Journal article
NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease
H Tye, CH Yu, LA Simms, MR de Zoete, ML Kim, M Zakrzewski, JS Penington, CR Harapas, F Souza-Fonseca-Guimaraes, LF Wockner, A Preaudet, LA Mielke, SA Wilcox, Y Ogura, SC Corr, K Kanojia, KA Kouremenos, DP De Souza, MJ McConville, RA Flavell Show all
Nature Communications | NATURE PUBLISHING GROUP | Published : 2018
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 reg..
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Awarded by Victorian Cancer Agency
Funding Acknowledgements
We thank L. Cengia and R. Lane for excellent technical assistance, and L. Scott, C. Hay and R. Crawley for outstanding animal husbandry. This work was supported by: Australian National Health and Medical Research Council (NHMRC) Project Grants (1057815, 1099262), Program Grants (461219, 1054618), fellowships (to B.T.K., S.L.M., M.J.M.) and an Independent Research Institutes Infrastructure Support Scheme Grant (361646). Fellowships from the Victorian Endowment for Science Knowledge and Innovation (to S.L.M.), HHMI-Wellcome International Research Scholarship (to S.L.M.), the Australian Research Council (to B.T.K.), the Sylvia and Charles Viertel Foundation (to B.T.K. and S.L.M.), the WEHI Centenary Fellowship (to C.-H.Y.) and Ormond College's Thwaites Gutch Fellowship in Physiology (to C.-H.Y.), the WEHI Centenary Dyson Bequest (to T.L.P.), and the Victorian Cancer Agency (to T.L.P.); the Australian Cancer Research Fund, the Australian Phenomics Network, the Ian Potter Centre for Genomics and Personalized Medicine and a Victorian State Government Operational Infrastructure Support Grant. The human microarray work was supported by a research grant from Amgen (South San Francisco, CA 94080). S.L.M. receives funding from Glaxosmithkline.