Pharmaceutical Impact of and Metformin Combination on High-Fat-Diet-Induced Metabolic Disorders: Link to Intestinal Microbiota and Metabolic Endotoxemia

Metformin and are representative anti-diabetic therapeutic agents in western and oriental medicinal fields, respectively. The present study examined the therapeutic effects of extract (HCE) and metformin in combination in a dysmetabolic mouse model. Metabolic disorders were induced in C57BL/6J mice by high fat diet (HFD) for 14 weeks. Combination of metformin and HCE significantly lowered body weight, abdominal fat, perirenal fat, liver and kidney weights, but did not change epididymal fat in HFD-fed animals. Metformin + HCE treatment markedly attenuated the elevated serum levels of TG, TC, AST, ALT, and endotoxin and restored the depleted HDL level. Both HCE and metformin + HCE treatment ameliorated glucose tolerance and high level of fasting blood glucose in association with AMPK activation. Moreover, treatment with HCE + metformin dramatically suppressed inflammation in HFD-fed animals via inhibition of proinflammatory cytokines (MCP-1 and IL-6) and LPS receptor (TLR4). Histopathological findings showed that exposure of HFD-treated animals to metformin + HCE ameliorated fatty liver, shrinkage of intestinal villi and adipocytes enlargement. Furthermore, HCE and metformin + HCE treatments markedly modulated the abundance of gut Gram-negative bacteria, including and , but not universal Gram-positive bacteria. Overall, HCE and metformin cooperatively exert their therapeutic effects via modulation of gut microbiota, especially reduction of Gram-negative bacteria, resulting in alleviation of endotoxemia.