The diet-derived gut microbial metabolite 3-phenylpropionic acid reverses insulin resistance and obesity-associated metabolic dysfunction

BACKGROUND/PURPOSE: Obesity-associated metabolic disorders, including type 2 diabetes and metabolic dysfunction associated fatty liver disease (MAFLD), are major global health burdens. While dietary polyphenols have shown promise in ameliorating these conditions, their efficacy is dependent on specialized gut microbial metabolism, and the underlying molecular mechanisms remain mostly elusive. Here, we demonstrate that dietary supplementation with polyphenol-rich elderberry (Eld) extract abrogates the effects of an obesogenic diet in a gut microbiota-dependent manner, preventing insulin resistance and reducing hepatic steatosis in mice. METHODS: We developed a targeted, quantitative liquid chromatography-tandem mass spectrometry method for detection of gut bacterial polyphenol catabolites and identified 3-phenylpropionic acid as a key microbial metabolite in the portal plasma of Eld supplemented animals. RESULTS: We showed that 3-phenylpropionic acid potently activates hepatic AMP-activated protein kinase α, explaining its role in improved liver lipid homeostasis. We further uncovered the metabolic pathway cumulating in 3-phenylpropionic acid for the common gut commensal Clostridium sporogenes. CONCLUSION: Our findings establish 3-phenylpropionic acid as a diet-derived, microbiota-dependent metabolite with insulin-sensitizing and anti-steatotic activities and provide a molecular basis for prebiotic interventions to improve host metabolic health.