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

2 Renz, H., Brandtzaeg, P. & Hornef, M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nature Rev. Immunol. 12, 9–23 (2011).

3 Stecher, B. & Hardt, W. D. Mechanisms controlling pathogen colonization of the gut. Curr. Opin. Microbiol. 14, 82–91 (2011).

4 Littman, D. R. & Pamer, E. G. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 10, 311–323 (2011).

5 Honda, K. & Littman, D. R. The microbiome in infectious disease and inflammation. Annu. Rev. Immunol. 30, 759–795 (2012).

6 Gordon, H. A., Bruckner-Kardoss, E. & Wostmann, B. S. Aging in germ-free mice: life tables and lesions observed at natural death. J. Gerontol. 21, 380–387 (1966).

7 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).

8 Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).

9 Moreau, M. C. & Corthier, G. Effect of the gastrointestinal microflora on induction and maintenance of oral tolerance to ovalbumin in C3H/HeJ mice. Infect. Immun. 56, 2766–2768 (1988).

10 Pabst, O. et al. Adaptation of solitary intestinal lymphoid tissue in response to microbiota and chemokine receptor CCR7 signaling. J. Immunol. 177, 6824–6832 (2006).

11 Littman, D. R. & Rudensky, A. Y. Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140, 845–858 (2010).

12 Atarashi, K. et al. ATP drives lamina propria TH17 cell differentiation. Nature 455, 808–812 (2008).

13 Ivanov, I. I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337–349 (2008).

14 Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009). This study identifies SFB as a main driver of intestinal T H 17 cell differentiation, which can protect the host against enteric pathogen infection.

15 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).

16 Shaw, M. H., Kamada, N., Kim, Y. G. & Nunez, G. Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine. J. Exp. Med. 209, 251–258 (2012).

17 Chung, H. et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell 149, 1578–1593 (2012).

18 Powrie, F., Leach, M. W., Mauze, S., Caddle, L. B. & Coffman, R. L. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int. Immunol. 5, 1461–1471 (1993).

19 Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011). In this study, the authors identify a cocktail of 46 strains of Clostridium spp. that efficiently induce the development of peripherally derived FOXP3+ T Reg cells in the colon, which are important for preventing intestinal inflammation and allergy.

20 Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011).

21 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).

22 Fagarasan, S., Kawamoto, S., Kanagawa, O. & Suzuki, K. Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol. 28, 243–273 (2010).

23 Strugnell, R. A. & Wijburg, O. L. The role of secretory antibodies in infection immunity. Nature Rev. Microbiol. 8, 656–667 (2010).

24 Macpherson, A. J., Geuking, M. B. & McCoy, K. D. Homeland security: IgA immunity at the frontiers of the body. Trends Immunol. 33, 160–167 (2012).

25 Fagarasan, S. et al. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science 298, 1424–1427 (2002). This report shows that intestinal IgA responses can shape the commensal bacterial community.

26 Wei, M. et al. Mice carrying a knock-in mutation of Aicda resulting in a defect in somatic hypermutation have impaired gut homeostasis and compromised mucosal defense. Nature Immunol. 12, 264–270 (2011).

27 Peterson, D. A., McNulty, N. P., Guruge, J. L. & Gordon, J. I. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2, 328–339 (2007).

28 Suzuki, K. et al. The sensing of environmental stimuli by follicular dendritic cells promotes immunoglobulin A generation in the gut. Immunity 33, 71–83 (2010).

29 Mora, J. R. et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314, 1157–1160 (2006).

30 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).

31 Tezuka, H. et al. Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature 448, 929–933 (2007).

32 Tezuka, H. et al. Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction. Immunity 34, 247–257 (2011).

33 Fritz, J. H. et al. Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut. Nature 481, 199–203 (2011).

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

35 Sonnenberg, G. F. & Artis, D. Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 37, 601–610 (2012).

36 Cella, M. et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009). In this report, the authors identify IL-22-producing ILC3s in mucosal tissues, including the intestine, in both mice and humans.

