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

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 secret...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2016-05, Vol.352 (6289), p.1116-1120
Main Authors: Chu, Hiutung, Khosravi, Arya, Kusumawardhani, Indah P., Kwon, Alice H. K., Vasconcelos, Anilton C., Cunha, Larissa D., Mayer, Anne E., Shen, Yue, Wu, Wei-Li, Kambal, Amal, Targan, Stephan R., Xavier, Ramnik J., Ernst, Peter B., Green, Douglas R., McGovern, Dermot P. B., Virgin, Herbert W., Mazmanian, Sarkis K.
Format: Article
Language:English
Subjects:
Adult
Aged
Animals
Autophagy - immunology
Autophagy-Related Proteins
Bacteroides fragilis
Bacteroides fragilis - immunology
Carrier Proteins - genetics
Dendritic Cells - immunology
Etiology
Extracellular Vesicles - immunology
Female
Gastrointestinal Microbiome - immunology
Gene-Environment Interaction
Genes
Genetic Predisposition to Disease
Genetics
Genome, Human
Government regulations
Human
Humans
Inflammatory bowel disease
Inflammatory Bowel Diseases - genetics
Inflammatory Bowel Diseases - immunology
Inflammatory Bowel Diseases - microbiology
Intestinal Mucosa - immunology
Intestinal Mucosa - microbiology
Male
Membranes
Mice
Mice, Inbred C57BL
Microbiology
Microorganisms
Middle Aged
Nod2 Signaling Adaptor Protein - genetics
Pathways
Polymorphism, Genetic
Risk
T-Lymphocytes, Regulatory - immunology
Vesicles
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aad9948