Roseburia hominis enriched by baicalin reverses the non-response to metformin via upregulating linolenic acid metabolism

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.