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Purpose: Metformin and Houttuynia cordata are representative anti-diabetic therapeutic agents in western and oriental medicinal fields, respectively. The present study examined the therapeutic effects of houttuynia cordata extract (HCE) and metformin in combination in a dysmetabolic mouse model.Methods: Metabolic disorders were induced in C57BL/6J mice by high fat diet (HFD) for 14 weeks.Results: 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 Escherichia coli and Bacteriodetes fragilis, but not universal Gram-positive bacteria.Conclusions: 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.