Baicalin Restores the Hypoglycemic Effect of Metformin by Regulating the Microbial Imidazole Propionate and Short‐Chain Fatty Acids

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Gut microbiota dysbiosis is implicated in metformin non-response. This study aimed to investigate whether baicalin, a microbiota-modulating flavonoid derived from Radix Scutellariae, could restore metformin sensitivity and explored the underlying mechanisms. Fecal samples from metformin-treated responders and non-responders were collected and used to establish mouse models via fecal microbiota transplantation (FMT). The hypoglycemic efficacy of baicalin in combination with metformin was then evaluated. Serum levels of imidazole propionate (ImP) and the expression of downstream signaling proteins were assessed. Gut microbiota analysis identified ImP-producing bacteria modulated by baicalin, which was further validated in vitro. The roles of these bacteria and short-chain fatty acids (SCFAs) in metformin responsiveness were also examined. In vitro experiments were conducted to investigate the mechanism of SCFAs affect the production of ImP. Metformin responder and non-responder mouse models were successfully established. Baicalin co-administration significantly ameliorated insulin resistance in non-responder mice, reduced serum ImP levels, suppressed p38γ/Akt/AMPK (S485) signaling, and restored AMPK (T172) phosphorylation. Baicalin markedly suppressed key ImP-producing bacteria- Staphylococcus epidermidis and Streptococcus mutans . Notably, colonization with S. epidermidis induced metformin non-response in previously responsive mice. Furthermore, baicalin increased the abundance of SCFA-producing bacteria and elevated colonic SCFAs levels. SCFAs reduced ImP production by inhibiting the growth of ImP-producing bacteria, thereby enhancing metformin responsiveness. These findings indicate that baicalin restores metformin sensitivity by enriching SCFAs, suppressing ImP-producing bacteria, and lowering serum ImP, thereby reinstating metformin's hypoglycemic action. This study supports the potential of baicalin as an adjunct therapy for overcoming metformin non-response.

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