37 Spits, H. & Di Santo, J. P. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nature Immunol. 12, 21–27 (2011).

38 Satoh-Takayama, N. et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29, 958–970 (2008).

39 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).

40 Sawa, S. et al. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nature Immunol. 12, 320–326 (2011).

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

42 Vaishnava, S. et al. The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258 (2011). In this study, the authors demonstrate that bacterial stimuli from commensal microbiota promote the production of the antimicrobial molecule REGIIIγ by the epithelium in a MYD88-dependent process. REGIIIγ functions as an additional barrier against the microbiota.

43 Sonnenberg, G. F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012).

44 Osawa, N. & Mitsuhashi, S. Infection of germfree mice with Shigella flexneri 3A. Jpn J. Exp. Med. 34, 77–80 (1964).

45 Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011).

46 Bohnhoff, M., Drake, B. L. & Miller, C. P. Effect of streptomycin on susceptibility of intestinal tract to experimental Salmonella infection. Proc. Soc. Exp. Biol. Med. 86, 132–137 (1954).

47 Hentges, D. J. & Freter, R. In vivo and in vitro antagonism of intestinal bacteria against Shigella flexneri I. Correlation between various tests. J. Infect. Dis. 110, 30–37 (1962).

48 Lawley, T. D. et al. Antibiotic treatment of Clostridium difficile carrier mice triggers a supershedder state, spore-mediated transmission, and severe disease in immunocompromised hosts. Infect. Immun. 77, 3661–3669 (2009).

49 Rupnik, M., Wilcox, M. H. & Gerding, D. N. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nature Rev. Microbiol. 7, 526–536 (2009).

50 Momose, Y., Hirayama, K. & Itoh, K. Competition for proline between indigenous Escherichia coli and E. coli O157:H7 in gnotobiotic mice associated with infant intestinal microbiota and its contribution to the colonization resistance against E. coli O157:H7. Antonie Van Leeuwenhoek 94, 165–171 (2008).

51 Momose, Y., Hirayama, K. & Itoh, K. Effect of organic acids on inhibition of Escherichia coli O157:H7 colonization in gnotobiotic mice associated with infant intestinal microbiota. Antonie Van Leeuwenhoek 93, 141–149 (2008).

52 Fabich, A. J. et al. Comparison of carbon nutrition for pathogenic and commensal Escherichia coli strains in the mouse intestine. Infect. Immun. 76, 1143–1152 (2008).

53 Leatham, M. P. et al. Precolonized human commensal Escherichia coli strains serve as a barrier to E. coli O157:H7 growth in the streptomycin-treated mouse intestine. Infect. Immun. 77, 2876–2886 (2009).

54 Kamada, N. et al. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science 336, 1325–1329 (2012). This study demonstrates the importance of commensal bacteria in eradicating pathogens by competing for shared nutrients. The expression of virulence factors by the pathogen allows it to localize to the epithelium as a means of escaping nutritional competition by the microbiota.

55 Endt, K. et al. The microbiota mediates pathogen clearance from the gut lumen after non-typhoidal Salmonella diarrhea. PLoS Pathog. 6, e1001097 (2010).

56 Pacheco, A. R. et al. Fucose sensing regulates bacterial intestinal colonization. Nature 492, 113–117 (2012).

57 Le Bouguenec, C. & Schouler, C. Sugar metabolism, an additional virulence factor in enterobacteria. Int. J. Med. Microbiol. 301, 1–6 (2010).

58 Bertin, Y. et al. Enterohaemorrhagic Escherichia coli gains a competitive advantage by using ethanolamine as a nitrogen source in the bovine intestinal content. Environ. Microbiol. 13, 365–377 (2011).

59 Winter, S. E. et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429 (2010). This study demonstrates that an enteric pathogen acquires a growth advantage in the presence of intestinal inflammation. Pathogen-induced inflammation promotes neutrophil recruitment and the conversion of a commensal metabolite to a form that can be used by the pathogen.

