Epilepsy is a heterogeneous neurological disorder， and its treatment has faced great challenges for a long time. Recent research advances in the gut-brain axis have revealed the important role of gut microbiota in the development， progression， and treatment of epilepsy. Gut microbiota dysbiosis is closely associated with epilepsy， and alterations in microbial diversity may affect the susceptibility and treatment response of seizure. Interventions targeting the microbiota， such as probiotics， fecal microbiota transplantation， and ketogenic diet， have shown therapeutic potentials in animal models and clinical studies. However， the specific molecular mechanisms of these interventions and their interaction with antiepileptic drugs remain unclear. This article summarizes the latest evidence on the association between the gut-brain axis and epilepsy， reviews the paradigm shift driven by spatial multi-omics technologies， and discusses the regulatory and ethical dilemmas surrounding microbiota-based therapies. In addition， it is proposed that future studies should integrate multi-omics approaches to deepen the understanding of gut-brain interaction and optimize microbiota-based therapies for epilepsy.