Inflammatory bowel disease (IBD) defines a spectrum of complex disorders. Understanding how environmental risk factors, alterations of the intestinal microbiota, and polygenetic and epigenetic susceptibility impact on immune pathways is key for developing targeted therapies. Mechanistic understanding of polygenic IBD is complemented by Mendelian disorders that present with IBD, pharmacological interventions that cause colitis, autoimmunity, and multiple animal models. Collectively, this multifactorial pathogenesis supports a concept of immune checkpoints that control microbial-host interactions in the gut by modulating innate and adaptive immunity, as well as epithelial and mesenchymal cell responses. In addition to classical immunosuppressive strategies, we discuss how resetting the microbiota and restoring innate immune responses, in particular autophagy and epithelial barrier function, might be key for maintaining remission or preventing IBD. Targeting checkpoints in genetically stratified subgroups of patients with Mendelian disorder–associated IBD increasingly directs treatment strategies as part of personalized medicine.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Peloquin JM, Goel G, Villablanca EJ, Xavier RJ. 1.  2016. Mechanisms of pediatric inflammatory bowel disease. Annu. Rev. Immunol. 34:31–64 [Google Scholar]
  2. Khor B, Gardet A, Xavier RJ. 2.  2011. Genetics and pathogenesis of inflammatory bowel disease. Nature 474:307–17 [Google Scholar]
  3. McGovern DP, Kugathasan S, Cho JH. 3.  2015. Genetics of inflammatory bowel diseases. Gastroenterology 149:1163–76.e2 [Google Scholar]
  4. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M. 4.  et al. 2012. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142:46–54 [Google Scholar]
  5. Danese S, Fiocchi C. 5.  2011. Ulcerative colitis. N. Engl. J. Med. 365:1713–25 [Google Scholar]
  6. Neurath MF. 6.  2017. Current and emerging therapeutic targets for IBD. Nat. Rev. Gastroenterol. Hepatol. 14:269–78 [Google Scholar]
  7. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP. 7.  et al. 2012. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–24 [Google Scholar]
  8. Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R. 8.  et al. 2015. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47:979–86 [Google Scholar]
  9. de Lange KM, Moutsianas L, Lee JC, Lamb CA, Luo Y. 9.  et al. 2017. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat. Genet. 49:256–61 [Google Scholar]
  10. Mirkov MU, Verstockt B, Cleynen I. 10.  2017. Genetics of inflammatory bowel disease: beyond NOD2. Lancet Gastroenterol. Hepatol. 2:224–34 [Google Scholar]
  11. Brant SR, Okou DT, Simpson CL, Cutler DJ, Haritunians T. 11.  et al. 2017. Genome-wide association study identifies African-specific susceptibility loci in African Americans with inflammatory bowel disease. Gastroenterology 152:206–17 [Google Scholar]
  12. Ellinghaus D, Jostins L, Spain SL, Cortes A, Bethune J. 12.  et al. 2016. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat. Genet. 48:510–18 [Google Scholar]
  13. Price AL, Spencer CC, Donnelly P. 13.  2015. Progress and promise in understanding the genetic basis of common diseases. Proc. Biol. Sci. 282:20151684 [Google Scholar]
  14. Parkes M, Cortes A, van Heel DA, Brown MA. 14.  2013. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat. Rev. Genet. 14:661–73 [Google Scholar]
  15. Li YR, Li J, Zhao SD, Bradfield JP, Mentch FD. 15.  et al. 2015. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nat. Med. 21:1018–27 [Google Scholar]
  16. Cleynen I, Boucher G, Jostins L, Schumm LP, Zeissig S. 16.  et al. 2016. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387:156–67 [Google Scholar]
  17. Huang H, Fang M, Jostins L, Umicevic Mirkov M, Boucher G. 17.  et al. 2017. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547:173–78 [Google Scholar]
  18. Boyle EA, Li YI, Pritchard JK. 18.  2017. An expanded view of complex traits: from polygenic to omnigenic. Cell 169:1177–86 [Google Scholar]
  19. Lee JC, Biasci D, Roberts R, Gearry RB, Mansfield JC. 19.  et al. 2017. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease. Nat. Genet. 49:262–68 [Google Scholar]
  20. Fairfax BP, Humburg P, Makino S, Naranbhai V, Wong D. 20.  et al. 2014. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression. Science 343:1246949 [Google Scholar]
  21. Farh KK, Marson A, Zhu J, Kleinewietfeld M, Housley WJ. 21.  et al. 2015. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518:337–43 [Google Scholar]
  22. Afzali B, Gronholm J, Vandrovcova J, O'Brien C, Sun HW. 22.  et al. 2017. BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat. Immunol. 18:813–23 [Google Scholar]
