title: Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease.
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.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. hiuchu@caltech.edu sarkis@caltech.edu.
authors.forename: Hiutung
authors.initials: H
authors.lastname: Chu
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Arya
authors.initials: A
authors.lastname: Khosravi
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Indah P
authors.initials: IP
authors.lastname: Kusumawardhani
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Alice H K
authors.initials: AH
authors.lastname: Kwon
authors.affiliation: Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Anilton C
authors.initials: AC
authors.lastname: Vasconcelos
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Larissa D
authors.initials: LD
authors.lastname: Cunha
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Mayer
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Wu
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Amal
authors.initials: A
authors.lastname: Kambal
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Ernst
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. hiuchu@caltech.edu sarkis@caltech.edu.
authors.forename: Sarkis K
authors.initials: SK
authors.lastname: Mazmanian
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001343:Autophagy / Q000276:immunology; D000071183:Autophagy-Related Proteins; D001441:Bacteroides fragilis / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics*; D003713:Dendritic Cells / Q000276:immunology; D000067128:Extracellular Vesicles / Q000276:immunology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology / Q000382:microbiology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D011110:Polymorphism, Genetic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein