Which of the following is used to hold together the epithelial layers that line the mucosa?

  1. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013; 504: 446–450.

    CAS  Article  Google Scholar 

  2. Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M et al. ATP drives lamina propria T(H)17 cell differentiation. Nature 2008; 455: 808–812.

    CAS  Article  Google Scholar 

  3. Kim YS, Ho SB . Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr Gastroenterol Rep 2010; 12: 319–330.

    Article  Google Scholar 

  4. Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H et al. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature 2010; 463: 540–544.

    CAS  Article  Google Scholar 

  5. Price AE, Liang HE, Sullivan BM, Reinhardt RL, Eisley CJ, Erle DJ et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci USA 2010; 107: 11489–11494.

    CAS  Article  Google Scholar 

  6. Shimotoyodome A, Meguro S, Hase T, Tokimitsu I, Sakata T . Short chain fatty acids but not lactate or succinate stimulate mucus release in the rat colon. Comp Biochem Physiol A Mol Integr Physiol 2000; 125: 525–531.

    CAS  Article  Google Scholar 

  7. Wlodarska M, Thaiss CA, Nowarski R, Henao-Mejia J, Zhang JP, Brown EM et al. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 2014; 156: 1045–1059.

    CAS  Article  Google Scholar 

  8. Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC . The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci USA 2008; 105: 15064–15069.

    CAS  Article  Google Scholar 

  9. Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 2016; 167: 1339–1353 e21.

    CAS  Article  Google Scholar 

  10. Cunliffe RN, Mahida YR . Expression and regulation of antimicrobial peptides in the gastrointestinal tract. J Leukoc Biol 2004; 75: 49–58.

    CAS  Article  Google Scholar 

  11. Okumura R, Kurakawa T, Nakano T, Kayama H, Kinoshita M, Motooka D et al. Lypd8 promotes the segregation of flagellated microbiota and colonic epithelia. Nature 2016; 532: 117–121.

    CAS  Article  Google Scholar 

  12. Shimada Y, Kinoshita M, Harada K, Mizutani M, Masahata K, Kayama H et al. Commensal bacteria-dependent indole production enhances epithelial barrier function in the colon. PLoS ONE 2013; 8: e80604.

    Article  Google Scholar 

  13. Venkatesh M, Mukherjee S, Wang H, Li H, Sun K, Benechet AP et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity 2014; 41: 296–310.

    CAS  Article  Google Scholar 

  14. Ayabe T, Satchell DP, Wilson CL, Parks WC, Selsted ME, Ouellette AJ . Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol 2000; 1: 113–118.

    CAS  Article  Google Scholar 

  15. Vaishnava S, Yamamoto M, Severson KM, Ruhn KA, Yu X, Koren O et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 2011; 334: 255–258.

    CAS  Article  Google Scholar 

  16. Brogden KA . Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 2005; 3: 238–250.

    CAS  Article  Google Scholar 

  17. Wilson CL, Ouellette AJ, Satchell DP, Ayabe T, Lopez-Boado YS, Stratman JL et al. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 1999; 286: 113–117.

    CAS  Article  Google Scholar 

  18. Cash HL, Whitham CV, Behrendt CL, Hooper LV . Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 2006; 313: 1126–1130.

    CAS  Article  Google Scholar 

  19. Mukherjee S, Zheng H, Derebe MG, Callenberg KM, Partch CL, Rollins D et al. Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature 2014; 505: 103–107.

    Article  Google Scholar 

  20. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005; 307: 731–734.

    CAS  Article  Google Scholar 

  21. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006; 203: 2271–2279.

    CAS  Article  Google Scholar 

  22. Kuhn KA, Manieri NA, Liu TC, Stappenbeck TS . IL-6 stimulates intestinal epithelial proliferation and repair after injury. PLoS ONE 2014; 9: e114195.

    Article  Google Scholar 

  23. Capaldo CT, Beeman N, Hilgarth RS, Nava P, Louis NA, Naschberger E et al. IFN-gamma and TNF-alpha-induced GBP-1 inhibits epithelial cell proliferation through suppression of beta-catenin/TCF signaling. Mucosal Immunol 2012; 5: 681–690.

