Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease

Hiutung Chu1,*, Arya Khosravi1, Indah P. Kusumawardhani1, Alice H. K. Kwon1, Anilton C. Vasconcelos2, Larissa D. Cunha3, Anne E. Mayer4, Yue Shen1, Wei-Li Wu1, Amal Kambal4, Stephan R. Targan5, Ramnik J. Xavier6, Peter B. Ernst2, Douglas R. Green3, Dermot P. B. McGovern5, Herbert W. Virgin4, Sarkis K. Mazmanian1,*

Science 27 May 2016

Speaker: Chu-Yi Hsieh (謝筑伊)                                          Time: 14:00~15:00, Nov. 9, 2016

Commentator: Dr. I-Hsiu Huang (黃一修老師)                   Place: Room 601

Abstract:

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, involves chronic inflammation of all or part of the digestive tract. The etiology of IBD is complex and is believed to be the consequence of genetic factors, the host immune system, and environmental factors such as the microbiota. Yet, unifying principles for these findings remain largely unclear. A human commensal Bacteroides fragilis has shown beneficial immunomodulatory properties. Capsular polysaccharide A (PSA) from B. fragilis which is packaged in outer membrane vesicles (OMVs) is delivered to intestinal dendritic cells (DCs) to induce interleukin-10 (IL-10) production from regulatory T cells (T_regs), leading to the protection from experimental colitis. In this study, the authors reveal that IBD-associated genes, ATG16L1 and NOD2, were essential for OMV-mediated Treginduction via a noncanonical autophagy pathway. And ATG16L1- or NOD2-deficient DCs failed to induce Treg cells to suppress mucosal inflammation during experimental colitis. Further studies demonstrated that immune cells from human subjects carrying the CD-associated variant of ATG16L1, T300A were impaired in OMV-mediated Treg induction. And the results show that T300A risk variant of ATG16L1 in human cells is unable to support OMV responses which means human DCs require functional ATG16L1 for induction of CD4+Foxp3+IL-10+ T_regs in response to B. fragilis OMVs. This study describes how interactions between genetic (ATG16L1/NOD2) and environmental (microbiome) factors cooperate to promote beneficial immune responses.

References:

1.     Y. Belkaid, T. W. Hand. (2014) Role of the microbiota in immunity and inflammation. Cell 157, 121–141.

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