  23. Kabakchiev B, Silverberg MS. 23.  2013. Expression quantitative trait loci analysis identifies associations between genotype and gene expression in human intestine. Gastroenterology 144:1488–96 [Google Scholar]
  24. Singh T, Levine AP, Smith PJ, Smith AM, Segal AW, Barrett JC. 24.  2015. Characterization of expression quantitative trait loci in the human colon. Inflamm. Bowel Dis. 21:251–56 [Google Scholar]
  25. Di Narzo AF, Peters LA, Argmann C, Stojmirovic A, Perrigoue J. 25.  et al. 2016. Blood and intestine eQTLs from an anti-TNF-resistant Crohn's disease cohort inform IBD genetic association loci. Clin. Transl. Gastroenterol. 7:e177 [Google Scholar]
  26. Ventham NT, Kennedy NA, Adams AT, Kalla R, Heath S. 26.  et al. 2016. Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease. Nat. Commun. 7:13507 [Google Scholar]
  27. Howell KJ, Kraiczy J, Nayak KM, Gasparetto M, Ross A. 27.  et al. 2018. DNA methylation and transcription patterns in intestinal epithelial cells from pediatric patients with inflammatory bowel diseases differentiate disease subtypes and associate with outcome. Gastroenterology 154:585–98 [Google Scholar]
  28. Hannon E, Weedon M, Bray N, O'Donovan M, Mill J. 28.  2017. Pleiotropic effects of trait-associated genetic variation on DNA methylation: utility for refining GWAS loci. Am. J. Hum. Genet. 100:954–59 [Google Scholar]
  29. Marigorta UM, Denson LA, Hyams JS, Mondal K, Prince J. 29.  et al. 2017. Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease. Nat. Genet. 49:1517–21 [Google Scholar]
  30. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS. 30.  et al. 2006. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–63 [Google Scholar]
  31. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF. 31.  et al. 2013. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 369:699–710 [Google Scholar]
  32. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF. 32.  et al. 2013. Vedolizumab as induction and maintenance therapy for Crohn's disease. N. Engl. J. Med. 369:711–21 [Google Scholar]
  33. Ley K, Rivera-Nieves J, Sandborn WJ, Shattil S. 33.  2016. Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat. Rev. Drug Discov. 15:173–83 [Google Scholar]
  34. Vermeer S, Sandborn WJ, Danese S, Hébuterne X, Salzberg BA. 34.  et al. 2017. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 390:135–44 [Google Scholar]
  35. Sandborn WJ, Lee SD, Tarabar D, Louis E, Klopocke M. 35.  et al. 2017. Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn's disease: report of the OPERA study. Gut press [Google Scholar]
  36. Rivas MA, Graham D, Sulem P, Stevens C, Desch AN. 36.  et al. 2016. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nat. Commun. 7:12342 [Google Scholar]
  37. Peters LA, Perrigoue J, Mortha A, Iuga A, Song WM. 37.  et al. 2017. A functional genomics predictive network model identifies regulators of inflammatory bowel disease. Nat. Genet. 49:1437–49 [Google Scholar]
  38. Uhlig HH. 38.  2013. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut 62:1795–805 [Google Scholar]
  39. Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J. 39.  et al. 2014. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147:990–1007 [Google Scholar]
  40. Glocker EO, Frede N, Perro M, Sebire N, Elawad M. 40.  et al. 2010. Infant colitis—it's in the genes. Lancet 376:1272 [Google Scholar]
  41. Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA. 41.  et al. 2009. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361:2033–45 [Google Scholar]
  42. Huang C, De Ravin SS, Paul AR, Heller T, Ho N. 42.  et al. 2016. Genetic risk for inflammatory bowel disease is a determinant of Crohn's disease development in chronic granulomatous disease. Inflamm. Bowel Dis. 22:2794–801 [Google Scholar]
  43. Uhlig HH, Muise AM. 43.  2017. Clinical genomics in inflammatory bowel disease. Trends Genet 33:629–41 [Google Scholar]
  44. Levy M, Arion A, Berrebi D, Cuisset L, Jeanne-Pasquier C. 44.  et al. 2013. Severe early-onset colitis revealing mevalonate kinase deficiency. Pediatrics 132:e779–83 [Google Scholar]
  45. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB. 45.  et al. 2014. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat. Med. 20:1410–16 [Google Scholar]
  46. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE. 46.  et al. 2014. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. . Science 345:1623–27 [Google Scholar]
  47. Shields CL, Say EA, Mashayekhi A, Garg SJ, Dunn JP, Shields JA. 47.  2016. Assessment of CTLA-4 deficiency-related autoimmune choroidopathy response to abatacept. JAMA Ophthalmol 134:844–46 [Google Scholar]
  48. Lo B, Zhang K, Lu W, Zheng L, Zhang Q. 48.  et al. 2015. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 349:436–40 [Google Scholar]
