Probiotic Supplementation With Bifidobacterium longum Subsp. Longum BL21 Improves Glycemic Control and Modulates Gut Microbiota in Type 2 Diabetes: A Randomized Controlled Trial

ABSTRACT Type 2 diabetes mellitus (T2DM) remains a major global health challenge, with emerging evidence highlighting the therapeutic potential of gut microbiota modulation. This study aimed to evaluate the efficacy and safety of Bifidobacterium longum subsp. longum BL21 as an adjunctive therapy to metformin in patients with T2DM. In this 12‐week, randomized, double‐blind, placebo‐controlled trial, patients with T2DM received either metformin plus BL21 or metformin plus placebo. The primary endpoint was the change in hemoglobin A1c (HbA1c), while secondary endpoints included changes in fasting blood glucose (FBG), insulin resistance, lipid profiles, and gut microbiota composition. Supplementation with BL21 led to a significant reduction in HbA1c levels ( p = 0.026) compared with placebo. Non‐significant trends toward reduction were also observed for FBG and insulin resistance. The intervention was well tolerated, with a safety profile comparable to placebo. Gut microbiota analysis revealed an increase in beneficial genera, including Bifidobacterium and Faecalibacterium , alongside a reduction in pathogenic taxa in the BL21 group. As an adjunct to metformin, BL21 supplementation improved glycemic control and modulated gut microbiota in patients with T2DM. These findings support the potential of BL21 as a novel adjunctive strategy for T2DM management, warranting further validation in larger and longer‐term studies. Clinical Trial Registration Number : ChiCTR2300073299.