Cell
Volume 145, Issue 5, 27 May 2011, Pages 745-757
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Article
NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis

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Summary

Inflammasomes are multiprotein complexes that function as sensors of endogenous or exogenous damage-associated molecular patterns. Here, we show that deficiency of NLRP6 in mouse colonic epithelial cells results in reduced IL-18 levels and altered fecal microbiota characterized by expanded representation of the bacterial phyla Bacteroidetes (Prevotellaceae) and TM7. NLRP6 inflammasome-deficient mice were characterized by spontaneous intestinal hyperplasia, inflammatory cell recruitment, and exacerbation of chemical colitis induced by exposure to dextran sodium sulfate (DSS). Cross-fostering and cohousing experiments revealed that the colitogenic activity of this microbiota is transferable to neonatal or adult wild-type mice, leading to exacerbation of DSS colitis via induction of the cytokine, CCL5. Antibiotic treatment and electron microscopy studies further supported the role of Prevotellaceae as a key representative of this microbiota-associated phenotype. Altogether, perturbations in this inflammasome pathway, including NLRP6, ASC, caspase-1, and IL-18, may constitute a predisposing or initiating event in some cases of human IBD.

Highlights

► NLRP6 inflammasome in colonic epithelium regulates gut microflora ► NLRP6−/− mice exhibit dysbiosis, with expansion of Prevotellaceae and TM7 ► Dysbiosis results in transmissible autoinflammation ► Microflora-induced inflammation is caused by epithelial CCL5 induction

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These authors contributed equally to this work