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

Metformin responder and non-responder mouse models were successfully established via fecal microbiota transplantation from human patients.

• Fecal samples were collected from metformin-treated responders and non-responders and used to establish mouse models via fecal microbiota transplantation (FMT).
• The models recapitulated the differential hypoglycemic efficacy of metformin observed in human patients.
• This approach allowed mechanistic investigation of gut microbiota contributions to metformin responsiveness in a controlled animal setting.

Baicalin co-administration with metformin significantly ameliorated insulin resistance in non-responder mice.

• Baicalin was administered in combination with metformin in the non-responder mouse model.
• Co-administration significantly improved insulin resistance compared to metformin alone in non-responder mice.
• Baicalin is described as a microbiota-modulating flavonoid derived from Radix Scutellariae.

Baicalin reduced serum imidazole propionate (ImP) levels and suppressed downstream p38γ/Akt/AMPK(S485) signaling while restoring AMPK(T172) phosphorylation in non-responder mice.

• Serum ImP levels were significantly reduced following baicalin co-administration in non-responder mice.
• Suppression of p38γ/Akt/AMPK(S485) signaling was observed, a pathway previously linked to ImP-mediated metformin resistance.
• AMPK(T172) phosphorylation, which is required for metformin's hypoglycemic action, was restored by baicalin treatment.
• These signaling changes are consistent with reinstatement of metformin's mechanism of action.

Baicalin markedly suppressed key ImP-producing bacteria, specifically Staphylococcus epidermidis and Streptococcus mutans.

• Gut microbiota analysis identified S. epidermidis and S. mutans as key ImP-producing bacteria modulated by baicalin.
• Suppression of these bacteria was further validated in vitro.
• Colonization with S. epidermidis alone was sufficient to induce metformin non-response in previously responsive mice, establishing a causal role for this bacterium.

Colonization with Staphylococcus epidermidis induced metformin non-response in previously metformin-responsive mice.

• Previously responsive mice that were colonized with S. epidermidis lost their metformin responsiveness.
• This finding establishes a causal relationship between S. epidermidis colonization and metformin non-response.
• This result validates S. epidermidis as a key mediator of metformin resistance through ImP production.

Baicalin increased the abundance of SCFA-producing bacteria and elevated colonic short-chain fatty acid (SCFA) levels.

• Gut microbiota analysis revealed that baicalin enriched SCFA-producing bacterial populations.
• Colonic SCFA levels were elevated following baicalin treatment.
• The increase in SCFAs was identified as a key mechanism through which baicalin exerts its effects on metformin responsiveness.

SCFAs reduced ImP production by inhibiting the growth of ImP-producing bacteria, thereby enhancing metformin responsiveness.

• In vitro experiments were conducted to investigate the mechanism by which SCFAs affect ImP production.
• SCFAs were found to inhibit the growth of ImP-producing bacteria (S. epidermidis and S. mutans).
• This inhibition of bacterial growth led to reduced ImP production.
• Reduced ImP levels were associated with enhanced metformin responsiveness, linking SCFA elevation to restored drug efficacy.