Gut microbiota-derived metabolite pantetheine modulates host lipid metabolism to protect against obesity

Obesity is intricately linked to the gut microbiota, yet the microbial effectors and molecular mechanisms that mediate this association remain poorly defined. Fecal microbiome analysis revealed a consistent depletion of the commensal bacterium Roseburia inulinivorans in obese individuals, with its relative abundance inversely correlating with adiposity. This inverse correlation was recapitulated in diet-induced obese mice. Supplementation with R. inulinivorans or its encapsulated form in these mice attenuated high-fat diet-induced weight gain and improved metabolic parameters. Subsequent metabolomic profiling of murine samples identified pantetheine as a key metabolite derived from R. inulinivorans. Administration of pantetheine alone was sufficient to recapitulate the anti-obesity effects observed with bacterial supplementation. Mechanistically, pantetheine modulates adrenergic receptor signaling and directly inhibits lipid droplet accumulation in adipocytes. These findings establish a causal gut-adipose axis wherein R. inulinivorans-derived pantetheine regulates host lipid metabolism to protect against obesity, revealing a novel target for microbiome-based metabolic therapeutics.