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Science. 2016 May 27;352(6289):1116-20. doi: 10.1126/science.aad9948. Epub 2016 May 5.

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

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. hiuchu@caltech.edu sarkis@caltech.edu.
2
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
3
Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, San Diego, CA 92093, USA.
4
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
5
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
6
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
7
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

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 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.

Comment in

PMID:
27230380
PMCID:
PMC4996125
DOI:
10.1126/science.aad9948
[Indexed for MEDLINE]
Free PMC Article

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