60 Thiennimitr, P. et al. Intestinal inflammation allows Salmonella to use ethanolamine to compete with the microbiota. Proc. Natl Acad. Sci. USA 108, 17480–17485 (2011).

61 Murdoch, S. L. et al. The opportunistic pathogen Serratia marcescens utilizes type VI secretion to target bacterial competitors. J. Bacteriol. 193, 6057–6069 (2011).

62 Gueguen, E. & Cascales, E. Promoter swapping unveils the role of the Citrobacter rodentium CTS1 type VI secretion system in interbacterial competition. Appl. Environ. Microbiol. 79, 32–38 (2013).

63 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).

64 Bergstrom, K. S. et al. Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathog. 6, e1000902 (2010).

65 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 (2010).

66 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).

67 Brandl, K., Plitas, G., Schnabl, B., DeMatteo, R. P. & Pamer, E. G. MyD88-mediated signals induce the bactericidal lectin RegIIIγ and protect mice against intestinal Listeria monocytogenes infection. J. Exp. Med. 204, 1891–1900 (2007).

68 Dessein, R. et al. Toll-like receptor 2 is critical for induction of Reg3β expression and intestinal clearance of Yersinia pseudotuberculosis. Gut 58, 771–776 (2009).

69 van Ampting, M. T. et al. Intestinally secreted C-type lectin Reg3β attenuates salmonellosis but not listeriosis in mice. Infect. Immun. 80, 1115–1120 (2012).

70 Denning, T. L., Wang, Y. C., Patel, S. R., Williams, I. R. & Pulendran, B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nature Immunol. 8, 1086–1094 (2007).

71 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). This study demonstrates that NLRC4 selectively recognizes pathogenic, but not commensal, bacteria and that it promotes protective immunity against pathogens via induction of mature IL-1β.

72 Kamada, N. et al. Abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria. J. Immunol. 175, 6900–6908 (2005).

73 Kiss, E. A. et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011).

74 Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2012).

75 Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012).

76 Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008). In this study, the authors report that a human commensal bacterium, B. fragilis , protects against pathobiont-induced intestinal inflammation, and that the PSA in its capsule is sufficient for this protection. Specifically, PSA induces IL-10 production from CD4+ T cells that protect against intestinal inflammation.

77 O'Mahony, C. et al. Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-κB activation. PLoS Pathog. 4, e1000112 (2008).

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

79 Lathrop, S. K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011).

80 Hand, T. W. et al. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science 337, 1553–1556 (2012).

81 Slack, E. et al. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science 325, 617–620 (2009).

82 Fagundes, C. T. et al. Transient TLR activation restores inflammatory response and ability to control pulmonary bacterial infection in germfree mice. J. Immunol. 188, 1411–1420 (2012).

83 Clarke, T. B. et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nature Med. 16, 228–231 (2010).

84 Ichinohe, T. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl Acad. Sci. USA 108, 5354–5359 (2011).

85 Abt, M. C. et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37, 158–170 (2012).

86 Ganal, S. C. et al. Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity 37, 171–186 (2012).

87 Benson, A., Pifer, R., Behrendt, C. L., Hooper, L. V. & Yarovinsky, F. Gut commensal bacteria direct a protective immune response against Toxoplasma gondii. Cell Host Microbe 6, 187–196 (2009).

88 Naik, S. et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115–1119 (2012).

89 Giel, J. L., Sorg, J. A., Sonenshein, A. L. & Zhu, J. Metabolism of bile salts in mice influences spore germination in Clostridium difficile. PLoS ONE 5, e8740 (2010).

90 Kane, M. et al. Successful transmission of a retrovirus depends on the commensal microbiota. Science 334, 245–249 (2011).

91 Kuss, S. K. et al. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science 334, 249–252 (2011).

92 Sellon, R. K. et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun. 66, 5224–5231 (1998).

93 Dianda, L. et al. T cell receptor-α β-deficient mice fail to develop colitis in the absence of a microbial environment. Am. J. Pathol. 150, 91–97 (1997).

