Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus

Immunity. 2014 Aug 21;41(2):311-24. doi: 10.1016/j.immuni.2014.06.015. Epub 2014 Jul 31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Typing Techniques
  • Bacteroides / immunology*
  • Crohn Disease / immunology
  • Disease Susceptibility / immunology*
  • Enteritis / genetics
  • Enteritis / immunology*
  • Goblet Cells / pathology
  • Inflammation / genetics
  • Inflammation / immunology
  • Interferon-gamma / biosynthesis
  • Intestinal Mucosa / immunology
  • Intestine, Small / immunology*
  • Intestine, Small / microbiology
  • Lymphocytes / immunology
  • Mice
  • Mice, Knockout
  • Microbiota / immunology
  • Myeloid Differentiation Factor 88 / immunology
  • Nod2 Signaling Adaptor Protein / genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Signal Transduction / immunology

Substances

  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Nod2 Signaling Adaptor Protein
  • Nod2 protein, mouse
  • Interferon-gamma
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk2 protein, mouse

Associated data

  • GEO/GSE58948