Maintenance of gut homeostasis by the mucosal immune system

1) Goto, Y., Kurashima, Y. and Kiyono, H. (2015) The gut microbiota and inflammatory bowel disease. Curr. Opin. Rheumatol. 27, 388–396.

2) Samuelson, D.R., Welsh, D.A. and Shellito, J.E. (2015) Regulation of lung immunity and host defense by the intestinal microbiota. Front. Microbiol. 6, 1085.

3) Bellaguarda, E. and Chang, E.B. (2015) IBD and the gut microbiota--from bench to personalized medicine. Curr. Gastroenterol. Rep. 17, 15.

4) Kayama, H. and Takeda, K. (2016) Functions of innate immune cells and commensal bacteria in gut homeostasis. J. Biochem. 159, 141–149.

5) Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. and Muller, W. (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274.

6) Takeda, K., Clausen, B.E., Kaisho, T., Tsujimura, T., Terada, N., Förster, I. and Akira, S. (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39–49.

7) Kobayashi, M., Kweon, M.N., Kuwata, H., Schreiber, R.D., Kiyono, H., Takeda, K. and Akira, S. (2003) Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice. J. Clin. Invest. 111, 1297–1308.

8) Peterson, L.W. and Artis, D. (2014) Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141–153.

9) Vitale, S., Picascia, S. and Gianfrani, C. (2016) The cross-talk between enterocytes and intraepithelial lymphocytes. Mol Cell Pediatr. 3, 20.

10) Strober, W. (2009) The multifaceted influence of the mucosal microflora on mucosal dendritic cell responses. Immunity 31, 377–388.

11) Laffont, S. and Powrie, F. (2009) Immunology: Dendritic-cell genealogy. Nature 462, 732–733.

12) Johansson-Lindbom, B., Svensson, M., Pabst, O., Palmqvist, C., Marquez, G., Förster, R. and Agace, W.W. (2005) Functional specialization of gut CD103⁺ dendritic cells in the regulation of tissue-selective T cell homing. J. Exp. Med. 202, 1063–1073.

13) Sun, C.M., Hall, J.A., Blank, R.B., Bouladoux, N., Oukka, M., Mora, J.R. and Belkaid, Y. (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785.

14) Mora, J.R., Iwata, M., Eksteen, B., Song, S.Y., Junt, T., Senman, B., Otipoby, K.L., Yokota, A., Takeuchi, H., Ricciardi-Castagnoli, P., Rajewsky, K., Adams, D.H. and von Andrian, U.H. (2006) Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314, 1157–1160.

15) Jeon, S.G., Kayama, H., Ueda, Y., Takahashi, T., Asahara, T., Tsuji, H., Tsuji, N.M., Kiyono, H., Ma, J.S., Kusu, T., Okumura, R., Hara, H., Yoshida, H., Yamamoto, M., Nomoto, K. and Takeda, K. (2012) Probiotic Bifidobacterium breve induces IL-10-producing Tr1 cells in the colon. PLoS Pathog. 8, e1002714.

16) Uematsu, S., Fujimoto, K., Jang, M.H., Yang, B.G., Jung, Y.J., Nishiyama, M., Sato, S., Tsujimura, T., Yamamoto, M., Yokota, Y., Kiyono, H., Miyasaka, M., Ishii, K.J. and Akira, S. (2008) Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat. Immunol. 9, 769–776.

17) Kinnebrew, M.A., Buffie, C.G., Diehl, G.E., Zenewicz, L.A., Leiner, I., Hohl, T.M., Flavell, R.A., Littman, D.R. and Pamer, E.G. (2012) Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36, 276–287.

18) Sonnenberg, G.F., Monticelli, L.A., Elloso, M.M., Fouser, L.A. and Artis, D. (2011) CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34, 122–134.

19) Sonnenberg, G.F., Fouser, L.A. and Artis, D. (2011) Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat. Immunol. 12, 383–390.

20) Liang, S.C., Tan, X.Y., Luxenberg, D.P., Karim, R., Dunussi-Joannopoulos, K., Collins, M. and Fouser, L.A. (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279.

