DPP-4 inhibitors may reduce drug-resistant epilepsy risk via the gut microbiota and GLP-1 axisDPP-4 Inhibitors May Offer New Hope for Drug-Resistant Epilepsy

Drug-resistant epilepsy (DRE) affects approximately one-third of patients with epilepsy and remains a major therapeutic challenge.Recent studies have demonstrated significant gut microbiota dysbiosis in patients with DRE, and certain interventions targeting the gut microbiota demonstrate therapeutic efficacy. However, pharmacological interventions that precisely modulate the gut microbiota in DRE have not yet been fully explored. This review aims to propose a systematic hypothesis that Dipeptidyl peptidase-4 inhibitors (DPP-4is) may alleviate peripheral and central pathological damage by regulating the “gut microbiota-short-chain fatty acids (SCFAs) -glucagon-like peptide-1 (GLP-1) axis”, thereby reducing susceptibility to DRE. Existing studies indicate that: (1)DPP-4is possess neuroprotective effects in experimental epilepsy models, partly by enhancing endogenous GLP-1 signaling. (2)DPP-4is have been reported to modulate gut microbiota composition and increase the abundance of SCFA-producing bacteria in metabolic diseases. (3)SCFAs can promote GLP-1 secretion by activating free fatty acid receptors (FFAR2/3) and improve intestinal barrier function and inflammatory status in metabolic and neurodegeneration disease. However, it remains unclear whether this pathway mediates the effects of DPP-4is in epilepsy. (4)Enhanced peripheral GLP-1 signaling can further influence central nervous system homeostasis, including enhancing inhibitory synaptic transmission, attenuating neuroinflammation, oxidative stress, and inhibiting neuronal apoptosis, thereby reducing susceptibility to seizures. By integrating cross-contextual evidence, we propose that DPP-4is may exert protective effects on DRE through gut microbiota-SCFAs-GLP-1 axis.