94 Taurog, J. D. et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J. Exp. Med. 180, 2359–2364 (1994).

95 Rath, H. C., Wilson, K. H. & Sartor, R. B. Differential induction of colitis and gastritis in HLA-B27 transgenic rats selectively colonized with Bacteroides vulgatus or Escherichia coli. Infect. Immun. 67, 2969–2974 (1999).

96 Schultz, M. et al. IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation. Am. J. Physiol. 276, G1461–G1472 (1999).

97 Bamias, G. et al. Commensal bacteria exacerbate intestinal inflammation but are not essential for the development of murine ileitis. J. Immunol. 178, 1809–1818 (2007).

98 Kobayashi, M. et al. Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice. J. Clin. Invest. 111, 1297–1308 (2003).

99 Rakoff-Nahoum, S., Hao, L. & Medzhitov, R. Role of Toll-like receptors in spontaneous commensal-dependent colitis. Immunity 25, 319–329 (2006).

100 Hoshi, N. et al. MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice. Nature Commun. 3, 1120 (2012).

101 Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).

102 Smythies, L. E. et al. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J. Clin. Invest. 115, 66–75 (2005).

103 Kamada, N. et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis. J. Clin. Invest. 118, 2269–2280 (2008).

104 Cho, J. H. The genetics and immunopathogenesis of inflammatory bowel disease. Nature Rev. Immunol. 8, 458–466 (2008).

105 Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

106 Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

107 Inohara, N. et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J. Biol. Chem. 278, 5509–5512 (2003).

108 Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genet. 39, 207–211 (2007).

109 Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nature Genet. 39, 830–832 (2007).

110 Travassos, L. H. et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nature Immunol. 11, 55–62 (2010).

111 Cooney, R. et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Med. 16, 90–97 (2010).

112 Homer, C. R., Richmond, A. L., Rebert, N. A., Achkar, J. P. & McDonald, C. ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn's disease pathogenesis. Gastroenterology 139, 1630–1641. e2 (2010).

113 Bevins, C. L. & Salzman, N. H. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nature Rev. Microbiol. 9, 356–368 (2011).

114 Ogura, Y. et al. Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis. Gut 52, 1591–1597 (2003).

115 Wehkamp, J. et al. NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal α-defensin expression. Gut 53, 1658–1664 (2004).

116 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).

117 Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).

118 Cadwell, K. et al. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell 141, 1135–1145 (2010).

119 Kim, S. C. et al. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology 128, 891–906 (2005).

120 Waidmann, M. et al. Bacteroides vulgatus protects against Escherichia coli-induced colitis in gnotobiotic interleukin-2-deficient mice. Gastroenterology 125, 162–177 (2003).

121 Bohn, E. et al. Host gene expression in the colon of gnotobiotic interleukin-2-deficient mice colonized with commensal colitogenic or noncolitogenic bacterial strains: common patterns and bacteria strain specific signatures. Inflamm. Bowel Dis. 12, 853–862 (2006).

122 Bloom, S. M. et al. Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease. Cell Host Microbe 9, 390–403 (2011).

123 Garrett, W. S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007). In this study, the authors show that colitogenic pathobionts can accumulate in genetically susceptible mice and can transmit disease to wild-type mice.

124 Garrett, W. S. et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8, 292–300 (2010).

125 Powell, N. et al. The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity 37, 674–684 (2012).

126 Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011). This report demonstrates that impaired NLRP6 signalling and IL-18 production is associated with the development of dysbiosis and the accumulation of potentially colitogenic pathobionts.

127 Couturier-Maillard, A. et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Invest. 123, 700–711 (2013).

128 Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 487, 104–108 (2012). In this study, the authors show that a milk-derived fat diet increases the level of bile acids in the intestine, which results in the accumulation of colitogenic pathobionts in genetically susceptible IBD-prone mice.

129 Lowe, E. L. et al. Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer. PLoS ONE 5, e13027 (2010).

130 Chen, G. Y., Shaw, M. H., Redondo, G. & Nunez, G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res. 68, 10060–10067 (2008).

131 Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nature Med. 15, 1016–1022 (2009).

