Targeting the Gut Microbiota-Metabolism Axis: Novel Pharmacological Mechanisms and Translational Application Strategies for Oral Antidiabetic Drugs.

Authors

Ruodi Yang, Shichao Zhang, Zishan Fu, Yufeng Yang, Qingfeng Wang, Ying Zhou, Jiaxin Li, Ruisi Yang, Shunyu Ning, Yan Shi, Juntong Liu

Published in

Medicinal research reviews. Oct 18, 2026. Epub Oct 18, 2026.

Abstract

Type 2 diabetes mellitus (T2DM) is a highly prevalent chronic metabolic disease worldwide, and the clinical prevention and control situation is severe. Although the various antidiabetic drugs currently in clinical use can lower blood glucose levels through different mechanisms, there are significant differences in efficacy among individuals. Existing evidence suggests that differences in gut microbiota (GM) composition and metabolic function may be one of the key factors contributing to the heterogeneity in drug efficacy. Based on this, this review describes the physiological and pathological mechanisms of the GM-metabolism axis and systematically reviews the modulatory effects of different classes of antidiabetic drugs on this axis and their underlying mechanisms. Available studies suggest that metformin, α-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), thiazolidinediones (TZDs), and oral glucagon-like peptide-1 receptor agonists (GLP-1RAs) may differentially affect GM composition and/or microbial metabolites, including short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), and bile acids. These alterations may be associated with glucose homeostasis and insulin resistance through pathways involving GPR41/43, HDACs, AMPK, mTORC1/S6K1, FXR-FGF15/19, and TGR5-GLP-1 signaling. By integrating clinical and mechanistic evidence, this review highlights the potential contribution of the GM-metabolism axis to the glucose-lowering effects of antidiabetic drugs. However, the quantity and confidence of evidence vary substantially across drug classes, and causal and clinical relevance requires further validation. These findings provide a basis for future research on personalized interventions for T2DM characterized by SCFA-producing bacterial deficiency, BCAA overload, or dysregulated bile acid metabolism.

PMID:
42893515
Bibliographic data and abstract were imported from PubMed on 19 Oct 2026.

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