DPP-4 inhibitors hypothesized to reduce drug-resistant epilepsy susceptibility via gut microbiota-SCFA-GLP-1 axis

Drug-resistant epilepsy (DRE) affects approximately one-third of epilepsy patients, posing a significant therapeutic challenge. Recent studies highlight substantial gut microbiota dysbiosis in DRE, with microbiota-targeting interventions showing promise. However, precise pharmacological strategies to modulate the gut microbiota in DRE remain largely unexplored. This gap necessitates identifying existing compounds that could leverage the gut-brain axis to improve DRE outcomes.

This systematic review aimed to propose a novel hypothesis regarding the therapeutic potential of Dipeptidyl peptidase-4 inhibitors (DPP-4is) in Drug-resistant epilepsy (DRE). The authors synthesized existing evidence across various research domains to construct a mechanistic framework. Their approach involved integrating findings on DPP-4is' known neuroprotective effects, their reported modulation of gut microbiota in metabolic diseases, the role of short-chain fatty acids (SCFAs) in GLP-1 secretion, and the influence of GLP-1 signaling on central nervous system homeostasis. The primary objective was to elucidate how DPP-4is might alleviate peripheral and central pathological damage by regulating the gut microbiota-SCFAs-GLP-1 axis.

The review integrated existing evidence to support a multi-faceted hypothesis that DPP-4is may exert protective effects on DRE through the gut microbiota-SCFAs-GLP-1 axis:

1. DPP-4is demonstrate neuroprotective effects in experimental epilepsy models, partly by enhancing endogenous GLP-1 signaling.
2. DPP-4is have been shown to modulate gut microbiota composition, specifically increasing the abundance of SCFA-producing bacteria in metabolic disease contexts.
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 neurodegenerative diseases.

1. Enhanced peripheral GLP-1 signaling further influences central nervous system homeostasis, including enhancing inhibitory synaptic transmission, attenuating neuroinflammation, oxidative stress, and inhibiting neuronal apoptosis, thereby reducing susceptibility to seizures.