132 Arthur, J. C. et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338, 120–123 (2012).

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

134 Hajishengallis, G., Darveau, R. P. & Curtis, M. A. The keystone–pathogen hypothesis. Nature Rev. Microbiol. 10, 717–725 (2012).

135 Kitajima, S., Morimoto, M., Sagara, E., Shimizu, C. & Ikeda, Y. Dextran sodium sulfate-induced colitis in germ-free IQI/Jic mice. Exp. Anim. 50, 387–395 (2001).

136 Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).

137 Saha, S. et al. Peptidoglycan recognition proteins protect mice from experimental colitis by promoting normal gut flora and preventing induction of interferon-γ. Cell Host Microbe 8, 147–162 (2010).

138 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).

139 Lee, J. et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nature Cell Biol. 8, 1327–1336 (2006).

140 Kirkland, D. et al. B cell-intrinsic MyD88 signaling prevents the lethal dissemination of commensal bacteria during colonic damage. Immunity 36, 228–238 (2012).

141 Vijay-Kumar, M. et al. Deletion of TLR5 results in spontaneous colitis in mice. J. Clin. Invest. 117, 3909–3921 (2007).

142 Carvalho, F. A. et al. Interleukin-1β (IL-1β) promotes susceptibility of Toll-like receptor 5 (TLR5) deficient mice to colitis. Gut 61, 373–384 (2012).

143 Katakura, K. et al. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J. Clin. Invest. 115, 695–702 (2005).

144 Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).

145 Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).

146 Shen, Y. et al. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 12, 509–520 (2012).

147 Diehl, G. E. et al. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells. Nature 494, 116–120 (2013).

148 Sokol, H. et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl Acad. Sci. USA 105, 16731–16736 (2008).

149 Ochoa-Reparaz, J. et al. Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J. Immunol. 183, 6041–6050 (2009).

150 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, S4615–S4622 (2011).

151 Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).

152 Ochoa-Reparaz, J. et al. A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol. 3, 487–495 (2010).

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

154 Nakae, S. et al. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc. Natl Acad. Sci. USA 100, 5986–5990 (2003).

155 Abdollahi-Roodsaz, S. et al. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J. Clin. Invest. 118, 205–216 (2008).

156 Wen, L. et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109–1113 (2008). This report demonstrates that altered microbial communities in MYD88-deficient NOD mice prevent the development of T1D, which indicates that certain subsets of commensal microbiota might have the capacity to protect against the development of T1D.

157 Ubeda, C. et al. Familial transmission rather than defective innate immunity shapes the distinct intestinal microbiota of TLR-deficient mice. J. Exp. Med. 209, 1445–1456 (2012). This study indicates that differences in bacterial communities in mice that are deficient in individual TLRs or MYD88 are more strongly related to maternal transmission and cage effects than to an inherent genetic susceptibility.

158 Kriegel, M. A. et al. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 108, 11548–11553 (2011).

159 Markle, J. G. et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084–1088 (2013).

160 Hill, D. A. et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nature Med. 18, 538–546 (2012).

161 Bashir, M. E., Louie, S., Shi, H. N. & Nagler-Anderson, C. Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy. J. Immunol. 172, 6978–6987 (2004).

162 Frossard, J. L., Steer, M. L. & Pastor, C. M. Acute pancreatitis. Lancet 371, 143–152 (2008).

163 Tsuji, Y. et al. Sensing of commensal organisms by the intracellular sensor NOD1 mediates experimental pancreatitis. Immunity 37, 326–338 (2012).

164 Lynch, S. V. et al. Cystic fibrosis transmembrane conductance regulator knockout mice exhibit aberrant gastrointestinal microbiota. Gut Microbes 4, 41–47 (2013).

165 Borody, T. J. & Khoruts, A. Fecal microbiota transplantation and emerging applications. Nature Rev. Gastroenterol. Hepatol. 9, 88–96 (2011).

166 Li, X. D. et al. Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis. Proc. Natl Acad. Sci. USA 108, 17390–17395 (2011).