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

被引：599

作者：

Chu, Hiutung ^{[1
]}

Khosravi, Arya ^{[1
]}

Kusumawardhani, Indah P. ^{[1
]}

Kwon, Alice H. K. ^{[1
]}

Vasconcelos, Anilton C. ^{[2
]}

Cunha, Larissa D. ^{[3
]}

Mayer, Anne E. ^{[4
]}

Shen, Yue ^{[1
]}

Wu, Wei-Li ^{[1
]}

Kambal, Amal ^{[4
]}

Targan, Stephan R. ^{[5
]}

Xavier, Ramnik J. ^{[6
,7
,8
]}

Ernst, Peter B. ^{[2
]}

Green, Douglas R. ^{[3
]}

McGovern, Dermot P. B. ^{[5
]}

Virgin, HerbertW. ^{[4
]}

Mazmanian, Sarkis K. ^{[1
]}

机构：

[1] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA

[2] Univ Calif San Diego, Ctr Vet Sci & Comparat Med, La Jolla, CA 92093 USA

[3] St Jude Childrens Res Hosp, Dept Immunol, 332 N Lauderdale St, Memphis, TN 38105 USA

[4] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[5] Cedars Sinai Med Ctr, F Widjaja Fdn Inflammatory Bowel & Immunobiol Res, Los Angeles, CA 90048 USA

[6] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA

[7] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA

[8] Harvard Univ, Sch Med, Boston, MA 02114 USA

来源：

SCIENCE | 2016年 / 352卷 / 6289期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; CROHNS-DISEASE; DENDRITIC CELLS; IMMUNE-SYSTEM; AUTOPHAGY; SUSCEPTIBILITY; ATG16L1; COMMENSAL; VARIANT; HERITABILITY;

D O I：

10.1126/science.aad9948

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (T-regs) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in T-reg responses to OMVs. We propose that polymorphisms in susceptibility genes promote disease through defects in "sensing" protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD.

引用

页码：1116 / 1120

页数：5

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