A study using mice with human gut microbes showed that adding the plant compound baicalin to metformin helped lower blood sugar in people who normally don’t respond to the drug. The benefit seemed to come from a boost in a gut bacterium called Roseburia hominis, which improved a fat‑acid pathway linked to energy metabolism. While promising, the work is still early and done in animals, so it’s not a ready‑to‑use protocol for humans yet.

Metformin is the most commonly used hypoglycemic drug for patients with type 2 diabetes (T2D), but about 30% of patients show non-response potentially linked to gut microbiota imbalance. Although baicalin exhibits potent gut microbiota-modulating activity, its role in reversing metformin non-response remains unclear. Here, we recruited patients with T2D who were non-responders to metformin treatment and collected their fecal samples to construct a humanized mouse model via fecal microbial transplantation. We found that baicalin combined with metformin improved the abnormal glucose tolerance in non-response mice, in which <i>Roseburia hominis</i> was considerably enriched. Mechanically, baicalin combined with metformin activated the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC)/carnitine palmitoyl transferase 1 (CPT1) pathway, and its enriched <i>R. hominis</i> promoted linolenic acid metabolism, thus reversing the non-response to metformin. Besides, the efficacy of <i>R. hominis</i> in reversing the non-response of metformin was dependent on phospholipase A2 (linolenic acid metabolism key enzyme). Our findings provide feasibility strategies for the metformin treatment of non-responsive patients.