NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis

• Published in: Cell Vol. 145; no. 5; pp. 745 - 757
• Main Authors: Elinav, Eran, Strowig, Till, Kau, Andrew L., Henao-Mejia, Jorge, Thaiss, Christoph A., Booth, Carmen J., Peaper, David R., Bertin, John, Eisenbarth, Stephanie C., Gordon, Jeffrey I., Flavell, Richard A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.05.2011
• Subjects: adults; Animals; Antibiotics; Antibodies; Bacteria - classification; Bacteroidetes; Caspase-1; chemokine CCL5; Chemokine CCL5 - metabolism; Colitis; Colitis - chemically induced; Colitis - immunology; Colitis - microbiology; Colitis - physiopathology; Colon - immunology; Colon - microbiology; Dextran; Dextran Sulfate; Disease Susceptibility; Electron microscopy; Epithelial cells; Fecal coliforms; humans; Hyperplasia; Inflammasomes - immunology; Inflammation; Interleukin 18; Interleukin-18 - immunology; Intestine; Mice; Mice, 129 Strain; Mice, Inbred C57BL; microbial ecology; microorganisms; Microscopy; multiprotein complexes; Neonates; phenotype; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; recruitment; risk; Sensors; Sodium; sodium sulfate; Sulfates
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2011.04.022

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. [Display omitted] [Display omitted] ► 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