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The role of the immune system in governing host-microbe interactions in the intestine Eric M Brown, Manish Sadarangani & B Brett Finlay AffiliationsCorresponding author Nature Immunology 14, 660–667 (2013) doi:10.1038/ni.2611 Received 15 February 2013 Accepted 11 April 2013 Published online 18 June 2013 The mammalian intestinal tract harbors a diverse community of trillions of microorganisms, which have co-evolved with the host immune system for millions of years. Many of these microorganisms perform functions critical for host physiology, but the host must remain vigilant to control the microbial community so that the symbiotic nature of the relationship is maintained. To facilitate homeostasis, the immune system ensures that the diverse microbial load is tolerated and anatomically contained, while remaining responsive to microbial breaches and invasion. Although the microbiota is required for intestinal immune development, immune responses also regulate the structure and composition of the intestinal microbiota. Here we discuss recent advances in our understanding of these complex interactions and their implications for human health and disease. Xu, J. & Gordon, J.I. Honor thy symbionts. Proc. Natl. Acad. Sci. USA 100, 10452–10459 (2003). CASPubMedArticle Eckburg, P.B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005). This is the first comprehensive study to use a culture-independent approach to describe the composition of the intestinal microbiota in healthy adult humans. ADSISIPubMedArticle Ley, R.E. et al. Evolution of mammals and their gut microbes. Science 320, 1647–1651 (2008). CASADSISIPubMedArticle Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012). CASPubMedArticle Sekirov, I., Russel, S.L., Antunes, L.C.M. & Finlay, B.B. Gut microbiota in health and disease. Physiol. Rev. 90, 859–904 (2010). CASISIPubMedArticle Garrett, W.S., Gordon, J.I. & Glimcher, L.H. Homeostasis and inflammation in the intestine. Cell 140, 859–870 (2010). CASISIPubMedArticle Willing, B.P., Russell, S.L. & Finlay, B.B. Shifting the balance: antibiotic effects on host-microbiota mutualism. Nat. Rev. Microbiol. 9, 233–243 (2011). CASISIPubMedArticle Maslowski, K.M. & Mackay, C.R. Diet, gut microbiota and immune responses. Nat. Immunol. 12, 5–9 (2011). CASISIPubMedArticle Gill, N., Wlodarska, M. & Finlay, B.B. Roadblocks in the gut: barriers to enteric infection. Cell. Microbiol. 13, 660–669 (2011). CASPubMedArticle Willing, B.P., Gill, N. & Finlay, B.B. The role of the immune system in regulating the microbiota. Gut Microbes 1, 213–223 (2010). PubMedArticle Hooper, L.V. & Macpherson, A.J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10, 159–169 (2010). CASISIPubMedArticle Kim, Y.S. & Ho, S.B. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr. Gastroenterol. Rep. 12, 319–330 (2010). PubMedArticle 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). This study provides the first visual evidence of the composition of the mucus layer, highlighting the function of the mucus layer in segregating the microbiota away from the host epithelium. ADSPubMedArticle Wlodarska, M. et al. Antibiotic treatment alters the colonic mucus layer and predisposes the host to exacerbated Citrobacter rodentium–induced colitis. Infect. Immun. 79, 1536–1545 (2011). CASPubMedArticle Fyderek, K. Mucosal bacterial microflora and mucus layer thickness in adolescents with inflammatory bowel disease. World J. Gastroenterol. 15, 5287 (2009). PubMedArticle Johansson, M., Larsson, J. & Hansson, G. 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). ADS Podolsky, D.K. et al. Identification of human intestinal trefoil factor. Goblet cell-specific expression of a peptide targeted for apical secretion. J. Biol. Chem. 268, 6694–6702 (1993). CASISIPubMed Artis, D. et al. RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc. Natl. Acad. Sci. USA 101, 13596–13600 (2004). CASADSPubMedArticle Bevins, C.L. & Salzman, N.H. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat. Rev. Microbiol. 9, 356–368 (2011). CASPubMedArticle Vaishnava, S., Behrendt, C.L., Ismail, A.S., Eckmann, L. & Hooper, L.V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl. Acad. Sci. USA 105, 20858–20863 (2008). PubMedArticle Vaishnava, S. et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258 (2011). CASADSPubMedArticle Selsted, M.E. & Ouellette, A.J. Mammalian defensins in the antimicrobial immune response. Nat. Immunol. 6, 551–557 (2005). CASISIPubMedArticle Salzman, N. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat. Immunol. 