    CAS  Article  Google Scholar 

  24. Pull SL, Doherty JM, Mills JC, Gordon JI, Stappenbeck TS . Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc Natl Acad Sci USA 2005; 102: 99–104.

    CAS  Article  Google Scholar 

  25. Seno H, Miyoshi H, Brown SL, Geske MJ, Colonna M, Stappenbeck TS . Efficient colonic mucosal wound repair requires Trem2 signaling. Proc Natl Acad Sci USA 2009; 106: 256–261.

    CAS  Article  Google Scholar 

  26. Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 2005; 129: 550–564.

    CAS  Article  Google Scholar 

  27. Heller F, Fromm A, Gitter AH, Mankertz J, Schulzke JD . Epithelial apoptosis is a prominent feature of the epithelial barrier disturbance in intestinal inflammation: effect of pro-inflammatory interleukin-13 on epithelial cell function. Mucosal Immunol 2008; 1 (Suppl 1): S58–S61.

    Article  Google Scholar 

  28. Zhang M, Yang XJ . Effects of a high fat diet on intestinal microbiota and gastrointestinal diseases. World J Gastroenterol 2016; 22: 8905–8909.

    CAS  Article  Google Scholar 

  29. Theriot CM, Koenigsknecht MJ, Carlson PE Jr, Hatton GE, Nelson AM, Li B et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun 2014; 5: 3114.

    Article  Google Scholar 

  30. Thaiss CA, Zeevi D, Levy M, Zilberman-Schapira G, Suez J, Tengeler AC et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 2014; 159: 514–529.

    CAS  Article  Google Scholar 

  31. Fujisaka S, Ussar S, Clish C, Devkota S, Dreyfuss JM, Sakaguchi M et al. Antibiotic effects on gut microbiota and metabolism are host dependent. J Clin Invest 2016; 126: 4430–4443.

    Article  Google Scholar 

  32. Bailey MT, Dowd SE, Parry NM, Galley JD, Schauer DB, Lyte M . Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by Citrobacter rodentium. Infect Immun 2010; 78: 1509–1519.

    CAS  Article  Google Scholar 

  33. Singh P, Teal TK, Marsh TL, Tiedje JM, Mosci R, Jernigan K et al. Intestinal microbial communities associated with acute enteric infections and disease recovery. Microbiome 2015; 3: 45.

    Article  Google Scholar 

  34. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009; 139: 485–498.

    CAS  Article  Google Scholar 

  35. Atarashi K, Tanoue T, Ando M, Kamada N, Nagano Y, Narushima S et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 2015; 163: 367–380.

    CAS  Article  Google Scholar 

  36. Sano T, Huang W, Hall JA, Yang Y, Chen A, Gavzy SJ et al. An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses. Cell 2015; 163: 381–393.

    CAS  Article  Google Scholar 

  37. Goto Y, Obata T, Kunisawa J, Sato S, Ivanov II, Lamichhane A et al. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 2014; 345: 1254009.

    Article  Google Scholar 

  38. Pham TA, Clare S, Goulding D, Arasteh JM, Stares MD, Browne HP et al. Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen. Cell Host Microbe 2014; 16: 504–516.

    CAS  Article  Google Scholar 

  39. Pickard JM, Maurice CF, Kinnebrew MA, Abt MC, Schenten D, Golovkina TV et al. Rapid fucosylation of intestinal epithelium sustains host–commensal symbiosis in sickness. Nature 2014; 514: 638–641.

    CAS  Article  Google Scholar 

  40. Yu Y, Zeng H, Lyons S, Carlson A, Merlin D, Neish AS et al. TLR5-mediated activation of p38 MAPK regulates epithelial IL-8 expression via posttranscriptional mechanism. Am J Physiol Gastrointest Liver Physiol 2003; 285: G282–G290.

    CAS  Article  Google Scholar 

  41. Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL . Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol 2001; 167: 1882–1885.

