Canine idiopathic epilepsy as a natural animal model for human epilepsy: a metabolic perspective beyond the brain

Abstract Emerging evidence indicates that epilepsy extends beyond the brain, involving systemic metabolic, immune, and microbiome perturbations that shape neuronal excitability and treatment response. Canine idiopathic epilepsy (CE) offers a naturally occurring, genetically diverse model with strong electrophysiological, pharmacological, and clinical homology to human epilepsies. In this review, we synthesise canine and human data on metabolic pathways (amino acids, lipids, vitamins, minerals, trace elements), the gut–brain axis and neurotransmitter signalling, inflammation and immunity, oxidative stress, the endocannabinoid system, and microRNAs. Across these systems, consistent alterations are reported in CE, paralleling human findings and supporting a view of epileptogenesis that expands beyond the brain. We highlight opportunities for translation, like biomarkers and stratifiers, dietary/metabolic interventions (e.g., MCT‑based nutrition), microbiome modulation, and immunometabolic targets, alongside critical pitfalls: small, heterogeneous cohorts, antiseizure medication confounding, variable fasting or diet status, breed effects and correlation without causal testing. Taken together, CE can bridge experimental models and clinical practice, advancing epilepsy research beyond the brain toward mechanism‑guided, multisystem therapeutics, offering a win-win for both species alike.