  49. Sandborn WJ, Colombel JF, Sands BE, Rutgeerts P, Targan SR. 49.  et al. 2012. Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology 143:62–69 [Google Scholar]
  50. Kiesler P, Fuss IJ, Strober W. 50.  2015. Experimental models of inflammatory bowel diseases. Cell Mol. Gastroenterol. Hepatol. 1:154–70 [Google Scholar]
  51. Mizoguchi A, Takeuchi T, Himuro H, Okada T, Mizoguchi E. 51.  2016. Genetically engineered mouse models for studying inflammatory bowel disease. J. Pathol. 238:205–19 [Google Scholar]
  52. Lindebo Holm T, Poulsen SS, Markholst H, Reedtz-Runge S. 52.  2012. Pharmacological evaluation of the SCID T cell transfer model of colitis: as a model of Crohn's disease. Int. J. Inflam. 2012:412178 [Google Scholar]
  53. Kosiewicz MM, Nast CC, Krishnan A, Rivera-Nieves J, Moskaluk CA. 53.  et al. 2001. Th1-type responses mediate spontaneous ileitis in a novel murine model of Crohn's disease. J. Clin. Invest. 107:695–702 [Google Scholar]
  54. Goettel JA, Biswas S, Lexmond WS, Yeste A, Passerini L. 54.  et al. 2015. Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3. Blood 125:3886–95 [Google Scholar]
  55. Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL. 55.  et al. 2016. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat. Rev. Clin. Oncol. 13:473–86 [Google Scholar]
  56. Stark AK, Sriskantharajah S, Hessel EM, Okkenhaug K. 56.  2015. PI3K inhibitors in inflammation, autoimmunity and cancer. Curr. Opin. Pharmacol. 23:82–91 [Google Scholar]
  57. Lord JD, Hackman RC, Moklebust A, Thompson JA, Higano CS. 57.  et al. 2010. Refractory colitis following anti-CTLA4 antibody therapy: analysis of mucosal FOXP3+ T cells. Dig. Dis. Sci. 55:1396–405 [Google Scholar]
  58. Zeissig S, Petersen BS, Tomczak M, Melum E, Huc-Claustre E. 58.  et al. 2014. Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4. Gut 64:1889–97 [Google Scholar]
  59. Charbit-Henrion F, Jeverica AK, Begue B, Markelj G, Parlato M. 59.  et al. 2016. Deficiency in mucosa associated lymphoid tissue lymphoma translocation 1 (MALT1): a novel cause of IPEX-like syndrome. J. Pediatr. Gastroenterol. Nutr. 64:378–84 [Google Scholar]
  60. Blaydon DC, Biancheri P, Di WL, Plagnol V, Cabral RM. 60.  et al. 2011. Inflammatory skin and bowel disease linked to ADAM17 deletion. N. Engl. J. Med. 365:1502–8 [Google Scholar]
  61. Rigaud S, Fondaneche MC, Lambert N, Pasquier B, Mateo V. 61.  et al. 2006. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444:110–14 [Google Scholar]
  62. Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N. 62.  et al. 2013. TTC7A mutations disrupt intestinal epithelial apicobasal polarity. J. Clin. Invest. 124:328–37 [Google Scholar]
  63. Esch EW, Bahinski A, Huh D. 63.  2015. Organs-on-chips at the frontiers of drug discovery. Nat. Rev. Drug Discov. 14:248–60 [Google Scholar]
  64. Browne HP, Forster SC, Anonye BO, Kumar N, Neville BA. 64.  et al. 2016. Culturing of ‘unculturable’ human microbiota reveals novel taxa and extensive sporulation. Nature 533:543–46 [Google Scholar]
  65. Peterson LW, Artis D. 65.  2014. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14:141–53 [Google Scholar]
  66. Odenwald MA, Turner JR. 66.  2017. The intestinal epithelial barrier: a therapeutic target?. Nat. Rev. Gastroenterol. Hepatol. 14:9–21 [Google Scholar]
  67. Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH. 67.  et al. 2016. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat. Genet. 48:67–73 [Google Scholar]
  68. Badran YR, Dedeoglu F, Leyva Castillo JM, Bainter W, Ohsumi TK. 68.  et al. 2017. Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration. J. Exp. Med. 214:1937–47 [Google Scholar]
  69. Nenci A, Becker C, Wullaert A, Gareus R, van Loo G. 69.  et al. 2007. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446:557–61 [Google Scholar]
  70. Miot C, Imai K, Imai C, Mancini AJ, Kucuk ZY. 70.  et al. 2017. Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations. Blood 30:1456–67 [Google Scholar]
  71. Taniguchi K, Wu LW, Grivennikov SI, de Jong PR, Lian I. 71.  et al. 2015. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519:57–62 [Google Scholar]
  72. Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T. 72.  et al. 2000. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. . Nat. Med. 6:583–88 [Google Scholar]
  73. Ito H, Takazoe M, Fukuda Y, Hibi T, Kusugami K. 73.  et al. 2004. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology 126:989–96 [Google Scholar]
  74. Atreya R, Billmeier U, Rath T, Mudter J, Vieth M. 74.  et al. 2015. First case report of exacerbated ulcerative colitis after anti-interleukin-6R salvage therapy. World J. Gastroenterol. 21:12963–69 [Google Scholar]
