The gut microbial lauroyl tryptamine antagonizes oxysterol-GPR183 signaling to modulate lipid-sensitive metabolic pathways in a sex-dependent manner

Objectives GPR183, a G protein–coupled receptor activated by oxysterols, regulates immune and metabolic signaling in a sex-dependent manner. Lauroyl tryptamine (LT), a lipid-modified microbial metabolite, was recently identified as a GPR183 antagonist. We hypothesized that LT disrupts oxysterol-driven metabolic regulation by antagonizing GPR183 activity. Methods LT's antagonistic properties were assessed using BRET-based assays for GPR183-mediated arrestin recruitment and G protein signaling. LT absorption was quantified in isolated perfused rat colon. Metabolic outcomes were evaluated in wild-type (WT) and Gpr183 knockout (Gpr183 − / − ) mice treated with LT or the synthetic antagonist NIBR189. To examine microbiota contributions, cecal contents from WT and Gpr183 − / − mice were transplanted into germ-free recipients, and metabolic phenotypes were analyzed. Results LT selectively inhibited oxysterol (7α,25-OHC)-induced arrestin recruitment via human and mouse GPR183 without altering Gαi signaling. LT was absorbed across the colonic epithelium in a dose-dependent manner. Female mice treated with NIBR189 but not LT exhibited differences in body weight change and glucose homeostasis. Microbiota transfer did not reproduce the phenotype. LT induced weight loss in male WT mice, but not in Gpr183 − / − males. Conclusion LT functions as a pathway-specific antagonist of oxysterol signaling via GPR183, modulating lipid-sensitive metabolic pathways in a sex-dependent manner.