2009).
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).
Walker, A. W. et al. Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J. 5, 220–230 (2010).
Robertson, M. D., Bickerton, A. S., Dennis, A. L., Vidal, H. & Frayn, K. N. Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism. Am. J. Clin. Nutr. 82, 559–567 (2005).
Hildebrandt, M. A. et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 137, 1716–1724 (2009).
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).
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).
Xu, J. et al. A genomic view of the human–Bacteroides thetaiotaomicron symbiosis. Science 299, 2074–2076 (2003).
Martens, E. C. et al. Recognition and degradation of plant cell wall polysaccharides by two human gut symbionts. PLoS Biol. 9, e1001221 (2011).
Donohoe, D. R. et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 13, 517–526 (2011).
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).
Velagapudi, V. R. et al. The gut microbiota modulates host energy and lipid metabolism in mice. J. Lipid Res. 51, 1101–1112 (2010).
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).
Sina, C. et al. G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J. Immunol. 183, 7514–7522 (2009).
Tolhurst, G. et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61, 364–371 (2012).
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).
Wostmann, B. S. Intestinal bile acids and cholesterol absorption in the germfree rat. J. Nutr. 103, 982–990 (1973).
Swann, J. R. et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc. Natl Acad. Sci. USA 108, 4523–4530 (2010).
Gustafsson, B. E., Bergstrom, S., Lindstedt, S. & Norman, A. Turnover and nature of fecal bile acids in germfree and infected rats fed cholic acid-24–14C; bile acids and steroids 41. Proc. Soc. Exp. Biol. Med. 94, 467–471 (1957).
Hylemon, P. B. et al. Bile acids as regulatory molecules. J. Lipid Res. 50, 1509–1520 (2009).
Sinal, C. J. et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102, 731–744 (2000).
van Dijk, T. H. et al. An increased flux through the glucose 6-phosphate pool in enterocytes delays glucose absorption in Fxr−/− mice. J. Biol. Chem. 284, 10315–10323 (2009).
Prawitt, J. et al. Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes 60, 1861–1871 (2011).
Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10, 167–177 (2009).
Watanabe, M. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484–489 (2006).
Vance, D. E. Role of phosphatidylcholine biosynthesis in the regulation of lipoprotein homeostasis. Curr. Opin. Lipidol. 19, 229–234 (2008).
Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).
This paper elegantly connects microbial recognition by inflammasomes in the gut with altered permeability and liver steatosis.
Spencer, M. D. et al. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology 140, 976–986 (2011).
Dumas, M. E. et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc. Natl Acad. Sci. USA 103, 12511–12516 (2006).
Prentiss, P. G. et al. The metabolism of choline by the germfree rat. Arch. Biochem. Biophys. 94, 424–429 (1961).
Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).
Osborn, O. & Olefsky, J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nature Med. 18, 363–374 (2012).
Creely, S. J. et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 292, E740–E747 (2007).
Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).
This paper reports that endotoxin is sufficient to alter metabolic inflammation and insulin sensitivity.
Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nature Med. 15, 914–920 (2009).
Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nature Med. 15, 921–929 (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).
Amar, J. et al. Energy intake is associated with endotoxemia in apparently healthy men. Am. J. Clin. Nutr. 87, 1219–1223 (2008).
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).
Wei, X. et al. Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin 2. Cell Host Microbe 11, 140–152 (2012).
Gummesson, A. et al. Intestinal permeability is associated with visceral adiposity in healthy women. Obesity 19, 2280–2282 (2011).
Amar, J. et al. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia 54, 3055–3061 (2011).
Amar, J. et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol. Med. 3, 559–572 (2011).
Schertzer, J. D. et al. NOD1 activators link innate immunity to insulin resistance. Diabetes 60, 2206–2215 (2011).
Saberi, M. et al. Hematopoietic cell-specific deletion of Toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab. 10, 419–429 (2009).
Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).
Strowig, T., Henao-Mejia, J., Elinav, E. & Flavell, R. Inflammasomes in health and disease. Nature 481, 278–286 (2012).
Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature Med. 17, 179–188 (2011).
Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).
Murphy, E. F. et al. Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity. Gut http://dx.doi.org/10.1136/gutjnl-2011-300705 (16 February, 2012).
Eiseman, B., Silen, W., Bascom, G. S. & Kauvar, A. J. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 44, 854–859 (1958).
Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in subjects with metabolic syndrome. Gastroenterology http://dx.doi.org/10.1053/j.gastro.2012.06.031 (20 June, 2012).
This article reports that insulin resistance in obese humans can be improved by transplantation of a lean microbiota.
Food and Agriculture Organization of the United Nations and World Health Organization. Working Group Report on Drafting Guidelines for the evaluation of Probiotics in Food. ftp://ftp.fao.org/es/esn/food/wgreport2.pdf (FAO and WHO, 2002).
Roberfroid, M. et al. Prebiotic effects: metabolic and health benefits. Br. J. Nutr. 104, S1–S63 (2010).