  75. Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM. 75.  et al. 2008. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14:282–89 [Google Scholar]
  76. Rutz S, Wang X, Ouyang W. 76.  2014. The IL-20 subfamily of cytokines—from host defence to tissue homeostasis. Nat. Rev. Immunol. 14:783–95 [Google Scholar]
  77. Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N. 77.  et al. 2009. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206:1465–72 [Google Scholar]
  78. Lindemans CA, Calafiore M, Mertelsmann AM, O'Connor MH, Dudakov JA. 78.  et al. 2015. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528:560–64 [Google Scholar]
  79. Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A. 79.  et al. 2008. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118:534–44 [Google Scholar]
  80. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA. 80.  2008. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29:947–57 [Google Scholar]
  81. Pelczar P, Witkowski M, Perez LG, Kempski J, Hammel AG. 81.  et al. 2016. A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease. Science 354:358–62 [Google Scholar]
  82. Kirchberger S, Royston DJ, Boulard O, Thornton E, Franchini F. 82.  et al. 2013. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med. 210:917–31 [Google Scholar]
  83. Huber S, Gagliani N, Zenewicz LA, Huber FJ, Bosurgi L. 83.  et al. 2012. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491:259–63 [Google Scholar]
  84. Kotlarz D, Beier R, Murugan D, Diestelhorst J, Jensen O. 84.  et al. 2012. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 143:347–55 [Google Scholar]
  85. Meyer S, Woodward M, Hertel C, Vlaicu P, Haque Y. 85.  et al. 2016. AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies. Cell 166:582–95 [Google Scholar]
  86. Gaffen SL, Jain R, Garg AV, Cua DJ. 86.  2014. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat. Rev. Immunol. 14:585–600 [Google Scholar]
  87. Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T. 87.  et al. 2006. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116:1310–16 [Google Scholar]
  88. O'Connor W Jr, Kamanaka M, Booth CJ, Town T, Nakae S. 88.  et al. 2009. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat. Immunol. 10:603–9 [Google Scholar]
  89. Song X, Dai D, He X, Zhu S, Yao Y. 89.  et al. 2015. Growth factor FGF2 cooperates with interleukin-17 to repair intestinal epithelial damage. Immunity 43:488–501 [Google Scholar]
  90. Lee JS, Tato CM, Joyce-Shaikh B, Gulen MF, Cayatte C. 90.  et al. 2015. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43:727–38 [Google Scholar]
  91. Maxwell JR, Zhang Y, Brown WA, Smith CL, Byrne FR. 91.  et al. 2015. Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation. Immunity 43:739–50 [Google Scholar]
  92. Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W. 92.  et al. 2012. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61:1693–700 [Google Scholar]
  93. Yiu ZZ, Griffiths CE. 93.  2016. Interleukin 17-A inhibition in the treatment of psoriasis. Expert Rev. Clin. Immunol. 12:1–4 [Google Scholar]
  94. Puel A, Picard C, Cypowyj S, Lilic D, Abel L, Casanova JL. 94.  2010. Inborn errors of mucocutaneous immunity to Candida albicans in humans: a role for IL-17 cytokines?. Curr. Opin. Immunol. 22:467–74 [Google Scholar]
  95. Baxt LA, Xavier RJ. 95.  2015. Role of autophagy in the maintenance of intestinal homeostasis. Gastroenterology 149:553–62 [Google Scholar]
  96. Tschurtschenthaler M, Adolph TE, Ashcroft JW, Niederreiter L, Bharti R. 96.  et al. 2017. Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease–like ileitis. J. Exp. Med. 214:401–22 [Google Scholar]
  97. Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Bock J. 97.  et al. 2013. Paneth cells as a site of origin for intestinal inflammation. Nature 503:272–76 [Google Scholar]
  98. Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC. 98.  et al. 2010. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell 141:1135–45 [Google Scholar]
  99. Murthy A, Li Y, Peng I, Reichelt M, Katakam AK. 99.  et al. 2014. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3. Nature 506:456–62 [Google Scholar]
  100. Nys K, Agostinis P, Vermeire S. 100.  2013. Autophagy: a new target or an old strategy for the treatment of Crohn's disease?. Nat. Rev. Gastroenterol. Hepatol. 10:395–401 [Google Scholar]
  101. Harrison OJ, Srinivasan N, Pott J, Schiering C, Krausgruber T. 101.  et al. 2015. Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3+ Treg cell function in the intestine. Mucosal Immunol 8:1226–36 [Google Scholar]
  102. Nowarski R, Jackson R, Gagliani N, de Zoete MR, Palm NW. 102.  et al. 2015. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163:1444–56 [Google Scholar]
