Molecular neurobiologyDec 8, 2025

Metformin Improves Memory in Epileptic Rats by Changing Gut Bacteria

Updated Jan 1, 2026

Abstract

Metformin treatment improved spatial learning and memory in a chronic epilepsy model in rats.

Metformin reduced hippocampal neuronal damage and enhanced synaptic plasticity in epileptic rats.
Treatment reversed microbiota changes associated with epilepsy, increasing beneficial bacteria and decreasing harmful ones.
Modulation of gut microbiota may help reduce the release of microbial toxins and support intestinal health.
Metformin inhibited the TLR4/MyD88/NF-κB pathway, which is linked to inflammation in the context of epilepsy.
The findings suggest a potential connection between gut microbiota and cognitive improvements in epilepsy treatment.

Simplified

Epilepsy (EP) is characterized by recurring spontaneous seizures, often leading to long-standing cognitive impairment, significantly impacting the quality of life. Due to the unknown pathogenic pathways, developing effective treatments for epilepsy-associated cognitive impairment has been challenging. Metformin, a first-line oral antidiabetic drug, has proven effective in various EP models. Recent studies have shown that metformin can modulate gut microbiota composition and improve cognitive function. However, the protective effect of metformin on cognitive function in the chronic phase of epilepsy in rats is still unclear. Furthermore, whether its effect has to do with the gut microbiota remains to be determined. This study used the pilocarpine-induced chronic epilepsy model to mimic the pathological process of epilepsy-related cognitive impairment. Combined with 16 s rDNA sequencing and 4D-Label free proteomics analysis, multi-omics analysis was performed. We discovered that metformin treatment improved spatial learning and memory, reduced hippocampal neuronal damage, and enhanced synaptic plasticity in epileptic rats. Additionally, 16S rDNA sequencing revealed that metformin treatment reversed microbiota alterations associated with epilepsy, particularly by increasing the abundances of Alloprevotella, Blautia, Romboutsia, and Phascolarctobacterium, while reducing Prevotellaceae NK3B31 group and Ruminococcus 1. This modulation helped reduce the release of microbial toxins and promoted intestinal homeostasis maintenance. Further mechanistic studies involving proteomics and ELISA testing showed that metformin treatment inhibited the TLR4/MyD88/NF-κB pathway and alleviated systemic inflammation in epileptic rats. As can be seen, metformin therapy's amelioration of cognitive impairment in epilepsy may be facilitated by the gut microbiota, with the underlying mechanism potentially involving the suppression of TLR4/MyD88/NF-κB signaling and the mitigation of inflammation.

Funding

Competing interests

Declarations. Ethics Approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Second Hospital of Hebei Medical University (Approval No. 2022-AE293). Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing interests: The authors declare no competing interests.

PubMed

Abstract

Funding

Competing interests

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