The gut microbiota — masters of host development and physiology

Nature Reviews Microbiology - Tập 11 Số 4 - Trang 227-238 - 2013
Felix Sommer1, Fredrik Bäckhed1
1Department of Molecular and Clinical Medicine, Wallenberg Laboratory for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, SE-413 45, Sweden

Tóm tắt

Từ khóa


Tài liệu tham khảo

Clemente, J. C., Ursell, L. K., Parfrey, L. W. & Knight, R. The impact of the gut microbiota on human health: an integrative view. Cell 148, 1258–1270 (2012).

Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012). A detailed catalogue of the human gut microbiome.

Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010). The first catalogue of the human microbiome.

Sekirov, I., Russell, S. L., Antunes, L. C. & Finlay, B. B. Gut microbiota in health and disease. Physiol. Rev. 90, 859–904 (2010).

Sina, C. et al. Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice. Gut 22 Mar 2012 (doi:10.1136/gutjnl-2011-300076).

Swidsinski, A., Loening-Baucke, V., Lochs, H. & Hale, L. P. Spatial organization of bacterial flora in normal and inflamed intestine: a fluorescence in situ hybridization study in mice. World J. Gastroenterol. 11, 1131–1140 (2005).

Xu, J. & Gordon, J. I. Honor thy symbionts. Proc. Natl Acad. Sci. USA 100, 10452–10459 (2003).

Human Microbiome Project Consortium. A framework for human microbiome research. Nature 486, 215–221 (2012).

Gill, S. R. et al. Metagenomic analysis of the human distal gut microbiome. Science 312, 1355–1359 (2006).

Smith, K., McCoy, K. D. & Macpherson, A. J. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin. Immunol. 19, 59–69 (2007).

Sjogren, K. et al. The gut microbiota regulates bone mass in mice. J. Bone Miner. Res. 27, 1357–1367 (2012). A study demonstrating that the gut microbiota affects bone mass, possibly by inhibiting osteoclastogenesis through modulation of the T cell profile.

Lederberg, J. Infectious history. Science 288, 287–293 (2000).

Arrieta, M. C. & Finlay, B. B. The commensal microbiota drives immune homeostasis. Front. Immunol. 3, 33 (2012).

McFall-Ngai, M. Adaptive immunity: care for the community. Nature 445, 153 (2007).

Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

O'Hara, A. M. & Shanahan, F. The gut flora as a forgotten organ. EMBO Rep. 7, 688–693 (2006).

Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008). An article showing that the inner mucus layer shields the intestinal epithelium from bacterial contact.

Johansson, M. E., Larsson, J. M. & Hansson, G. C. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host–microbial interactions. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4659–4665 (2011).

Juge, N. Microbial adhesins to gastrointestinal mucus. Trends Microbiol. 20, 30–39 (2012).

Derrien, M. et al. Mucin-bacterial interactions in the human oral cavity and digestive tract. Gut Microbes 1, 254–268 (2010).

Ambort, D. et al. Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin. Proc. Natl Acad. Sci. USA 109, 5645–5650 (2012).

Sharma, R., Schumacher, U., Ronaasen, V. & Coates, M. Rat intestinal mucosal responses to a microbial flora and different diets. Gut 36, 209–214 (1995).

Petersson, J. et al. Importance and regulation of the colonic mucus barrier in a mouse model of colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G327–G333 (2011).

An, G. et al. Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans. J. Exp. Med. 204, 1417–1429 (2007).

Fu, J. et al. Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J. Clin. Invest. 121, 1657–1666 (2011).

van de Pavert, S. A. & Mebius, R. E. New insights into the development of lymphoid tissues. Nature Rev. Immunol. 10, 664–674 (2010).

Mebius, R. E. Organogenesis of lymphoid tissues. Nature Rev. Immunol. 3, 292–303 (2003).

Renz, H., Brandtzaeg, P. & Hornef, M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nature Rev. Immunol. 12, 9–23 (2012).

Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nature Rev. Immunol. 9, 313–323 (2009).

Kanamori, Y. et al. Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors develop. J. Exp. Med. 184, 1449–1459 (1996).

Eberl, G. Inducible lymphoid tissues in the adult gut: recapitulation of a fetal developmental pathway? Nature Rev. Immunol. 5, 413–420 (2005).

Eberl, G. & Littman, D. R. Thymic origin of intestinal αβ T cells revealed by fate mapping of RORγt+ cells. Science 305, 248–251 (2004).