  103. Ludwiczek O, Kaser A, Novick D, Dinarello CA, Rubinstein M, Tilg H. 103.  2005. Elevated systemic levels of free interleukin-18 (IL-18) in patients with Crohn's disease. Eur. Cytokine Netw. 16:27–33 [Google Scholar]
  104. Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E. 104.  et al. 2014. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat. Genet. 46:1135–39 [Google Scholar]
  105. Canna SW, Girard C, Malle L, de Jesus A, Romberg N. 105.  et al. 2017. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J. Allergy Clin. Immunol. 139:1698–701 [Google Scholar]
  106. Valatas V, Filidou E, Drygiannakis I, Kolios G. 106.  2017. Stromal and immune cells in gut fibrosis: the myofibroblast and the scarface. Ann. Gastroenterol. 30:393–404 [Google Scholar]
  107. Kim YG, Kamada N, Shaw MH, Warner N, Chen GY. 107.  et al. 2011. The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity 34:769–80 [Google Scholar]
  108. Karin M, Clevers H. 108.  2016. Reparative inflammation takes charge of tissue regeneration. Nature 529:307–15 [Google Scholar]
  109. Theiss AL, Simmons JG, Jobin C, Lund PK. 109.  2005. Tumor necrosis factor (TNF) α increases collagen accumulation and proliferation in intestinal myofibroblasts via TNF receptor 2. J. Biol. Chem. 280:36099–109 [Google Scholar]
  110. Reinisch W, Panes J, Khurana S, Toth G, Hua F. 110.  et al. 2015. Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study. Gut 64:894–900 [Google Scholar]
  111. Danese S, Rudzinski J, Brandt W, Dupas JL, Peyrin-Biroulet L. 111.  et al. 2015. Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study. Gut 64:243–49 [Google Scholar]
  112. Armaka M, Apostolaki M, Jacques P, Kontoyiannis DL, Elewaut D, Kollias G. 112.  2008. Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases. J. Exp. Med. 205:331–37 [Google Scholar]
  113. Koliaraki V, Pasparakis M, Kollias G. 113.  2015. IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer. J. Exp. Med. 212:2235–51 [Google Scholar]
  114. West NR, Hegazy AN, Owens BMJ, Bullers SJ, Linggi B. 114.  et al. 2017. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat. Med. 23:579–89 [Google Scholar]
  115. Segal AW. 115.  2016. Making sense of the cause of Crohn's – a new look at an old disease. F1000Res 5:2510 [Google Scholar]
  116. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP. 116.  et al. 2001. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411:599–603 [Google Scholar]
  117. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF. 117.  et al. 2001. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411:603–6 [Google Scholar]
  118. Cooney R, Baker J, Brain O, Danis B, Pichulik T. 118.  et al. 2010. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat. Med. 16:90–97 [Google Scholar]
  119. Schwerd T, Pandey S, Yang HT, Bagola K, Jameson E. 119.  et al. 2017. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. Gut 66:1060–73 [Google Scholar]
  120. Gutierrez A, Scharl M, Sempere L, Holler E, Zapater P. 120.  et al. 2014. Genetic susceptibility to increased bacterial translocation influences the response to biological therapy in patients with Crohn's disease. Gut 63:272–80 [Google Scholar]
  121. Massey DC, Bredin F, Parkes M. 121.  2008. Use of sirolimus (rapamycin) to treat refractory Crohn's disease. Gut 57:1294–96 [Google Scholar]
  122. Mutalib M, Borrelli O, Blackstock S, Kiparissi F, Elawad M. 122.  et al. 2014. The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children. J. Crohn's Colitis 8:1730–34 [Google Scholar]
  123. Shaw SY, Tran K, Castoreno AB, Peloquin JM, Lassen KG. 123.  et al. 2013. Selective modulation of autophagy, innate immunity, and adaptive immunity by small molecules. ACS Chem. Biol. 8:2724–33 [Google Scholar]
  124. Coccia M, Harrison OJ, Schiering C, Asquith MJ, Becher B. 124.  et al. 2012. IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells. J. Exp. Med. 209:1595–609 [Google Scholar]
  125. Shouval DS, Biswas A, Kang YH, Griffith AE, Konnikova L. 125.  et al. 2016. Interleukin 1β mediates intestinal inflammation in mice and patients with interleukin 10 receptor deficiency. Gastroenterology 151:1100–4 [Google Scholar]
  126. Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B. 126.  et al. 2014. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat. Genet. 46:1140–46 [Google Scholar]
  127. Teng MW, Bowman EP, McElwee JJ, Smyth MJ, Casanova JL. 127.  et al. 2015. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat. Med. 21:719–29 [Google Scholar]
  128. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K. 128.  et al. 2007. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8:967–74 [Google Scholar]
