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

Abstract

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. Microbiota-host nuclear receptor communication is increasingly recognized to regulate human health and disease. This study describes vaccenic acid, isolated from gut bacteria, as a novel LRH-1 ligand and activator, capable of improving metabolic disease development when administered in vivo. LRH-1 is a nuclear receptor, regulating metabolic processes. Lipids from gut bacteria were found to regulate activity of LRH-1. Vaccenic acid (VA), a natural fatty acid found mainly in meat and dairy products, was identified from these lipids as a novel LRH-1 activator. In a mouse model of diet-induced metabolic syndrome, VA improved glucose homeostasis and reduced hepatic lipogenesis. These findings reveal a new microbiota-liver communication pathway through VA-mediated LRH-1 activation, and suggest potential therapeutic approaches employing diet, probiotics, prebiotics, or VA-based therapies. LRH-1 is a nuclear receptor, regulating metabolic processes. Lipids from gut bacteria were found to regulate activity of LRH-1. Vaccenic acid (VA), a natural fatty acid found mainly in meat and dairy products, was identified from these lipids as a novel LRH-1 activator. In a mouse model of diet-induced metabolic syndrome, VA improved glucose homeostasis and reduced hepatic lipogenesis. These findings reveal a new microbiota-liver communication pathway through VA-mediated LRH-1 activation, and suggest potential therapeutic approaches employing diet, probiotics, prebiotics, or VA-based therapies. Microbiota-host nuclear receptor communication is increasingly recognized to regulate human health and disease. This study describes vaccenic acid, isolated from gut bacteria, as a novel LRH-1 ligand and activator, capable of improving metabolic disease development when administered in vivo.