Metformin, the first-line treatment for type 2 diabetes, exerts antidiabetic effects partly by modulating gut microbiota. However, it can also increase Escherichia species capable of inducing endotoxemia via lipopolysaccharide (LPS). Clinical trials have reported a 21% failure rate of metformin monotherapy within 5 years. This study investigated gut microbiota composition and metabolic endotoxemia represented by LPS-binding protein (LBP), in relation to therapeutic responses to metformin-based therapy in type 2 diabetes.

We recruited 86 participants from a cohort of about 700 patients with type 2 diabetes treated at a medical center in southern Taiwan (from 2016 to 2024). Subjects were categorized into three groups: (1) good control on metformin monotherapy (GM, HbA1c ≤7%), (2) good control with metformin plus dipeptidyl peptidase-4 inhibitors (DPP4i) after failure on metformin monotherapy (GC, HbA1c ≤7%), and (3) poor control on metformin or metformin plus DPP4i (PC, HbA1c >7% but ≤9%). Biochemical parameters and plasma LBP levels were measured, and gut microbiota compositions were analyzed via 16S rRNA sequencing.

The GM, GC, and PC groups included 31, 32, and 23 participants, respectively. LBP levels were significantly higher in PC than in GM, paralleling greater HOMA-IR and GPT in PC. Total cholesterol was significantly higher in GM than in GC. Increased LBP in PC reflected greater metabolic endotoxemia. GM exhibited significantly reduced microbial richness and distinct microbial clustering compared with GC. Three taxa were enriched and 11 were depleted in GM versus both GC and PC. Among the 14 taxa significantly different between GM and either GC or PC, Ruminococcaceae (enriched in GM) was the only taxon demonstrating significantly negative correlation with LBP. Heatmap analysis further showed negative correlations of Ruminococcaceae with fasting glucose and HOMA-IR.

Our study demonstrated reduced gut microbiota diversity and distinct microbiota composition associated with lower metabolic endotoxemia in type 2 diabetes with durable metformin efficacy. SCFA (short-chain fatty acid) produced by gut microbes from undigested dietary fibers was known to decrease LBP. Being a SCFA producer specialized in butyrate production, the enriched Ruminococcaceae may contribute to sustained antidiabetic effects of metformin by counteracting metabolic endotoxemia with butyrate.