Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease
Creators
Abstract
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 non-canonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (T_(reg)) 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.
Additional Information
© 2016 American Association for the Advancement of Science. 3 December 2015; accepted 21 April 2016. Published online 5 May 2016. We thank L. Hwang, E. Park, and M. Salas for clinical research coordination (Cedars-Sinai); A. Maskell, L. Sandoval, and C. Rumaldo for animal husbandry (Caltech); and members of the Mazmanian laboratory for discussions and critical reading of the manuscript. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. This work was supported by the National Institutes of Health (NIH) under a Ruth L. Kirschtein National Research Service Award (DK100109) to H.C.; NIH DK097485 to R.J.X.; NIH PO1DK046763, the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds, and The Feintech Family Chair in IBD to S.R.T.; Wayne and Gladys Valley Foundation and NIH AI079145 to P.B.E.; The Lupus Research Institute and NIH AI40646 to D.R.G; NIH U19 AI109725 to H.W.V.; The Lisa Z. Greer Endowed Chair in IBD Genetics, NIH DK062413, NIH DE023789-01, grant 305479 from the European Union, The Crohn's and Colitis Foundation of America, and The Leona M. and Harry B. Helmsley Charitable Trust to D.P.B.M.; NIH AI109725 to H.W.V.; and NIH DK078938, NIH GM099535, The Crohn's and Colitis Foundation of America, and the Heritage Medical Research Institute to S.K.M. Rubicon and ULK1 knockout mice were obtained from D. R. Green and M. Kundu, respectively, under a materials transfer agreement with St. Jude Children's Research Hospital. A provisional patent application entitled "Beneficial Activation of Autophagy Components by the Microbiome" has been filed by H.C., H.W.V., and S.K.M.Attached Files
Accepted Version - nihms-810101.pdf
Supplemental Material - 04/science.aad9948.DC1/Chu.SM.pdf
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nihms-810101.pdf
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Additional details
Identifiers
- PMCID
- PMC4996125
- Eprint ID
- 66692
- DOI
- 10.1126/science.aad9948
- Resolver ID
- CaltechAUTHORS:20160505-114004703
Related works
- Describes
- 10.1126/science.aad9948 (DOI)
Funding
- NIH
- DK100109
- NIH
- DK097485
- NIH
- PO1DK046763
- Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds
- Feintech Family Chair in IBD
- Wayne and Gladys Valley Foundation
- NIH
- AI079145
- Lupus Research Institute
- NIH
- AI40646
- NIH
- U19 AI109725
- Lisa Z. Greer Endowed Chair in IBD Genetics
- NIH
- DK062413
- NIH
- DE023789-01
- European Research Council (ERC)
- 305479
- Crohn's and Colitis Foundation of America
- Leona M. and Harry B. Helmsley Charitable Trust
- NIH
- AI109725
- NIH
- DK078938
- NIH
- GM099535
- Heritage Medical Research Institute
Dates
- Created
-
2016-05-05Created from EPrint's datestamp field
- Updated
-
2022-04-28Created from EPrint's last_modified field