Gut Roseburia hominis-derived 10-hydroxystearic acid alleviates metabolic disorder by restoring hepatic fatty acid metabolism

Abstract

Metabolic disorders and health-promoting dietary interventions represent complementary contexts of metabolic impairment and improvement, providing an opportunity to identify gut microbial taxa associated with both disease status and dietary response. Here, we integrated five independent human cohorts spanning metabolic disorders and dietary interventions and identified Roseburia hominis as a gut microbial taxon that consistently decreased in metabolic disorders and increased after dietary interventions. Beyond species abundance, strain-level genetic variation in R. hominis provided additional information for distinguishing metabolic disorder status and stratifying cardiometabolic severity. Integration of phenotype-associated variants with circulating metabolomics prioritized ohyA, encoding an oleate hydratase, as a candidate functional determinant linking R. hominis genetic variation to host metabolic heterogeneity. An ohyA-based genetic burden score was associated with adverse cardiometabolic traits and changed longitudinally during dietary intervention, while circulating metabolites statistically accounted for part of the associations between ohyA variants and host phenotypes. Functional experiments demonstrated that R. hominis OhyA protein converts oleic acid to 10-hydroxystearic acid (10-HSA), whereas an OhyA carrying five prioritized missense substitutions showed markedly impaired enzymatic activity. In high-fat diet-fed mice, 10-HSA attenuated body-weight gain, improved glucose homeostasis and insulin sensitivity, and reduced dyslipidemia and hepatic steatosis. Multi-omics profiling revealed limited remodeling of the gut microbiota but pronounced hepatic transcriptional and metabolic responses, characterized by activation of PPAR-associated lipid-metabolic pathways, altered fatty-acid oxidation and desaturation, and remodeling of hepatic lipid composition. Together, these findings establish a diet-responsive R. hominis-OhyA-10-HSA axis linking microbial variation to host metabolic dysfunction and show that 10-HSA can improve metabolic health in mice.