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

Chu, Huitung and Khosravi, Arya and Kusumawardhani, Indah P. and Kwon, Alice H. K. and Vasconcelos, Anitilton C. and Cunha, Larissa D. and Mayer, Anne E. and Shen, Yue and Wu, Wei-Li and Kambal, Amal and Targan, Stephan R. and Xavier, Ramnik J. and Ernest, Peter B. and Green, Douglas R. and McGovern, Dermot P. B. and Virgin, Herbt W. and Mazmanian, Sarkis K. (2016) Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science, 352 (6289). pp. 1116-1120. ISSN 0036-8075. PMCID PMC4996125. http://resolver.caltech.edu/CaltechAUTHORS:20160505-114004703

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1126/science.aad9948DOIArticle
http://science.sciencemag.org/content/352/6289/1116PublisherArticle
http://science.sciencemag.org/content/suppl/2016/05/04/science.aad9948.DC1PublisherSupplementary Materials
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996125PubMed CentralArticle
ORCID:
AuthorORCID
Mazmanian, Sarkis K.0000-0003-2713-1513
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.
Funders:
Funding AgencyGrant Number
NIHDK100109
NIHDK097485
NIHPO1DK046763
Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research FundsUNSPECIFIED
Feintech Family Chair in IBDUNSPECIFIED
Wayne and Gladys Valley FoundationUNSPECIFIED
NIHAI079145
Lupus Research InstituteUNSPECIFIED
NIHAI40646
NIHU19 AI109725
Lisa Z. Greer Endowed Chair in IBD GeneticsUNSPECIFIED
NIHDK062413
NIHDE023789-01
European Union305479
Crohn's and Colitis Foundation of AmericaUNSPECIFIED
Leona M. and Harry B. Helmsley Charitable TrustUNSPECIFIED
NIHAI109725
NIHDK078938
NIHGM099535
Heritage Medical Research InstituteUNSPECIFIED
PubMed Central ID:PMC4996125
Record Number:CaltechAUTHORS:20160505-114004703
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160505-114004703
Official Citation: Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease By 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 Science27 May 2016 : 1116-1120
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66692
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:05 May 2016 19:02
Last Modified:18 Jul 2017 14:45

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