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This study investigates how metformin affects cognitive performance in diabetic mice through changes in gut microbiota.

April 14, 2026Endocrine Metabolic & Immune Disorders - Drug Targets0 citationsOpen Access

The Key Genus of Gut Microbiota in Cognition Improvement Following Metformin Treatment in T2DM: A Two-sample Mendelian Randomization Study Combined 16s Rrna Sequencing

Key Points

This study investigates how metformin affects cognitive performance in diabetic mice through changes in gut microbiota.
Divided mice into five groups: control, diabetes, Metformin + diabetes, control + fecal microbiota transplantation (FMT), diabetes + FMT.
Assessed cognitive function and plasma long-chain fatty acid levels across groups.
Performed 16S rRNA sequencing on stool samples and conducted Mendelian randomization analysis.
Mice treated with metformin or FMT showed significant improvements in long-term and short-term memory and spatial cognition (P < 0.05).
Changes in plasma fatty acids: increased phosphatidic acid and decreased phosphatidylcholine, phosphatidylethanolamine, and lysophosphatidylcholine (P < 0.05).
16S rRNA sequencing and Mendelian randomization revealed Lachnospiraceae_NK4A136 as a significant differential genus.

Abstract

Introduction: Diabetes increases the risk of cognitive impairment. Metformin, a standard treatment for type 2 diabetes mellitus (T2DM), may potentially improve cognitive dysfunction. This study aims to explore the role of metformin in the cognitive performance of diabetic mice. Methods: We divided experimental animals into five groups, including a control group, a diabetes group, a Metformin + Diabetes group, a Control + Fecal Microbiota Transplantation (FMT) group, and a Diabetes + FMT group. These groups assessed cognitive function and plasma longchain fatty acid levels. Gut microbiota composition and the relationship between diabetes and gut microbiota were analyzed using 16S rRNA sequencing of stool samples and Mendelian randomization analysis. Results: Compared to the Diabetes group and Control + FMT group, mice receiving metformin or FMT treatment showed improved long-term memory, short-term memory, and spatial cognition (P < 0. 05), accompanied by increased phosphatidic acid and decreased phosphatidylcholine, phosphatidylethanolamine, and lysophosphatidylcholine (P < 0. 05). Bioinformatics analysis of 16S rRNA sequencing (P < 0. 01) and Mendelian Randomization analysis (OR: 1. 071, 95% CI: 1. 003−1. 144, P = 0. 040) showed changed gut microbial composition, and Lachnospiraceae_ NK4A136 was the common significantly differential genus. Discussion: Metformin appears to enhance cognitive function in diabetic mice through mechanisms independent of blood sugar control, likely involving the brain-gut axis. Metformin increased the abundance of LachnospiraceaeNK4A136, a genus found at lower levels in T2DM patients compared to healthy individuals. Thus, supplementing LachnospiraceaeNK4A136 might improve cognitive function in diabetics. Conclusion: Metformin can improve cognitive function in diabetic mice by modulating the gutbrain axis and altering plasma long-chain fatty acids.

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