Heptamethoxyflavone Alleviates Metabolic Syndrome in High-Fat Diet-Fed Mice by Regulating the Composition, Function, and Metabolism of Gut Microbiota

3,5,6,7,8,3',4'-Heptamethoxyflavone (HMF) could prevent obesity and hyperlipidemia, but its effects on gut microbiota and fecal metabolites remain unclear. Here, the effect of HMF on metabolic syndrome (MS) was evaluated in high-fat diet (HFD)-fed mice, and its underlying mechanisms were revealed by integrative metagenomic and metabolomic analyses. We demonstrated that HMF could effectively ameliorate HFD-induced MS by alleviating body-weight gain, fat accumulation, hepatic steatosis, and lipid and glucose abnormalities. HMF significantly altered the gut microbiota composition in HFD-fed mice with enrichment of short-chain fatty acid (SCFA)- and bile acid-producing beneficial bacteria and inhibition of harmful bacteria. Also, HMF improved microbial functions by up-regulating bile acid metabolism and down-regulating fatty acid metabolism and inflammatory response-related pathways. Consistent with the gut microbial changes, HMF altered the fecal metabolite profile of HFD-fed mice, mainly characterized by increasing SCFA and several bile acid levels as well as lowering several lysophospholipids and fatty acid levels. Correlation analysis indicated that three key species Faecalibaculum rodentium, Collinsella aerofaciens, and Lactobacillus fermentum and the increase in microbial metabolites, i.e., SCFAs and secondary bile acids, might play a positive role in alleviating MS. Our results suggested that HMF alleviated HFD-induced MS possibly by modulating the composition, function, and metabolism of gut microbiota.