21) Edelson, B.T., Wumesh, K.C., Juang, R., Kohyama, M., Benoit, L.A., Klekotka, P.A., Moon, C., Albring, J.C., Ise, W., Michael, D.G., Bhattacharya, D., Stappenbeck, T.S., Holtzman, M.J., Sung, S.S., Murphy, T.L., Hildner, K. and Murphy, K.M. (2010) Peripheral CD103⁺ dendritic cells form a unified subset developmentally related to CD8alpha⁺ conventional dendritic cells. J. Exp. Med. 207, 823–836.

22) Eickhoff, S., Brewitz, A., Gerner, M.Y., Klauschen, F., Komander, K., Hemmi, H., Garbi, N., Kaisho, T., Germain, R.N. and Kastenmüller, W. (2015) Robust anti-viral immunity requires multiple distinct T cell-dendritic cell interactions. Immunity 39, 722–732.

23) Hor, J.L., Whitney, P.G., Zaid, A., Brooks, A.G., Heath, W.R. and Mueller, S.N. (2015) Spatiotemporally distinct interactions with dendritic cell subsets facilitates CD4⁺ and CD8⁺ T cell activation to localized viral infection. Immunity 43, 554–565.

24) Gao, Y., Nish, S.A., Jiang, R., Hou, L., Licona-Limón, P., Weinstein, J.S., Zhao, H. and Medzhitov, R. (2013) Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells. Immunity 39, 722–732.

25) Persson, E.K., Uronen-Hansson, H., Semmrich, M., Rivollier, A., Hägerbrand, K., Marsal, J., Gudjonsson, S., Håkansson, U., Reizis, B., Kotarsky, K. and Agace, W.W. (2013) IRF4 transcription-factor-dependent CD103(+)CD11b(+) dendritic cells drive mucosal T helper 17 cell differentiation. Immunity 38, 958–969.

26) Schlitzer, A., McGovern, N., Teo, P., Zelante, T., Atarashi, K., Low, D., Ho, A.W., See, P., Shin, A., Wasan, P.S., Hoeffel, G., Malleret, B., Heiseke, A., Chew, S., Jardine, L., Purvis, H.A., Hilkens, C.M., Tam, J., Poidinger, M., Stanley, E.R., Krug, A.B., Renia, L., Sivasankar, B., Ng, L.G., Collin, M., Ricciardi-Castagnoli, P., Honda, K., Haniffa, M. and Ginhoux, F. (2013) IRF4 transcription factor-dependent CD11b⁺ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38, 970–983.

27) Niess, J.H. and Adler, G. (2010) Enteric flora expands gut lamina propria CX3CR1+ dendritic cells supporting inflammatory immune responses under normal and inflammatory conditions. J. Immunol. 184, 2026–2037.

28) Atarashi, K., Nishimura, J., Shima, T., Umesaki, Y., Yamamoto, M., Onoue, M., Yagita, H., Ishii, N., Evans, R., Honda, K. and Takeda, K. (2008) ATP drives lamina propria T(H)17 cell differentiation. Nature 455, 808–812.

29) Ogino, T., Nishimura, J., Barman, S., Kayama, H., Uematsu, S., Okuzaki, D., Osawa, H., Haraguchi, N., Uemura, M., Hata, T., Takemasa, I., Mizushima, T., Yamamoto, H., Takeda, K., Doki, Y. and Mori, M. (2013) Increased Th17-inducing activity of CD14+ CD163 low myeloid cells in intestinal lamina propria of patients with Crohn’s disease. Gastroenterology 145, 1380–1391.

30) Lombardi, V.C. and Khaiboullina, S.F. (2014) Plasmacytoid dendritic cells of the gut: relevance to immunity and pathology. Clin. Immunol. 153, 165–177.

31) Tezuka, H., Abe, Y., Asano, J., Sato, T., Liu, J., Iwata, M. and Ohteki, T. (2011) Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction. Immunity 34, 247–257.