  129. Ahern PP, Izcue A, Maloy KJ, Powrie F. 129.  2008. The interleukin-23 axis in intestinal inflammation. Immunol. Rev. 226:147–59 [Google Scholar]
  130. Ahern PP, Schiering C, Buonocore S, McGeachy MJ, Cua DJ. 130.  et al. 2010. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33:279–88 [Google Scholar]
  131. McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B. 131.  et al. 2009. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat. Immunol. 10:314–24 [Google Scholar]
  132. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B. 132.  et al. 2005. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201:233–40 [Google Scholar]
  133. Stockinger B, Omenetti S. 133.  2017. The dichotomous nature of T helper 17 cells. Nat. Rev. Immunol. 17:535–44 [Google Scholar]
  134. Griseri T, McKenzie BS, Schiering C, Powrie F. 134.  2012. Dysregulated hematopoietic stem and progenitor cell activity promotes interleukin-23-driven chronic intestinal inflammation. Immunity 37:1116–29 [Google Scholar]
  135. Izcue A, Hue S, Buonocore S, Arancibia-Carcamo CV, Ahern PP. 135.  et al. 2008. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28:559–70 [Google Scholar]
  136. Schiering C, Krausgruber T, Chomka A, Frohlich A, Adelmann K. 136.  et al. 2014. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513:564–68 [Google Scholar]
  137. Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP. 137.  et al. 2013. Innate lymphoid cells–a proposal for uniform nomenclature. Nat. Rev. Immunol. 13:145–49 [Google Scholar]
  138. Takatori H, Kanno Y, Watford WT, Tato CM, Weiss G. 138.  et al. 2009. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J. Exp. Med. 206:35–41 [Google Scholar]
  139. Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR. 139.  et al. 2010. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464:1371–75 [Google Scholar]
  140. Sonnenberg GF, Monticelli LA, Elloso MM, Fouser LA, Artis D. 140.  2011. CD4+ lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34:122–34 [Google Scholar]
  141. Geremia A, Arancibia-Carcamo CV, Fleming MP, Rust N, Singh B. 141.  et al. 2011. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J. Exp. Med. 208:1127–33 [Google Scholar]
  142. Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y. 142.  et al. 2016. Ustekinumab as induction and maintenance therapy for Crohn's disease. N. Engl. J. Med. 375:1946–60 [Google Scholar]
  143. Feagan BG, Sandborn WJ, D'Haens G, Panes J, Kaser A. 143.  et al. 2017. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 389:1699–709 [Google Scholar]
  144. Sands BE, Chen J, Feagan BG, Penney M, Rees WA. 144.  et al. 2017. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn's disease: a phase 2a study. Gastroenterology 153:77–86 [Google Scholar]
  145. Villarino AV, Kanno Y, O'Shea JJ. 145.  2017. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol. 18:374–84 [Google Scholar]
  146. Kojetin DJ, Burris TP. 146.  2014. REV-ERB and ROR nuclear receptors as drug targets. Nat. Rev. Drug Discov. 13:197–216 [Google Scholar]
  147. Withers DR, Hepworth MR, Wang X, Mackley EC, Halford EE. 147.  et al. 2016. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nat. Med. 22:319–23 [Google Scholar]
  148. Abraham C, Dulai PS, Vermeire S, Sandborn WJ. 148.  2017. Lessons learned from trials targeting cytokine pathways in patients with inflammatory bowel diseases. Gastroenterology 152:374–88 [Google Scholar]
  149. Konjar S, Ferreira C, Blankenhaus B, Veldhoen M. 149.  2017. Intestinal barrier interactions with specialized CD8 T cells. Front. Immunol. 8:1281 [Google Scholar]
  150. Steinhoff U, Brinkmann V, Klemm U, Aichele P, Seiler P. 150.  et al. 1999. Autoimmune intestinal pathology induced by hsp60-specific CD8 T cells. Immunity 11:349–58 [Google Scholar]
  151. Lee JC, Lyons PA, McKinney EF, Sowerby JM, Carr EJ. 151.  et al. 2011. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J. Clin. Invest. 121:4170–79 [Google Scholar]
  152. McKinney EF, Lee JC, Jayne DR, Lyons PA, Smith KG. 152.  2015. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 523:612–16 [Google Scholar]
  153. Palm NW, de Zoete MR, Cullen TW, Barry NA, Stefanowski J. 153.  et al. 2014. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158:1000–10 [Google Scholar]
  154. Elkadri AA, Stempak JM, Walters TD, Lal S, Griffiths AM. 154.  et al. 2013. Serum antibodies associated with complex inflammatory bowel disease. Inflamm. Bowel Dis. 19:1499–505 [Google Scholar]
  155. Reddy H, Shipman AR, Wojnarowska F. 155.  2013. Epidermolysis bullosa acquisita and inflammatory bowel disease: a review of the literature. Clin. Exp. Dermatol. 38:225–30 [Google Scholar]
  156. Ishii N, Recke A, Mihai S, Hirose M, Hashimoto T. 156.  et al. 2011. Autoantibody-induced intestinal inflammation and weight loss in experimental epidermolysis bullosa acquisita. J. Pathol. 224:234–44 [Google Scholar]
