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.
Highlights
Anti-microbial signaling pathways are normally triggered by innate immune receptors when detecting pathogenic microbes to provide protective immunity
We studied mice with single deletion of Nlrp1a, and found a similar protection from dextran sulfate sodium (DSS)-induced colitis associated with reduced weight loss and decreased severity of inflammation quantified by colonoscopy (Supplementary Fig. 1a, b)
We have shown that loss of the Nlrp[1] inflammasome ameliorates DSS-induced colitis by promoting expansion of beneficial gut microbes belonging to the Clostridiales phylum, with concomitant increased butyrate production in the colon
Summary
Anti-microbial signaling pathways are normally triggered by innate immune receptors when detecting pathogenic microbes to provide protective immunity. Systems Biology and Personalized Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. The genetic deletion of IL-18 from mice has opposing effects in models of colitis, depending on whether it is produced by hematopoietic or non-hematopoietic cells[7,8,9] Both IL1β and IL-18 may have pleiotropic effects in IBD, perhaps depending on localization, disease severity, kinetics of cytokine production or other factors such as microbiome colonization and species differences. The last decade has seen a dramatic increase in research regarding the role of the microbiome and inflammasomes in IBD7,10 This link was initially established with the finding that severe dextran sulfate sodium (DSS)-induced colitis observed in NLRP3- and NLRP6-deficient mice could be transferred to co-housed wild-type (WT) mice[7,10]. Rare mutations in a linker region between the NACHT and LRR domains can cause a similar disease[18], which is the same location as we observed for the mutation activating mouse Nlrp1a13
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