Microbiome-host communication via vaccenic acid modulates LRH-1/NR5A2 activity and ameliorates metabolic liver disease.

Interactions between microbiota and the host can profoundly affect human health. In particular, microbiota-derived metabolites influence liver physiology and contribute to the development of metabolic diseases, yet the molecular mechanisms underlying microbiome-host communication remain incompletely understood. Here, we identify bacterial lipids as modulators of the nuclear receptor Liver Receptor Homolog-1 (LRH-1/NR5A2), a regulator of hepatic metabolism. Lipid extracts from multiple bacterial species, including the probiotic Bifidobacterium animalis subsp. lactis B420TM, activated LRH-1, leading to the identification of the long-chain fatty acid vaccenic acid (VA) as a previously unrecognized endogenous LRH-1 ligand. VA directly bound the LRH-1 ligand-binding domain and stimulated receptor-dependent transcriptional activity. In high-fat diet-induced obese and hyperglycemic mice, VA-mediated LRH-1 activation improved glucose homeostasis and attenuated metabolic liver disease. Transcriptomic analyses revealed suppression of hepatic de novo lipogenesis as a principle downstream response to LRH-1 activation. Together, these findings establish a microbiota-LRH-1 signaling axis that links bacterial lipid metabolism to host metabolic regulation, identify VA as a functional LRH-1 agonist, and provide a mechanistic rationale for targeting LRH-1 in metabolic liver disease.