Elsevier

Mucosal Immunology

Volume 10, Issue 4, July 2017, Pages 971-982
Mucosal Immunology

Article
Genetic deletion of the bacterial sensor NOD2 improves murine Crohn's disease-like ileitis independent of functional dysbiosis

https://doi.org/10.1038/mi.2016.98Get rights and content
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Abstract

Although genetic polymorphisms in NOD2 (nucleotide-binding oligomerization domain-containing 2) have been associated with the pathogenesis of Crohn's disease (CD), little is known regarding the role of wild-type (WT) NOD2 in the gut. To date, most murine studies addressing the role of WT Nod2 have been conducted using healthy (ileitis/colitis-free) mouse strains. Here, we evaluated the effects of Nod2 deletion in a murine model of spontaneous ileitis, i.e., the SAMP1Yit/Fc (SAMP) strain, which closely resembles CD. Remarkably, Nod2 deletion improved both chronic cobblestone ileitis (by 50% assessed, as the % of abnormal mucosa at 24 wks of age), as well as acute dextran sodium sulfate (DSS) colitis. Mechanistically, Th2 cytokine production and Th2-transcription factor activation (i.e., STAT6 phosphorylation) were reduced. Microbiologically, the effects of Nod2 deletion appeared independent of fecal microbiota composition and function, assessed by 16S rRNA and metatranscriptomics. Our findings indicate that pharmacological blockade of NOD2 signaling in humans could improve health in Th2-driven chronic intestinal inflammation.

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Published online: 16 November 2016

Author contributions D.C., A.R.-P., E.B.C., K.O.A., T.T.P. and F.C. designed experimental studies, analyzed data and wrote the manuscript. D.C., A.R.-P., G.D.S., L.D.M. and D.A.A. conducted experiments, acquired and analyzed data.

SUPPLEMENTARY MATERIAL is linked to the online version of the paper

D Corridoni and A Rodriguez-Palacios: Co-First Authors.