The microbiota-gut-brain axis in epilepsy: Mechanistic insights and emerging probiotic-based therapeutics

Epilepsy is a chronic neurological disorder affecting more than 50 million people globally. Over one-third of patients remain pharmacoresistant to conventional antiepileptic therapy, creating a substantial healthcare and societal burden. Recently, the gut-brain axis has emerged as a novel and pivotal route in the pathophysiology and progression of epilepsy. The gut microbiota regulates brain function by influencing immune responses, neurotransmitter levels, and the integrity of the gut-brain barrier. Studies increasingly show that epilepsy is linked to gut dysbiosis, reflected by reduced abundance of beneficial genera such as Lactobacillus, Bifidobacterium, and Faecalibacterium, and an increased abundance of Ruminococcus, Bacteroides and Enterococcus. These microbial shifts disrupt the homeostatic production of short-chain fatty acids and GABA, and elevate systemic inflammation, thereby contributing to epileptogenesis. Furthermore, mental stress and neuroinflammation may indirectly trigger gut disturbances, disrupting the bidirectional gut-brain homeostasis. Considering the crucial role of the microbiota-gut-brain axis (MGBA) in epilepsy, research attention has increasingly focused on therapeutic interventions that can positively modulate the MGBA to prevent disease progression and severity. Various preclinical studies using PTZ-kindling, pilocarpine, and kainic acid models demonstrate that selected probiotic strains can significantly reduce seizure severity, restore antioxidant balance, dampen hippocampal inflammation, improve SCFA levels, strengthen gut barrier integrity, and preserve dendritic spine density. This chapter provides an integrative overview of the evolving role of the MGBA in the pathogenesis and management of epilepsy, emphasizing the mechanisms of gut-brain communication and how biotics, particularly GABA-producing probiotics, may beneficially modulate these pathways to offer promising adjunctive therapeutic opportunities.