Myricetin alleviates diabetic cardiomyopathy by regulating gut microbiota and their metabolites

BACKGROUND: The gut microbiota is involved in the pathogenesis of diabetic cardiomyopathy (DCM). Myricetin protects cardiac function in DCM, but its low bioavailability does not fully explain its mechanisms. Given reported beneficial effects of myricetin on gut microbiota, the authors hypothesized that myricetin improves DCM by regulating gut microbiota. METHODS: DCM was induced in mice using streptozotocin (STZ) and a high-fat diet (HFD), followed by 16 weeks of myricetin treatment by gavage. Gut microbiota composition, cardiac structure/function, intestinal barrier function, and inflammation were assessed. Fecal microbiota transplantation (FMT) using gut contents from treated or control mice was performed in DCM mice to evaluate microbiota-mediated effects. RESULTS: Myricetin improved cardiac function in DCM mice, reducing cardiomyocyte hypertrophy and interstitial fibrosis. It increased the abundance of short-chain fatty acid-producing bacteria (e.g., Roseburia, Faecalibaculum, Bifidobacterium), elevated occludin expression and goblet cell numbers, and reduced TLR4/MyD88 pathway-related proteins. FMT from myricetin-treated or control donors improved cardiac function, increased goblet cells and occludin expression, and reduced hypertrophy and TLR4/MyD88 signaling in recipient DCM mice. CONCLUSIONS: Myricetin can prevent DCM development by increasing beneficial gut microbiota and restoring gut barrier function.