Hamada, H. et al. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J. Immunol. 168, 57–64 (2002).

Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008). A study which reveals that microbial induction of ileal lymphoid follicles is mediated via peptidoglycans that are recognized mainly by the intracellular NOD1 receptor.

Cupedo, T. et al. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nature Immunol. 10, 66–74 (2009).

Luci, C. et al. Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin. Nature Immunol. 10, 75–82 (2009).

Sanos, S. L. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nature Immunol. 10, 83–91 (2009).

Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14, 282–289 (2008).

Cohen, N. R., Garg, S. & Brenner, M. B. Antigen presentation by CD1 lipids, T cells, and NKT cells in microbial immunity. Adv. Immunol. 102, 1–94 (2009).

Van Kaer, L., Parekh, V. V. & Wu, L. Invariant natural killer T cells: bridging innate and adaptive immunity. Cell Tissue Res. 343, 43–55 (2011).

Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012). An elegant study demonstrating that the gut microbiota is required for normal development of iNKT cells in neonates and thereby protects from inflammatory diseases, thus confirming the hygiene hypothesis.

Kieper, W. C. et al. Recent immune status determines the source of antigens that drive homeostatic T cell expansion. J. Immunol. 174, 3158–3163 (2005).

Smith, P. M. & Garrett, W. S. The gut microbiota and mucosal T cells. Front. Microbiol. 2, 111 (2011).

Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nature Rev. Immunol. 10, 159–169 (2010).

Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).

Maynard, C. L. et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10. Nature Immunol. 8, 931–941 (2007).

Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (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).

Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4615–4622 (2011).

Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004).

Uematsu, S. et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nature Immunol. 9, 769–776 (2008).

Macpherson, A. J. et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226 (2000).

Kawamoto, S. et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science 336, 485–489 (2012). An article which shows that the gut microbiota is required for the development of completely functional IgA-producing cells and thereby maintains microbial homeostasis in the intestine.

Gallo, R. L. & Hooper, L. V. Epithelial antimicrobial defence of the skin and intestine. Nature Rev. Immunol. 12, 503–516 (2012).

Putsep, K. et al. Germ-free and colonized mice generate the same products from enteric prodefensins. J. Biol. Chem. 275, 40478–40482 (2000).

Cash, H. L., Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006).

Hooper, L. V., Stappenbeck, T. S., Hong, C. V. & Gordon, J. I. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nature Immunol. 4, 269–273 (2003).

Franchi, L. et al. NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nature Immunol. 13, 449–456 (2012). Work revealing that intestinal phagocytes discriminate commensals from pathogens using the intracellular NLRC4 (NOD-, LRR- and CARD-containing 4) inflammasome and by being hyporesponsive to commensal-derived TLR stimuli.

Schauber, J. et al. Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways. Gut 52, 735–741 (2003).

Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).

Petnicki-Ocwieja, T. et al. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc. Natl Acad. Sci. USA 106, 15813–15818 (2009).

Salzman, N. H. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nature Immunol. 11, 76–83 (2010).

Vaishnava, S. et al. The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258 (2011).

Shin, S. C. et al. Drosophila microbiome modulates host developmental and metabolic homeostasis via insulin signaling. Science 334, 670–674 (2011). A detailed analysis revealing the molecular pathway of a symbiotic interaction between the fruit fly and one of its gut bacteria; this interaction is required for a normal developmental rate, body size, wing area and metabolism, as well as for normal stem cell activity.

Koropatnick, T. A. et al. Microbial factor-mediated development in a host-bacterial mutualism. Science 306, 1186–1188 (2004).

Troll, J. V. et al. Peptidoglycan induces loss of a nuclear peptidoglycan recognition protein during host tissue development in a beneficial animal–bacterial symbiosis. Cell. Microbiol. 11, 1114–1127 (2009).

McFall-Ngai, M. Host-microbe symbiosis: the squid-Vibrio association—a naturally occurring, experimental model of animal/bacterial partnerships. Adv. Exp. Med. Biol. 635, 102–112 (2008).

Wagner, C. L., Taylor, S. N. & Johnson, D. Host factors in amniotic fluid and breast milk that contribute to gut maturation. Clin. Rev. Allergy Immunol. 34, 191–204 (2008).

Reinhardt, C., Reigstad, C. S. & Bäckhed, F. Intestinal microbiota during infancy and its implications for obesity. J. Pediatr. Gastroenterol. Nutr. 48, 249–256 (2009).

