Gut Microbiota Mediate the Metabolism of Colonic Prostaglandins

Prostaglandins (PGs) are endogenous lipid signaling molecules that regulate diverse physiological and pathological processes, and their biosynthetic pathways are targets of widely used drugs such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) 1-7. However, previous research of PG biosynthesis has focused on host metabolic pathways; as such, the contribution of gut microbiota remains unknown 1. Here, we demonstrate a colonic pathway in which gut microbes directly participate in PG metabolism, thereby regulating intestinal PG levels and their biological effects. Comparison of germ-free and conventionally raised mice reveals that the gut microbiota markedly increase gut levels of multiple PGs. This effect is driven by bacterial β-glucuronidases (GUS), which hydrolyze host-derived PG glucuronides – less active or inactive conjugates – to regenerate bioactive, free-form PGs. Administration of purified GUS enzyme or mono-colonization with wild-type or GUS-deficient bacteria in germ-free mice demonstrates the critical role for microbial GUS in regulating intestinal PG levels and downstream biological responses. Together, these findings reveal a previously unrecognized function of the gut microbiota in PG metabolism and highlight microbial pathways as potential targets for modulating colonic PG signaling to prevent or treat gastrointestinal disease.