32) Ueda, Y., Kayama, H., Jeon, S.G., Kusu, T., Isaka, Y., Rakugi, H., Yamamoto, M. and Takeda, K. (2010) Commensal microbiota induce LPS hyporesponsiveness in colonic macrophages via the production of IL-10. Int. Immunol. 22, 953–962.

33) Murai, M., Turovskaya, O., Kim, G., Madan, R., Karp, C.L., Cheroutre, H. and Kronenberg, M. (2009) Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat. Immunol. 10, 1178–1184.

34) Hadis, U., Wahl, B., Schulz, O., Hardtke-Wolenski, M., Schippers, A., Wagner, N., Müller, W., Sparwasser, T., Förster, R. and Pabst, O. (2011) Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity 34, 237–246.

35) Mortha, A., Chudnovskiy, A., Hashimoto, D., Bogunovic, M., Spencer, S.P., Belkaid, Y. and Merad, M. (2014) Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288.

36) Kayama, H., Ueda, Y., Sawa, Y., Jeon, S.G., Ma, J.S., Okumura, R., Kubo, A., Ishii, M., Okazaki, T., Murakami, M., Yamamoto, M., Yagita, H. and Takeda, K. (2012) Intestinal CX3C chemokine receptor 1(high) (CX3CR1(high)) myeloid cells prevent T-cell-dependent colitis. Proc. Natl. Acad. Sci. U.S.A. 109, 5010–5015.

37) Palm, N.W., de Zoete, M.R. and Flavell, R.A. (2015) Immune-microbiota interactions in health and disease. Clin. Immunol. 159, 122–127.

38) Pollard, M. and Sharon, N. (1970) Responses of the Peyer’s Patches in Germ-Free Mice to Antigenic Stimulation. Infect. Immun. 2, 96–100.

39) Macpherson, A.J., Gatto, D., Sainsbury, E., Harriman, G.R., Hengartner, H. and Zinkernagel, R.M. (2000) A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226.

40) Ivanov, I.I., Atarashi, K., Manel, N., Brodie, E.L., Shima, T., Karaoz, U., Wei, D., Goldfarb, K.C., Santee, C.A., Lynch, S.V., Tanoue, T., Imaoka, A., Itoh, K., Takeda, K., Umesaki, Y., Honda, K. and Littman, D.R. (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498.

41) Mtller, C.P. and Bohnhoff, M. (1963) Changes in the mouse’s enteric microflora associated with enhanced susceptibility to Salmonella infection following streptomycin treatment. J. Infect. Dis. 113, 59–66.

42) Atarashi, K., Tanoue, T., Ando, M., Kamada, N., Nagano, Y., Narushima, S., Suda, W., Imaoka, A., Setoyama, H., Nagamori, T., Ishikawa, E., Shima, T., Hara, T., Kado, S., Jinnohara, T., Ohno, H., Kondo, T., Toyooka, K., Watanabe, E., Yokoyama, S., Tokoro, S., Mori, H., Noguchi, Y., Morita, H., Ivanov, I.I., Sugiyama, T., Nuñez, G., Camp, J.G., Hattori, M., Umesaki, Y. and Honda, K. (2015) Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells. Cell 163, 367–380.

43) Umesaki, Y., Setoyama, H., Matsumoto, S., Imaoka, A. and Itoh, K. (1999) Differential roles of segmented filamentous bacteria and clostridia in development of the intestinal immune system. Infect. Immun. 67, 3504–3511.

44) Wu, H.J., Ivanov, I.I., Darce, J., Hattori, K., Shima, T., Umesaki, Y., Littman, D.R., Benoist, C. and Mathis, D. (2010) Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827.

45) Berer, K., Mues, M., Koutrolos, M., Rasbi, Z.A., Boziki, M., Johner, C., Wekerle, H. and Krishnamoorthy, G. (2011) Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541.

46) Atarashi, K., Tanoue, T., Shima, T., Imaoka, A., Kuwahara, T., Momose, Y., Cheng, G., Yamasaki, S., Saito, T., Ohba, Y., Taniguchi, T., Takeda, K., Hori, S., Ivanov, I.I., Umesaki, Y., Itoh, K. and Honda, K. (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341.

