title: NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis.
abstract: 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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Eran
authors.initials: E
authors.lastname: Elinav
authors.forename: Till
authors.initials: T
authors.lastname: Strowig
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kau
authors.forename: Jorge
authors.initials: J
authors.lastname: Henao-Mejia
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Thaiss
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Booth
authors.forename: David R
authors.initials: DR
authors.lastname: Peaper
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Gordon
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D001419:Bacteria / Q000145:classification; D041963:Bacteroidetes; D018946:Chemokine CCL5 / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000382:microbiology* / Q000503:physiopathology; D003106:Colon / Q000276:immunology / Q000382:microbiology*; D016264:Dextran Sulfate; D004198:Disease Susceptibility; D058847:Inflammasomes / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D058847:Inflammasomes; D020382:Interleukin-18; C559901:Nod-like receptor pyrin domain-containing protein 6, mouse; D011956:Receptors, Cell Surface; D016264:Dextran Sulfate