Abstract
Bile acids are critical metabolites in the gastrointestinal tract and contribute to maintaining intestinal immune homeostasis through cross-talk with the gut microbiota. The conversion of bile acids by the gut microbiome is now recognized as a factor affecting both host metabolism and immune responses, but its physiological roles remain unclear. We conducted a screen for microbiome metabolites that would function as inflammasome activators and herein report the identification of 12-oxo-lithocholic acid (BAA485), a potential microbiome-derived bile acid metabolite. We demonstrate that the more potent analogue 11-oxo-12S-hydroxylithocholic acid methyl ester (BAA473) can induce secretion of interleukin-18 (IL-18) through activation of the inflammasome in both myeloid and intestinal epithelial cells. Using a genome-wide CRISPR screen with compound induced pyroptosis in THP-1 cells, we identified that inflammasome activation by BAA473 is pyrin-dependent (MEFV). To our knowledge, the bile acid analogues BAA485 and BAA473 are the first small molecule activators of the pyrin inflammasome. We surmise that pyrin inflammasome activation through microbiota-modified bile acid metabolites such as BAA473 and BAA485 plays a role in gut microbiota regulated intestinal immune response. The discovery of these two bioactive compounds may help to further unveil the importance of pyrin in gut homeostasis and autoimmune diseases.
Highlights
Bile acids are critical metabolites in the gastrointestinal tract and contribute to maintaining intestinal immune homeostasis through cross-talk with the gut microbiota
The stimulation of microbe-associated molecular patterns or damage-associated molecular patterns triggers the assembly of the cytosolic inflammasome, a multiprotein complex that leads to the release of interleukin 1 (IL-1)3 and interleukin 18 (IL18) and induction of pyroptosis, a type of inflammasome-associated cell death [1]
Whereas none of the principal bile acids, including deoxycholic acid (DCA), induced IL-18 production (Fig. S1 and see Fig. 6, B and C), 12-oxo-lithocholic acid (BAA485), a putative intestinal bacteria-produced derivative of DCA [12], induced secretion of IL-18 in LPS-primed peripheral blood mononuclear cells (PBMCs) (Fig. 1, A and B). These results suggest that BAA485 could be an inflammasome activator and that C12 oxidation of DCA by the gut microbiota may potentially play a role in the immunogenicity of BAA485 [13]
Summary
We surmise that pyrin inflammasome activation through microbiota-modified bile acid metabolites such as BAA473 and BAA485 plays a role in gut microbiota regulated intestinal immune response. The discovery of these two bioactive compounds may help to further unveil the importance of pyrin in gut homeostasis and autoimmune diseases. Our results suggest that intestinal microbiota-mediated bile acid conversion may regulate intestinal immune homeostasis by modulating pyrin inflammasome signaling.
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