Gut microbiota–neuroinflammation axis: A new mechanism and therapeutic target for comorbid depression in epilepsy

This review systematically summarizes the key pathological mechanisms and therapeutic potential of the gut microbiota-neuroinflammation axis in comorbid depression in epilepsy. Approximately 30-50 % of epilepsy patients suffer from depression, which leads to poor treatment adherence and significantly increases the risk of mortality and suicide. Studies have shown that dysbiosis of the gut microbiota and central nervous system inflammation interact through multiple pathways-including microbial metabolites, immune modulation, and the vagus nerve-to form a "gut-brain-emotion" regulatory network. Epilepsy patients often exhibit reduced diversity and abnormal composition of gut microbiota, most notably dysregulation of Firmicutes, which promotes systemic inflammation and activation of local central nervous system inflammation. Neuroinflammation, by affecting neurotransmitter metabolism, blood-brain barrier function, and neuroplasticity, exacerbates abnormal neuronal discharges and depressive symptoms, thereby creating a vicious cycle. Intervention strategies targeting this axis have shown promising prospects, including supplementation with probiotics or prebiotics, modulation of microbial metabolites, anti-inflammatory therapies, and dietary regulation, all of which can significantly improve both the frequency of epileptic seizures and emotional states. Multi-omics analysis and precise subtyping are advancing the development of individualized treatment plans, bridging the gaps among neuroscience, immunology, and microbiology. Although challenges remain in standardized sampling, causal mechanism validation, and long-term follow-up studies, the gut microbiota-neuroinflammation axis has emerged as a new frontier in the precise prevention and treatment of comorbid depression in epilepsy, providing a tangible theoretical foundation and practical strategies for improving patient outcomes.