Wostmann, B. S. The germfree animal in nutritional studies. Annu. Rev. Nutr. 1, 257–279 (1981).

Gordon, H. A. & Bruckner-Kardoss, E. Effect of normal microbial flora on intestinal surface area. Am. J. Physiol. 201, 175–178 (1961).

Abrams, G. D., Bauer, H. & Sprinz, H. Influence of the normal flora on mucosal morphology and cellular renewal in the ileum. A comparison of germ-free and conventional mice. Lab. Invest. 12, 355–364 (1963).

Reinhardt, C. et al. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 483, 627–631 (2012). An investigation which demonstrates that bacteria promote vessel formation in the intestinal epithelium by modulating tissue factor signalling.

Banasaz, M., Norin, E., Holma, R. & Midtvedt, T. Increased enterocyte production in gnotobiotic rats mono-associated with Lactobacillus rhamnosus GG. Appl. Environ. Microbiol. 68, 3031–3034 (2002).

Alam, M., Midtvedt, T. & Uribe, A. Differential cell kinetics in the ileum and colon of germfree rats. Scand. J. Gastroenterol. 29, 445–451 (1994).

Wikoff, W. R. et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl Acad. Sci. USA 106, 3698–3703 (2009).

Husebye, E., Hellstrom, P. M. & Midtvedt, T. Intestinal microflora stimulates myoelectric activity of rat small intestine by promoting cyclic initiation and aboral propagation of migrating myoelectric complex. Dig. Dis. Sci. 39, 946–956 (1994).

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).

Hooper, L. V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001).

Lutgendorff, F., Akkermans, L. M. & Soderholm, J. D. The role of microbiota and probiotics in stress-induced gastro-intestinal damage. Curr. Mol. Med. 8, 282–298 (2008).

Cario, E., Gerken, G. & Podolsky, D. K. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132, 1359–1374 (2007).

Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).

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).

Buchon, N., Broderick, N. A., Chakrabarti, S. & Lemaitre, B. Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes Dev. 23, 2333–2344 (2009).

Crawford, P. A. & Gordon, J. I. Microbial regulation of intestinal radiosensitivity. Proc. Natl Acad. Sci. USA 102, 13254–13259 (2005).

Savage, D. C., Siegel, J. E., Snellen, J. E. & Whitt, D. D. Transit time of epithelial cells in the small intestines of germfree mice and ex-germfree mice associated with indigenous microorganisms. Appl. Environ. Microbiol. 42, 996–1001 (1981).

Blumberg, R. & Powrie, F. Microbiota, disease, and back to health: a metastable journey. Sci. Transl. Med. 4, 137rv7 (2012).

Hope, M. E., Hold, G. L., Kain, R. & El-Omar, E. M. Sporadic colorectal cancer – role of the commensal microbiota. FEMS Microbiol. Lett. 244, 1–7 (2005).

Swidsinski, A. et al. Association between intraepithelial Escherichia coli and colorectal cancer. Gastroenterology 115, 281–286 (1998).

Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).

Sanapareddy, N. et al. Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans. ISME J. 6, 1858–1868 (2012).

Uronis, J. M. & Jobin, C. Microbes and colorectal cancer: is there a relationship? Curr. Oncol. 16, 22–24 (2009).

Dove, W. F. et al. Intestinal neoplasia in the ApcMin mouse: independence from the microbial and natural killer (beige locus) status. Cancer Res. 57, 812–814 (1997).

Breuer, N. & Goebell, H. The role of bile acids in colonic carcinogenesis. Klin. Wochenschr. 63, 97–105 (1985).

Toprak, N. U. et al. A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin. Microbiol. Infect. 12, 782–786 (2006).

Abdulamir, A. S., Hafidh, R. R. & Abu Bakar, F. The association of Streptococcus bovis/gallolyticus with colorectal tumors: the nature and the underlying mechanisms of its etiological role. J. Exp. Clin. Cancer Res. 30, 11 (2011).

Kostic, A. D. et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 22, 292–298 (2012).

Del Fattore, A., Teti, A. & Rucci, N. Bone cells and the mechanisms of bone remodelling. Front. Biosci. (Elite Ed.) 4, 2302–2321 (2012).

Bliziotes, M. et al. Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells. Bone 39, 1313–1321 (2006).

Yadav, V. K. et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135, 825–837 (2008).

Kong, Y. Y. et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304–309 (1999).

Sato, K. et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 203, 2673–2682 (2006).