47) Round, J.L., Lee, S.M., Li, J., Tran, G., Jabri, B., Chatila, T.A. and Mazmanian, S.K. (2011) The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977.

48) Shimada, Y., Kinoshita, M., Harada, K., Mizutani, M., Masahata, K., Kayama, H. and Takeda, K. (2013) Commensal bacteria-dependent indole production enhances epithelial barrier function in the colon. PLoS One 8, e80604.

49) Furusawa, Y., Obata, Y., Fukuda, S., Endo, T.A., Nakato, G., Takahashi, D., Nakanishi, Y., Uetake, C., Kato, K., Kato, T., Takahashi, M., Fukuda, N.N., Murakami, S., Miyauchi, E., Hino, S., Atarashi, K., Onawa, S., Fujimura, Y., Lockett, T., Clarke, J.M., Topping, D.L., Tomita, M., Hori, S., Ohara, O., Morita, T., Koseki, H., Kikuchi, J., Honda, K., Hase, K. and Ohno, H. (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450.

50) Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., Liu, H., Cross, J.R., Pfeffer, K., Coffer, P.J. and Rudensky, A.Y. (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455.

51) Chang, P.V., Hao, L., Offermanns, S. and Medzhitov, R. (2014) The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc. Natl. Acad. Sci. U.S.A. 111, 2247–2252.

52) Michail, S., Durbin, M., Turner, D., Griffiths, A.M., Mack, D.R., Hyams, J., Leleiko, N., Kenche, H., Stolfi, A. and Wine, E. (2012) Alterations in the gut microbiome of children with severe ulcerative colitis. Inflamm. Bowel Dis. 18, 1799–1808.

53) Elinav, E., Strowig, T., Kau, A.L., Henao-Mejia, J., Thaiss, C.A., Booth, C.J., Peaper, D.R., Bertin, J., Eisenbarth, S.C., Gordon, J.I. and Flavell, R.A. (2011) NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757.

54) Devkota, S., Wang, Y., Musch, M.W., Leone, V., Fehlner-Peach, H., Nadimpalli, A., Antonopoulos, D.A., Jabri, B. and Chang, E.B. (2012) Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature 487, 104–108.

55) Diehl, G.E., Longman, R.S., Zhang, J.X., Breart, B., Galan, C., Cuesta, A., Schwab, S.R. and Littman, D.R. (2013) Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX(3)CR1(hi) cells. Nature 494, 116–120.

56) Jostins, L., Ripke, S., Weersma, R.K., Duerr, R.H., McGovern, D.P., Hui, K.Y., Lee, J.C., Schumm, L.P., Sharma, Y., Anderson, C.A., Essers, J., Mitrovic, M., Ning, K., Cleynen, I., Theatre, E., Spain, S.L., Raychaudhuri, S., Goyette, P., Wei, Z., Abraham, C., Achkar, J.P., Ahmad, T., Amininejad, L., Ananthakrishnan, A.N., Andersen, V., Andrews, J.M., Baidoo, L., Balschun, T., Bampton, P.A., Bitton, A., Boucher, G., Brand, S., Büning, C., Cohain, A., Cichon, S., D’Amato, M., De Jong, D., Devaney, K.L., Dubinsky, M., Edwards, C., Ellinghaus, D., Ferguson, L.R., Franchimont, D., Fransen, K., Gearry, R., Georges, M., Gieger, C., Glas, J., Haritunians, T., Hart, A., Hawkey, C., Hedl, M., Hu, X., Karlsen, T.H., Kupcinskas, L., Kugathasan, S., Latiano, A., Laukens, D., Lawrance, I.C., Lees, C.W., Louis, E., Mahy, G., Mansfield, J., Morgan, A.R., Mowat, C., Newman, W., Palmieri, O., Ponsioen, C.Y., Potocnik, U., Prescott, N.J., Regueiro, M., Rotter, J.I., Russell, R.K., Sanderson, J.D., Sans, M., Satsangi, J., Schreiber, S., Simms, L.A., Sventoraityte, J., Targan, S.R., Taylor, K.D., Tremelling, M., Verspaget, H.W., De Vos, M., Wijmenga, C., Wilson, D.C., Winkelmann, J., Xavier, R.J., Zeissig, S., Zhang, B., Zhang, C.K., Zhao, H.; International IBD Genetics Consortium (IIBDGC), Silverberg, M.S., Annese, V., Hakonarson, H., Brant, S.R., Radford-Smith, G., Mathew, C.G., Rioux, J.D., Schadt, E.E., Daly, M.J., Franke, A., Parkes, M., Vermeire, S., Barrett, J.C. and Cho, J.H. (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124.

