This study indicates that colonization of the intestinal mucosa by highly invasive strains of F. nucleatum may be a useful biomarker for gastrointestinal disease.
Attenuated innate immune responses to the intestinal microbiota have been linked to the pathogenesis of Crohn’s disease (CD). Recent genetic studies have revealed that hypofunctional mutations of NLRP3, a member of the NOD-like receptor (NLR) superfamily, are associated with an increased risk of developing CD. NLRP3 is a key component of the inflammasome, an intracellular danger sensor of the innate immune system. When activated, the inflammasome triggers caspase-1-dependent processing of inflammatory mediators, such as IL-1β and IL-18. In the current study we sought to assess the role of the NLRP3 inflammasome in the maintenance of intestinal homeostasis through its regulation of innate protective processes. To investigate this role, Nlrp3−/− and wild-type (WT) mice were assessed in the DSS- and TNBS-models of experimental colitis. Nlrp3−/− mice were found to be more susceptible to experimental colitis, an observation that was associated with reduced IL-1β reduced anti-inflammatory cytokine IL-10, and reduced protective growth factor TGF-β. Macrophages isolated from Nlrp3−/− mice failed to respond to bacterial muramyl dipeptide. Furthermore, Nlrp3-deficient neutrophils exhibited reduced chemotaxis and enhanced spontaneous apoptosis, but no change in oxidative burst. Lastly, Nlrp3−/− mice displayed altered colonic β-defensin expression, reduced colonic antimicrobial secretions and a unique intestinal microbiota. Our data confirm an essential role for the NLRP3 inflammasome in the regulation of intestinal homeostasis and provide biological insight into disease mechanisms associated with increased risk of CD in individuals with NLRP3 mutations.
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