Wei, S., Kitaura, H., Zhou, P., Ross, F. P. & Teitelbaum, S. L. IL-1 mediates TNF-induced osteoclastogenesis. J. Clin. Invest. 115, 282–290 (2005).

Zwerina, J. et al. TNF-induced structural joint damage is mediated by IL-1. Proc. Natl Acad. Sci. USA 104, 11742–11747 (2007).

Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).

Ley, R. E. Obesity and the human microbiome. Curr. Opin. Gastroenterol. 26, 5–11 (2010).

Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

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 metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012). A report which reveals that there are alterations in the gut microbiome in Chinese patients with type 2 diabetes, and that these alterations can predict the occurrence of diabetes.

Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004). The first demonstration that the gut microbiota modulates adiposity.

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).

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).

Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).

Karlsson, F. H. et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nature Commun. 3, 1245 (2012).

Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).

Tremaroli, V. & Bäckhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).

Koch, H. & Schmid-Hempel, P. Socially transmitted gut microbiota protect bumble bees against an intestinal parasite. Proc. Natl Acad. Sci. USA 108, 19288–19292 (2011).

Boettcher, K. J., Ruby, E. G. & McFall-Ngai, M. J. Bioluminescence in the symbiotic squid Euprymna scolopes is controlled by a daily biological rhythm. J. Comp. Physiol. A Neuroethol. Sens. Neural Behav. Physiol. 179, 65–73 (1996).

Degnan, P. H. et al. Factors associated with the diversification of the gut microbial communities within chimpanzees from Gombe National Park. Proc. Natl Acad. Sci. USA 109, 13034–13039 (2012).

Sharon, G. et al. Commensal bacteria play a role in mating preference of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 107, 20051–20056 (2010).

Huang, Y., Callahan, S. & Hadfield, M. G. Recruitment in the sea: bacterial genes required for inducing larval settlement in a polychaete worm. Sci. Rep. 2, 228 (2012).

Verhulst, N. O. et al. Composition of human skin microbiota affects attractiveness to malaria mosquitoes. PLoS ONE 6, e28991 (2011).

Forsythe, P. & Kunze, W. A. Voices from within: gut microbes and the CNS. Cell. Mol. Life Sci. 70, 55–69 (2012).

Amaral, F. A. et al. Commensal microbiota is fundamental for the development of inflammatory pain. Proc. Natl Acad. Sci. USA 105, 2193–2197 (2008).

Sudo, N. et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J. Physiol. 558, 263–275 (2004).

Bercik, P. et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141, 599–609 (2011).

Lyte, M., Li, W., Opitz, N., Gaykema, R. P. & Goehler, L. E. Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium. Physiol. Behav. 89, 350–357 (2006).

Heijtz, R. D. et al. Normal gut microbiota modulates brain development and behavior. Proc. Natl Acad. Sci. USA 108, 3047–3052 (2011). The finding that the gut microbiota affects the development of the brain and anxiety-like behaviour.

Neufeld, K. M., Kang, N., Bienenstock, J. & Foster, J. A. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255–e119 (2011).

Diamond, B., Huerta, P. T., Tracey, K. & Volpe, B. T. It takes guts to grow a brain: increasing evidence of the important role of the intestinal microflora in neuro- and immune-modulatory functions during development and adulthood. Bioessays 33, 588–591 (2011).

Collins, S. M., Surette, M. & Bercik, P. The interplay between the intestinal microbiota and the brain. Nature Rev. Microbiol. 10, 735–742 (2012).

Kellermayer, R. et al. Colonic mucosal DNA methylation, immune response, and microbiome patterns in Toll-like receptor 2-knockout mice. FASEB J. 25, 1449–1460 (2011).

Ley, R. E. et al. Evolution of mammals and their gut microbes. Science 320, 1647–1651 (2008).

Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).

Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012). An extensive analysis of the gut microbiome of healthy children and adults from three different geographical regions.

Koboziev, I., Karlsson, F. & Grisham, M. B. Gut-associated lymphoid tissue, T cell trafficking, and chronic intestinal inflammation. Ann. NY Acad. Sci. 1207 (Suppl. 1), e86–e93 (2010).

Veenbergen, S. & Samsom, J. N. Maintenance of small intestinal and colonic tolerance by IL-10-producing regulatory T cell subsets. Curr. Opin. Immunol. 24, 269–276 (2012).

Walker, J. A., Barlow, J. L. & McKenzie, A. N. Innate lymphoid cells - how did we miss them? Nature Rev. Immunol. 13, 75–87 (2013).