NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease

• DOI: 10.1038/s41467-018-06125-0
• Publication Date: 2018-09-07T13:29:45Z
• Authors: Hazel Tye; Chien-Hsiung Yu; Lisa A. Simms; Marcel R. de Zoete; Man Lyang Kim; Martha Zakrzewski; Jocelyn S. Penington; Cassandra R. Harapas; Fernando Souza-Fo...; Leesa F. Wockner; Adele Preaudet; Lisa A. Mielke; Stephen A. Wilcox; Yasunori Ogura; Sinead C. Corr; Komal Kanojia; Konstantinos A. K...; David P. De Souza; Malcolm J. McConv...; Richard A. Flavell; Motti Gerlic; Benjamin T. Kile; Anthony T. Papenfuss; Tracy L. Putoczki; Graham L. Radford...; Seth L. Masters
• Keywords: Male; Inflammasomes; T-Lymphocytes; Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/genetics; Inbred C57BL; Transgenic; Mice; Colon/pathology; 3100 Physics and Astronomy; Intestinal Mucosa; Ifn-Gamma; Clostridiales; 0303 health sciences; Microbiota; Q; Interleukin-18; Adaptor Proteins; Vancomycin/pharmacology; 1600 Chemistry; Colitis; 3. Good health; Butyrates; Female; Signal Transduction; T-Lymphocytes/cytology; 1300 Biochemistry; Colon; Science; Rectum/metabolism; Activation; 610; Genetics and Molecular Biology; Mice, Transgenic; Severity; Article; Interferon-gamma; 03 medical and health sciences; SDG 3 - Good Health and Well-being; Inflammatory Bowel Diseases/drug therapy; Pyroptosis; Animals; Humans; Butyrates/metabolism; Crohns-Disease; Polymorphism; Interleukin-18/metabolism; Interferon-gamma/metabolism; Adaptor Proteins, Signal Transducing; Inflammatory Bowel Diseases; Gastrointestinal Microbiome; Mice, Inbred C57BL; Susceptibility; Apoptosis Regulatory Proteins/genetics; Apoptosis Regulatory Proteins; Intestinal Mucosa/metabolism; Gene Deletion; Colitis/metabolism

AbstractAnti-microbial signaling pathways are normally triggered by innate immune receptors when detecting pathogenic microbes to provide protective immunity. Here we show that the inflammasome sensor Nlrp1 aggravates DSS-induced experimental mouse colitis by limiting beneficial, butyrate-producingClostridialesin the gut. The colitis-protective effects ofNlrp1deficiency are thus reversed by vancomycin treatment, but recapitulated with butyrate supplementation in wild-type mice. Moreover, an activating mutation inNlrp1aincreases IL-18 and IFNγ production, and decreases colonic butyrate to exacerbate colitis. We also show that, in patients with ulcerative colitis, increasedNLRP1in inflamed regions of the colon is associated with increasedIFN-γ. In this context,NLRP1,IL-18orIFN-γexpression negatively correlates with the abundance ofClostridialesin human rectal mucosal biopsies. Our data identify the NLRP1 inflammasome to be a key negative regulator of protective, butyrate-producing commensals, which therefore promotes inflammatory bowel disease.