Gut–brain–immune crosstalk in drug-resistant epilepsy: mechanisms and therapeutic perspectives

Epilepsy is one of the most prevalent neurological disorders worldwide, affecting approximately 50–52 million individuals. Approximately 30% of patients develop drug-resistant epilepsy (DRE) despite appropriate antiseizure medications (ASMs). Conventional ASMs control neuronal hyperexcitability by two methods: sodium and calcium channel voltage-gated modulation and GABA-dependent neuronal inhibition. Although these approaches are effective in many cases, they provide only temporary seizure control and do not address the underlying biological mechanisms that are responsible for epileptogenesis and pharmacoresistance. Growing clinical and experimental evidence supports a broader disease model. Neuroinflammation, immune activation, blood–brain barrier dysfunction, and gut microbiota dysbiosis play central roles in seizure persistence and drug resistance. Sustained activation of microglia and astrocytes demonstrates neuroimmune modulation, with NLRP3 inflammasome signaling and caspase-1–dependent IL-1 β maturation contributing to lowered seizure thresholds and reduced ASM responsiveness. In parallel, alterations in gut microbial composition and microbial enzyme activity lead to decreased short-chain fatty acid production, with butyric acid specifically affected through the butyryl-CoA:acetate CoA-transferase pathway. The review further highlights that microbiota regulated metabolic pathways, particularly tryptophan catabolism mediated by indoleamine-2,3-dioxygenase and kynurenine monooxygenase. These pathways influence the neurotoxic balance between quinolinic acid and kynurenic acid and protect against neurotoxicity. New treatment methods include NLRP3 inflammasome inhibitors (MCC950 and OLT1177), microbiota-based therapies and anti-inflammatory phytochemicals as well as drugs that target multiple biological pathways. Targeting neuroimmune pathways may provide disease-modifying therapies for patients with drug-resistant epilepsy, highlighting a translational strategy for clinical intervention.