NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease

Hazel Tye, Chien-Hsiung Yu, Lisa A. Simms, Marcel R. Zoete, Man Lyang Kim, Martha Zakrzewski, Jocelyn S. Penington, Cassandra R. Harapas, Fernando Souza-Fonseca-Guimaraes, Leesa F. Wockner, Adele Preaudet, Lisa A. Mielke, Stephen A. Wilcox, Yasunori Ogura, Sinead C. Corr, Komal Kanojia, Konstantinos A. Kouremenos, David P. Souza, Malcolm J. McConville, Richard A. Flavell, Motti Gerlic, Benjamin T. Kile, Anthony T. Papenfuss, Tracy L. Putoczki, Graham L. Radford-Smith and Seth L. Masters ()
Additional contact information
Hazel Tye: The Walter and Eliza Hall Institute of Medical Research
Chien-Hsiung Yu: The Walter and Eliza Hall Institute of Medical Research
Lisa A. Simms: QIMR Berghofer Medical Research Institute
Marcel R. Zoete: Yale University School of Medicine
Man Lyang Kim: The Walter and Eliza Hall Institute of Medical Research
Martha Zakrzewski: QIMR Berghofer Medical Research Institute
Jocelyn S. Penington: The Walter and Eliza Hall Institute of Medical Research
Cassandra R. Harapas: The Walter and Eliza Hall Institute of Medical Research
Fernando Souza-Fonseca-Guimaraes: University of Melbourne
Leesa F. Wockner: QIMR Berghofer Medical Research Institute
Adele Preaudet: The Walter and Eliza Hall Institute of Medical Research
Lisa A. Mielke: University of Melbourne
Stephen A. Wilcox: University of Melbourne
Yasunori Ogura: Nara Women’s University
Sinead C. Corr: School of Genetics and Microbiology, Trinity College Dublin
Komal Kanojia: University of Melbourne
Konstantinos A. Kouremenos: University of Melbourne
David P. Souza: University of Melbourne
Malcolm J. McConville: University of Melbourne
Richard A. Flavell: Yale University School of Medicine
Motti Gerlic: Tel Aviv University
Benjamin T. Kile: University of Melbourne
Anthony T. Papenfuss: University of Melbourne
Tracy L. Putoczki: The Walter and Eliza Hall Institute of Medical Research
Graham L. Radford-Smith: QIMR Berghofer Medical Research Institute
Seth L. Masters: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Anti-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-producing Clostridiales in the gut. The colitis-protective effects of Nlrp1 deficiency are thus reversed by vancomycin treatment, but recapitulated with butyrate supplementation in wild-type mice. Moreover, an activating mutation in Nlrp1a increases IL-18 and IFNγ production, and decreases colonic butyrate to exacerbate colitis. We also show that, in patients with ulcerative colitis, increased NLRP1 in inflamed regions of the colon is associated with increased IFN-γ. In this context, NLRP1, IL-18 or IFN-γ expression negatively correlates with the abundance of Clostridiales in 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.

Date: 2018
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DOI: 10.1038/s41467-018-06125-0

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