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

Hiutung Chu, Arya Khosravi, Indah P. Kusumawardhani, Alice H.K. Kwon, Anilton C. Vasconcelos, Larissa D. Cunha, Anne E. Mayer, Yue Shen, Wei Li Wu, Amal Kambal, Stephan R. Targan, Ramnik J. Xavier, Peter B. Ernst, Douglas R. Green, Dermot P.B. McGovern, Herbert W. Virgin, Sarkis K. Mazmanian

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243 Scopus citations


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 (Tregs ) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in Treg 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.

Original languageEnglish
Pages (from-to)1116-1120
Number of pages5
Issue number6289
StatePublished - May 27 2016

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    Chu, H., Khosravi, A., Kusumawardhani, I. P., Kwon, A. H. K., Vasconcelos, A. C., Cunha, L. D., Mayer, A. E., Shen, Y., Wu, W. L., Kambal, A., Targan, S. R., Xavier, R. J., Ernst, P. B., Green, D. R., McGovern, D. P. B., Virgin, H. W., & Mazmanian, S. K. (2016). Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science, 352(6289), 1116-1120.