  157. Gathungu G, Kim MO, Ferguson JP, Sharma Y, Zhang W. 157.  et al. 2013. Granulocyte-macrophage colony-stimulating factor autoantibodies: a marker of aggressive Crohn's disease. Inflamm. Bowel Dis. 19:1671–80 [Google Scholar]
  158. Chuang LS, Villaverde N, Hui KY, Mortha A, Rahman A. 158.  et al. 2016. A frameshift in CSF2RB predominant among Ashkenazi Jews increases risk for Crohn's disease and reduces monocyte signaling via GM-CSF. Gastroenterology 151:710–23 [Google Scholar]
  159. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. 159.  1993. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75:263–74 [Google Scholar]
  160. Spencer SD, Di Marco F, Hooley J, Pitts-Meek S, Bauer M. 160.  et al. 1998. The orphan receptor CRF2–4 is an essential subunit of the interleukin 10 receptor. J. Exp. Med. 187:571–78 [Google Scholar]
  161. Engelhardt KR, Grimbacher B. 161.  2014. IL-10 in humans: lessons from the gut, IL-10/IL-10 receptor deficiencies, and IL-10 polymorphisms. Curr. Top. Microbiol. Immunol. 380:1–18 [Google Scholar]
  162. Franke A, Balschun T, Karlsen TH, Sventoraityte J, Nikolaus S. 162.  et al. 2008. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40:1319–23 [Google Scholar]
  163. Saraiva M, O'Garra A. 163.  2010. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10:170–81 [Google Scholar]
  164. Zigmond E, Bernshtein B, Friedlander G, Walker CR, Yona S. 164.  et al. 2014. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity 40:720–33 [Google Scholar]
  165. Shouval DS, Biswas A, Goettel JA, McCann K, Conaway E. 165.  et al. 2014. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity 40:706–19 [Google Scholar]
  166. Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. 166.  2017. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356:513–19 [Google Scholar]
  167. Schreiber S, Fedorak RN, Nielsen OH, Wild G, Williams CN. 167.  et al. 2000. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Gastroenterology 119:1461–72 [Google Scholar]
  168. Fedorak RN, Gangl A, Elson CO, Rutgeerts P, Schreiber S. 168.  et al. 2000. Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. Gastroenterology 119:1473–82 [Google Scholar]
  169. Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F. 169.  et al. 2000. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289:1352–55 [Google Scholar]
  170. Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E. 170.  et al. 2006. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. Clin. Gastroenterol. Hepatol. 4:754–59 [Google Scholar]
  171. Chen W, Ten Dijke P. 171.  2016. Immunoregulation by members of the TGFβ superfamily. Nat. Rev. Immunol. 16:723–40 [Google Scholar]
  172. Monteleone G, Kumberova A, Croft NM, McKenzie C, Steer HW, MacDonald TT. 172.  2001. Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease. J. Clin. Invest. 108:601–9 [Google Scholar]
  173. Monteleone G, Neurath MF, Ardizzone S, Di Sabatino A, Fantini MC. 173.  et al. 2015. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. N. Engl. J. Med. 372:1104–13 [Google Scholar]
  174. Corp Celgene. 174.  2017. Calgene provides update on GED-0301 (mongersen) inflammatory bowel disease program News release, Oct. 19. https://www.businesswire.com/news/home/20171019006519/en/ [Google Scholar]
  175. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ. 175.  et al. 2001. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. . Nat. Genet. 27:20–21 [Google Scholar]
  176. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB. 176.  et al. 2001. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27:68–73 [Google Scholar]
  177. Ohkura N, Kitagawa Y, Sakaguchi S. 177.  2013. Development and maintenance of regulatory T cells. Immunity 38:414–23 [Google Scholar]
  178. Newton R, Priyadharshini B, Turka LA. 178.  2016. Immunometabolism of regulatory T cells. Nat. Immunol. 17:618–25 [Google Scholar]
  179. Izcue A, Coombes JL, Powrie F. 179.  2009. Regulatory lymphocytes and intestinal inflammation. Annu. Rev. Immunol. 27:313–38 [Google Scholar]
  180. Simeonov DR, Gowen BG, Boontanrart M, Roth TL, Gagnon JD. 180.  et al. 2017. Discovery of stimulation-responsive immune enhancers with CRISPR activation. Nature 549:111–15 [Google Scholar]
  181. Canavan JB, Scotta C, Vossenkamper A, Goldberg R, Elder MJ. 181.  et al. 2016. Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn's disease. Gut 65:584–94 [Google Scholar]
  182. Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B. 182.  et al. 2011. Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med. 365:2055–66 [Google Scholar]