11, 76–83 (2010). CASISIPubMedArticle Brandl, K., Plitas, G., Schnabl, B., DeMatteo, R.P. & Pamer, E.G. MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection. J. Exp. Med. 204, 1891–1900 (2007). CASISIPubMedArticle Kaiser, V. & Diamond, G. Expression of mammalian defensin genes. J. Leukoc. 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Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 37, 601–610 (2012). CASPubMedArticle Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2012). CASPubMedArticle Sawa, S. et al. RORgammat+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol. 12, 320–326 (2011). CASISIPubMedArticle Lochner, M. et al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORgamma t and LTi cells. J. Exp. Med. 208, 125–134 (2011). CASISIPubMedArticle Sonnenberg, G. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012). CASADSPubMedArticle Sonnenberg, G.F., Monticelli, L.A., Elloso, M.M., Fouser, L.A. & Artis, D. 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This study provides the first visual evidence of the composition of the mucus layer, highlighting the function of the mucus layer in segregating the microbiota away from the host epithelium. ADSPubMedArticle Wlodarska, M. et al. Antibiotic treatment alters the colonic mucus layer and predisposes the host to exacerbated Citrobacter rodentium–induced colitis. Infect. Immun. 79, 1536–1545 (2011). CASPubMedArticle Fyderek, K. Mucosal bacterial microflora and mucus layer thickness in adolescents with inflammatory bowel disease. World J. Gastroenterol. 15, 5287 (2009). PubMedArticle Johansson, M., Larsson, J. & Hansson, G. 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). ADS Podolsky, D.K. et al. Identification of human intestinal trefoil factor. Goblet cell-specific expression of a peptide targeted for apical secretion. J. Biol. Chem. 268, 6694–6702 (1993). CASISIPubMed Artis, D. et al. RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc. Natl. Acad. Sci. USA 101, 13596–13600 (2004). CASADSPubMedArticle Bevins, C.L. & Salzman, N.H. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat. Rev. Microbiol. 9, 356–368 (2011). CASPubMedArticle Vaishnava, S., Behrendt, C.L., Ismail, A.S., Eckmann, L. & Hooper, L.V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl. Acad. Sci. USA 105, 20858–20863 (2008). PubMedArticle Vaishnava, S. et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258 (2011). CASADSPubMedArticle Selsted, M.E. & Ouellette, A.J. Mammalian defensins in the antimicrobial immune response. Nat. Immunol. 6, 551–557 (2005). CASISIPubMedArticle Salzman, N. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat. Immunol. 11, 76–83 (2010). CASISIPubMedArticle Brandl, K., Plitas, G., Schnabl, B., DeMatteo, R.P. & Pamer, E.G. MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection. J. Exp. Med. 204, 1891–1900 (2007). CASISIPubMedArticle Kaiser, V. & Diamond, G. Expression of mammalian defensin genes. J. Leukoc. Biol. 68, 779–784 (2000). CASPubMed Menendez, A. et al. Bacterial stimulation of the TLR-MyD88 pathway modulates the homeostatic expression of ileal Paneth cell α-defensins. J. Innate Immun. 5, 39–49 (2013). CASPubMedArticle Chu, H. et al. Human alpha-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science 337, 477–481 (2012). CASADSPubMedArticle Schroeder, B. et al. Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1. Nature 469, 419–423 (2011). CASADSISIPubMedArticle Spits, H. & Di Santo, J.P. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat. Immunol. 12, 21–27 (2011). CASISIPubMedArticle Spits, H. & Cupedo, T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 30, 647–675 (2012). CASPubMedArticle Sonnenberg, G. & Artis, D. Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 37, 601–610 (2012). CASPubMedArticle Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2012). CASPubMedArticle Sawa, S. et al. RORgammat+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol. 12, 320–326 (2011). CASISIPubMedArticle Lochner, M. et al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORgamma t and LTi cells. J. Exp. Med. 208, 125–134 (2011). CASISIPubMedArticle Sonnenberg, G. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012). CASADSPubMedArticle Sonnenberg, G.F., Monticelli, L.A., Elloso, M.M., Fouser, L.A. & Artis, D. CD4+ lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34, 122–134 (2011). CASISIPubMedArticle Monticelli, L.A. et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054 (2011). CASPubMedArticle 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). CASPubMedArticle Cebra, J.J. Influences of microbiota on intestinal immune system development. Am. J. Clin. 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