The gut microbiota mediates epoxy eicosanoid metabolism in the colon

The metabolism of polyunsaturated fatty acids by cytochrome P450 (CYP) mono-oxygenases generates fatty acid epoxides, which are endogenous lipid mediators with potent actions to regulate inflammation, immune responses, vascular tone, and other critical biological processes. While previous research about their biosynthesis has focused on host metabolic enzymes, the role of gut microbiota remains largely unknown. Here, we demonstrate that the gut microbiota directly participates in the metabolism of fatty acid epoxides in the colon by catalyzing their conversion to fatty acid diols, thereby modulating colonic concentrations of these lipid mediators and associated biological actions. Using LC-MS/MS to analyze CYP-derived eicosanoids in the colons of conventionally raised versus germ-free or antibiotic-treated mice, we find that gut microbiota decreases colonic levels of fatty acid epoxides. Mechanistically, we find that the gut microbiota-mediated changes in colonic CYP eicosanoids are not driven by altered host biosynthetic enzyme expression; instead, gut microbes directly catalyze the hydrolysis of fatty acid epoxides to diols. Given the critical roles of CYP eicosanoids in regulating human health, our findings suggest that microbial metabolism of these lipid mediators may contribute to the mechanism by which gut microbiota influences host metabolism and disease development.