57) Jager, S., Stange, E.F. and Wehkamp, J. (2013) Inflammatory bowel disease: an impaired barrier disease. Langenbecks Arch. Surg. 398, 1–12.

58) Van der Sluis, M., De Koning, B.A., De Bruijn, A.C., Velcich, A., Meijerink, J.P., Van Goudoever, J.B., Büller, H.A., Dekker, J., Van Seuningen, I., Renes, I.B. and Einerhand, A.W. (2006) Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129.

59) Tanaka, H., Takechi, M., Kiyonari, H., Shioi, G., Tamura, A. and Tsukita, S. (2015) Intestinal deletion of Claudin-7 enhances paracellular organic solute flux and initiates colonic inflammation in mice. Gut. 64, 1529–1538.

60) Biswas, A., Liu, Y.J., Hao, L., Mizoguchi, A., Salzman, N.H., Bevins, C.L. and Kobayashi, K.S. (2010) Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proc. Natl. Acad. Sci. U.S.A. 107, 14739–14744.

61) Johansson, M.E., Phillipson, M., Petersson, J., Velcich, A., Holm, L. and Hansson, G.C. (2008) The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl. Acad. Sci. U.S.A. 105, 15064–15069.

62) Fu, J., Wei, B., Wen, T., Johansson, M.E., Liu, X., Bradford, E., Thomsson, K.A., McGee, S., Mansour, L., Tong, M., McDaniel, J.M., Sferra, T.J., Turner, J.R., Chen, H., Hansson, G.C., Braun, J. and Xia, L. (2011) Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J. Clin. Invest. 121, 1657–1666.

63) Wlodarska, M., Thaiss, C.A., Nowarski, R., Henao-Mejia, J., Zhang, J.P., Brown, E.M., Frankel, G., Levy, M., Katz, M.N., Philbrick, W.M., Elinav, E., Finlay, B.B. and Flavell, R.A. (2014) NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045–1059.

64) Okumura, R., Kurakawa, T., Nakano, T., Kayama, H., Kinoshita, M., Motooka, D., Gotoh, K., Kimura, T., Kamiyama, N., Kusu, T., Ueda, Y., Wu, H., Iijima, H., Barman, S., Osawa, H., Matsuno, H., Nishimura, J., Ohba, Y., Nakamura, S., Iida, T., Yamamoto, M., Umemoto, E., Sano, K. and Takeda, K. (2016) Lypd8 promotes the segregation of flagellated microbiota and colonic epithelia. Nature 532, 117–121.

65) Ayabe, T., Satchell, D.P., Wilson, C.L., Parks, W.C., Selsted, M.E. and Ouellette, A.J. (2000) Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat. Immunol. 1, 113–118.

66) Vaishnava, S., Yamamoto, M., Severson, K.M., Ruhn, K.A., Yu, X., Koren, O., Ley, R., Wakeland, E.K. and Hooper, L.V. (2011) The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258.

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

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

69) Mukherjee, S., Zheng, H., Derebe, M.G., Callenberg, K.M., Partch, C.L., Rollins, D., Propheter, D.C., Rizo, J., Grabe, M., Jiang, Q.X. and Hooper, L.V. (2014) Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature 505, 103–107.

