title: Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus.
abstract: Nod2 has been extensively characterized as a bacterial sensor that induces an antimicrobial and inflammatory gene expression program. Therefore, it is unclear why Nod2 mutations that disrupt bacterial recognition are paradoxically among the highest risk factors for Crohn's disease, which involves an exaggerated immune response directed at intestinal bacteria. Here, we identified several abnormalities in the small-intestinal epithelium of Nod2(-/-) mice including inflammatory gene expression and goblet cell dysfunction, which were associated with excess interferon-γ production by intraepithelial lymphocytes and Myd88 activity. Remarkably, these abnormalities were dependent on the expansion of a common member of the intestinal microbiota Bacteroides vulgatus, which also mediated exacerbated inflammation in Nod2(-/-) mice upon small-intestinal injury. These results indicate that Nod2 prevents inflammatory pathologies by controlling the microbiota and support a multihit disease model involving specific gene-microbe interactions.
authors.affiliation: Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Sackler Institute of Graduate Biomedical Science, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Deepshika
authors.initials: D
authors.lastname: Ramanan
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Mei San
authors.initials: MS
authors.lastname: Tang
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Rowann
authors.initials: R
authors.lastname: Bowcutt
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: P'ng
authors.initials: P
authors.lastname: Loke
authors.affiliation: Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: ken.cadwell@med.nyu.edu.
authors.forename: Ken
authors.initials: K
authors.lastname: Cadwell
mesh_terms: D000818:Animals; D015373:Bacterial Typing Techniques; D001439:Bacteroides / Q000276:immunology*; D003424:Crohn Disease / Q000276:immunology; D004198:Disease Susceptibility / Q000276:immunology*; D004751:Enteritis / Q000235:genetics / Q000276:immunology*; D020397:Goblet Cells / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology; D007421:Intestine, Small / Q000276:immunology* / Q000382:microbiology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D064307:Microbiota / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D007371:Interferon-gamma; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse
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