    CAS  Article  Google Scholar 

  42. Gerbe F, Sidot E, Smyth DJ, Ohmoto M, Matsumoto I, Dardalhon V et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 2016; 529: 226–230.

    CAS  Article  Google Scholar 

  43. Howitt MR, Lavoie S, Michaud M, Blum AM, Tran SV, Weinstock JV et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 2016; 351: 1329–1333.

    CAS  Article  Google Scholar 

  44. von Moltke J, Ji M, Liang HE, Locksley RM . Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 2016; 529: 221–225.

    CAS  Article  Google Scholar 

  45. Humphreys NE, Xu D, Hepworth MR, Liew FY, Grencis RK . IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J Immunol 2008; 180: 2443–2449.

    CAS  Article  Google Scholar 

  46. Duan L, Chen J, Zhang H, Yang H, Zhu P, Xiong A et al. Interleukin-33 ameliorates experimental colitis through promoting Th2/Foxp3(+) regulatory T-cell responses in mice. Mol Med 2012; 18: 753–761.

    CAS  Article  Google Scholar 

  47. Schiering C, Krausgruber T, Chomka A, Frohlich A, Adelmann K, Wohlfert EA et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 2014; 513: 564–568.

    CAS  Article  Google Scholar 

  48. Taylor BC, Zaph C, Troy AE, Du Y, Guild KJ, Comeau MR et al. TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J Exp Med 2009; 206: 655–667.

    CAS  Article  Google Scholar 

  49. He B, Xu W, Santini PA, Polydorides AD, Chiu A, Estrella J et al. Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 2007; 26: 812–826.

    CAS  Article  Google Scholar 

  50. Shan M, Gentile M, Yeiser JR, Walland AC, Bornstein VU, Chen K et al. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 2013; 342: 447–453.

    CAS  Article  Google Scholar 

  51. Worthington JJ . The intestinal immunoendocrine axis: novel cross-talk between enteroendocrine cells and the immune system during infection and inflammatory disease. Biochem Soc Trans 2015; 43: 727–733.

    CAS  Article  Google Scholar 

  52. Li Q, Han D, Cong B, Shan B, Zhang J, Chen H et al. Cholecystokinin octapeptide significantly suppresses collagen-induced arthritis in mice by inhibiting Th17 polarization primed by dendritic cells. Cell Immunol 2011; 272: 53–60.

    CAS  Article  Google Scholar 

  53. Saia RS, Mestriner FL, Bertozi G, Cunha FQ, Carnio EC . Cholecystokinin inhibits inducible nitric oxide synthase expression by lipopolysaccharide-stimulated peritoneal macrophages. Mediat Inflamm 2014; 2014: 896029.

    Article  Google Scholar 

  54. Zhang JG, Liu JX, Jia XX, Geng J, Yu F, Cong B . Cholecystokinin octapeptide regulates the differentiation and effector cytokine production of CD4(+) T cells in vitro. Int Immunopharmacol 2014; 20: 307–315.

    CAS  Article  Google Scholar 

  55. Zhang JG, Cong B, Li QX, Chen HY, Qin J, Fu LH . Cholecystokinin octapeptide regulates lipopolysaccharide-activated B cells co-stimulatory molecule expression and cytokines production in vitro. Immunopharmacol Immunotoxicol 2011; 33: 157–163.

    Article  Google Scholar 

  56. Luyer MD, Greve JW, Hadfoune M, Jacobs JA, Dejong CH, Buurman WA . Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve. J Exp Med 2005; 202: 1023–1029.

    CAS  Article  Google Scholar 

  57. Kusu T, Kayama H, Kinoshita M, Jeon SG, Ueda Y, Goto Y et al. Ecto-nucleoside triphosphate diphosphohydrolase 7 controls Th17 cell responses through regulation of luminal ATP in the small intestine. J Immunol 2013; 190: 774–783.

    CAS  Article  Google Scholar 

  58. Mabbott NA, Donaldson DS, Ohno H, Williams IR, Mahajan A . Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol 2013; 6: 666–677.

    CAS  Article  Google Scholar 

  59. Ohno H, Hase K . Glycoprotein 2 (GP2): grabbing the FimH bacteria into M cells for mucosal immunity. Gut Microbes 2010; 1: 407–410.

    Article  Google Scholar 

  60. Hase K, Kawano K, Nochi T, Pontes GS, Fukuda S, Ebisawa M et al. Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature 2009; 462: 226–230.

    CAS  Article  Google Scholar 

  61. Kanaya T, Hase K, Takahashi D, Fukuda S, Hoshino K, Sasaki I et al. The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells. Nat Immunol 2012; 13: 729–736.

    CAS  Article  Google Scholar 

  62. Sato S, Kaneto S, Shibata N, Takahashi Y, Okura H, Yuki Y et al. Transcription factor Spi-B-dependent and -independent pathways for the development of Peyer's patch M cells. Mucosal Immunol 2013; 6: 838–846.

    CAS  Article  Google Scholar 

  63. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142: 46–54 e42.

    Article  Google Scholar 

  64. Goto Y, Kurashima Y, Kiyono H . The gut microbiota and inflammatory bowel disease. Curr Opin Rheumatol 2015; 27: 388–396.

    CAS  Article  Google Scholar 

  65. Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 2011; 43: 246–252.

    CAS  Article  Google Scholar 

  66. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 2010; 42: 1118–1125.

    CAS  Article  Google Scholar 

  67. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012; 491: 119–124.

    CAS  Article  Google Scholar 

  68. Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 2015; 47: 979–986.

    CAS  Article  Google Scholar 

  69. Jager S, Stange EF, Wehkamp J . Inflammatory bowel disease: an impaired barrier disease. Langenbecks Arch Surg 2013; 398: 1–12.

    Article  Google Scholar 

  70. Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 2006; 131: 117–129.

    CAS  Article  Google Scholar 

  71. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 2011; 145: 745–757.

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  73. Frantz AL, Rogier EW, Weber CR, Shen L, Cohen DA, Fenton LA et al. Targeted deletion of MyD88 in intestinal epithelial cells results in compromised antibacterial immunity associated with downregulation of polymeric immunoglobulin receptor, mucin-2, and antibacterial peptides. Mucosal Immunol 2012; 5: 501–512.

    CAS  Article  Google Scholar 

  74. Bhinder G, Stahl M, Sham HP, Crowley SM, Morampudi V, Dalwadi U et al. Intestinal epithelium-specific MyD88 signaling impacts host susceptibility to infectious colitis by promoting protective goblet cell and antimicrobial responses. Infect Immun 2014; 82: 3753–3763.

    Article  Google Scholar 

  75. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA . Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 2008; 29: 947–957.

    CAS  Article  Google Scholar 

  76. Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 2007; 446: 557–561.

    CAS  Article  Google Scholar 

  77. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411: 599–603.

    CAS  Article  Google Scholar 

  78. Biswas A, Liu YJ, Hao L, Mizoguchi A, Salzman NH, Bevins CL et al. Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proc Natl Acad Sci USA 2010; 107: 14739–14744.

    CAS  Article  Google Scholar 

  79. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001; 411: 603–606.

    CAS  Article  Google Scholar 

  80. Takahashi D, Hase K, Kimura S, Nakatsu F, Ohmae M, Mandai Y et al. The epithelia-specific membrane trafficking factor AP-1B controls gut immune homeostasis in mice. Gastroenterology 2011; 141: 621–632.

    CAS  Article  Google Scholar 

Page 2

Mucosal barriers in the gut. In the small intestine, chemical barriers, including AMPs produced by Paneth cells, have major roles in the segregation of intestinal bacteria and intestinal epithelial cells. In contrast, in the large intestine, which is inhabited by a tremendous number of bacteria, intestinal bacteria and intestinal epithelial cells are separated by the inner mucus layer containing polymerized MUC2. Lypd8, a GPI-anchored protein expressed in the epithelial cells, promotes the segregation of the two by binding to intestinal bacteria, especially flagellated bacteria. AMP, antimicrobial peptides; LZ, lysozyme; TLR, toll-like receptor; ILC3, type 3 innate lymphoid cell.

Última postagem

Tag