70) Worthington, J.J. (2015) The intestinal immunoendocrine axis: novel cross-talk between enteroendocrine cells and the immune system during infection and inflammatory disease. Biochem. Soc. Trans. 43, 727–733.

71) Kusu, T., Kayama, H., Kinoshita, M., Jeon, S.G., Ueda, Y., Goto, Y., Okumura, R., Saiga, H., Kurakawa, T., Ikeda, K., Maeda, Y., Nishimura, J., Arima, Y., Atarashi, K., Honda, K., Murakami, M., Kunisawa, J., Kiyono, H., Okumura, M., Yamamoto, M. and Takeda, K. (2013) Ecto-nucleoside triphosphate diphosphohydrolase 7 controls Th17 cell responses through regulation of luminal ATP in the small intestine. J. Immunol. 190, 774–783.

72) Shan, M., Gentile, M., Yeiser, J.R., Walland, A.C., Bornstein, V.U., Chen, K., He, B., Cassis, L., Bigas, A., Cols, M., Comerma, L., Huang, B., Blander, J.M., Xiong, H., Mayer, L., Berin, C., Augenlicht, L.H., Velcich, A. and Cerutti, A. (2013) Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 342, 447–453.

73) Mabbott, N.A., Donaldson, D.S., Ohno, H., Williams, I.R. and Mahajan, A. (2013) Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 6, 666–677.

74) Gerbe, F., Sidot, E., Smyth, D.J., Ohmoto, M., Matsumoto, I., Dardalhon, V., Cesses, P., Garnier, L., Pouzolles, M., Brulin, B., Bruschi, M., Harcus, Y., Zimmermann, V.S., Taylor, N., Maizels, R.M. and Jay, P. (2016) Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230.

75) von Moltke, J., Ji, M., Liang, H.E. and Locksley, R.M. (2016) Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529, 221–225.

76) Howitt, M.R., Lavoie, S., Michaud, M., Blum, A.M., Tran, S.V., Weinstock, J.V., Gallini, C.A., Redding, K., Margolskee, R.F., Osborne, L.C., Artis, D. and Garrett, W.S. (2016) Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351, 1329–1333.

77) Saia, R.S., Mestriner, F.L., Bertozi, G., Cunha, F.Q. and Carnio, E.C. (2014) Cholecystokinin inhibits inducible nitric oxide synthase expression by lipopolysaccharide-stimulated peritoneal macrophages. Mediators Inflamm. 2014, 896029.

78) Mann, E.R., Landy, J.D., Bernardo, D., Peake, S.T., Hart, A.L., Al-Hassi, H.O. and Knight, S.C. (2013) Intestinal dendritic cells: their role in intestinal inflammation, manipulation by the gut microbiota and differences between mice and men. Immunol. Lett. 150, 30–40.

79) Nguyen, T.L., Vieira-Silva, S., Liston, A. and Raes, J. (2015) How informative is the mouse for human gut microbiota research? Dis. Model. Mech. 8, 1–16.

80) Kuhn, K.A., Manieri, N.A., Liu, T.C. and Stappenbeck, T.S. (2014) IL-6 stimulates intestinal epithelial proliferation and repair after injury. PLoS One 9, e114195.

81) Capaldo, C.T., Beeman, N., Hilgarth, R.S., Nava, P., Louis, N.A., Naschberger, E., Stürzl, M., Parkos, C.A. and Nusrat, A. (2012) IFN-γ and TNF-α-induced GBP-1 inhibits epithelial cell proliferation through suppression of β-catenin/TCF signaling. Mucosal Immunol. 5, 681–690.

82) Pull, S.L., Doherty, J.M., Mills, J.C., Gordon, J.I. and Stappenbeck, T.S. (2005) Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl. Acad. Sci. U.S.A. 102, 99–104.

83) Seno, H., Miyoshi, H., Brown, S.L., Geske, M.J., Colonna, M. and Stappenbeck, T.S. (2009) Efficient colonic mucosal wound repair requires Trem2 signaling. Proc. Natl. Acad. Sci. U.S.A. 106, 256–261.