  183. Matsuoka K, Koreth J, Kim HT, Bascug G, McDonough S. 183.  et al. 2013. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci. Transl. Med. 5:179ra43 [Google Scholar]
  184. Klatzmann D, Abbas AK. 184.  2015. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat. Rev. Immunol. 15:283–94 [Google Scholar]
  185. Cao Y, Shen J, Ran ZH. 185.  2014. Association between Faecalibacterium prausnitzii reduction and inflammatory bowel disease: a meta-analysis and systematic review of the literature. Gastroenterol. Res. Pract. 2014:872725 [Google Scholar]
  186. Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. 186.  2017. Dysbiosis and the immune system. Nat. Rev. Immunol. 17:219–32 [Google Scholar]
  187. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T. 187.  et al. 2009. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–98 [Google Scholar]
  188. Morrison PJ, Bending D, Fouser LA, Wright JF, Stockinger B. 188.  et al. 2013. Th17-cell plasticity in Helicobacter hepaticus–induced intestinal inflammation. Mucosal Immunol 6:1143–56 [Google Scholar]
  189. Yang Y, Torchinsky MB, Gobert M, Xiong H, Xu M. 189.  et al. 2014. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510:152–56 [Google Scholar]
  190. Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL. 190.  et al. 2006. IL-23 plays a key role in Helicobacter hepaticus–induced T cell–dependent colitis. J. Exp. Med. 203:2485–94 [Google Scholar]
  191. Dalal SR, Chang EB. 191.  2014. The microbial basis of inflammatory bowel diseases. J. Clin. Invest. 124:4190–96 [Google Scholar]
  192. Mukhopadhya I, Hansen R, Meharg C, Thomson JM, Russell RK. 192.  et al. 2015. The fungal microbiota of de-novo paediatric inflammatory bowel disease. Microbes Infect 17:304–10 [Google Scholar]
  193. Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY. 193.  et al. 2015. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160:447–60 [Google Scholar]
  194. Ghouri YA, Richards DM, Rahimi EF, Krill JT, Jelinek KA, DuPont AW. 194.  2014. Systematic review of randomized controlled trials of probiotics, prebiotics, and synbiotics in inflammatory bowel disease. Clin. Exp. Gastroenterol. 7:473–87 [Google Scholar]
  195. Paramsothy S, Paramsothy R, Rubin DT, Kamm MA, Kaakoush NO. 195.  et al. 2017. Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. J. Crohn's Colitis 11:1180–99 [Google Scholar]
  196. Ananthakrishnan AN. 196.  2015. Epidemiology and risk factors for IBD. Nat. Rev. Gastroenterol. Hepatol. 12:205–17 [Google Scholar]
  197. Round JL, Mazmanian SK. 197.  2010. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. PNAS 107:12204–9 [Google Scholar]
  198. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G. 198.  et al. 2013. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:446–50 [Google Scholar]
  199. Gerada J, DeGaetano J, Sebire NJ, Hill S, Vassallo M, Attard TM. 199.  2013. Mucosal inflammation as a component of tufting enteropathy. Immuno-Gastroenterology 2:62–67 [Google Scholar]
  200. Kammermeier J, Drury S, James CT, Dziubak R, Ocaka L. 200.  et al. 2014. Targeted gene panel sequencing in children with very early onset inflammatory bowel disease—evaluation and prospective analysis. J. Med. Genet. 51:748–55 [Google Scholar]
  201. Avitzur Y, Guo C, Mastropaolo LA, Bahrami E, Chen H. 201.  et al. 2014. Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology 146:1028–39 [Google Scholar]
  202. Kammermeier J, Lucchini G, Pai SY, Worth A, Rampling D. 202.  et al. 2016. Stem cell transplantation for tetratricopeptide repeat domain 7A deficiency: long-term follow-up. Blood 128:1306–8 [Google Scholar]
  203. Hawkey CJ, Allez M, Clark MM, Labopin M, Lindsay JO. 203.  et al. 2015. Autologous hematopoetic stem cell transplantation for refractory Crohn disease: a randomized clinical trial. JAMA 314:2524–34 [Google Scholar]
  204. Duran NE, Hommes DW. 204.  2016. Stem cell-based therapies in inflammatory bowel disease: promises and pitfalls. Therap. Adv. Gastroenterol. 9:533–47 [Google Scholar]
  205. Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W. 205.  et al. 2016. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Lancet 388:1281–90 [Google Scholar]
  206. Boztug K, Schmidt M, Schwarzer A, Banerjee PP, Diez IA. 206.  et al. 2010. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N. Engl. J. Med. 363:1918–27 [Google Scholar]
  207. Braun CJ, Boztug K, Paruzynski A, Witzel M, Schwarzer A. 207.  et al. 2014. Gene therapy for Wiskott-Aldrich syndrome—long-term efficacy and genotoxicity. Sci. Transl. Med. 6:227ra33 [Google Scholar]
  208. Ng M, Freeman MK, Fleming TD, Robinson M, Dwyer-Lindgren L. 208.  et al. 2014. Smoking prevalence and cigarette consumption in 187 countries, 1980–2012. JAMA 311:183–92 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error