Plasma metabolites link healthy lifestyle to the risk of epilepsy in the UK Biobank

Unhealthy lifestyles are linked to epilepsy, but the underlying mechanisms involving metabolism and brain structure are unclear. This prospective study analyzed 130,530 UK Biobank participants with multimodal data including lifestyle factors, genotyping, metabolomics, and brain MRI. We examined associations between a composite healthy lifestyle score and incident epilepsy using Cox regression, stratified by polygenic risk score (PRS). We derived a metabolic signature using elastic net regression and identified causal metabolites using Mendelian randomization. Mediation analyses and structural equation modeling (SEM) were performed to elucidate the lifestyle-metabolite-brain-epilepsy axis. During 15.87 years of follow-up, a healthy lifestyle was associated with a lower risk of epilepsy (HR, 0.89; 95% CI: 0.84-0.95), even among individuals with high genetic risk. We identified 94 metabolites characterizing a healthy lifestyle, including specific lipid subclasses and inflammatory markers like GlycA. This metabolic signature was strongly associated with reduced epilepsy risk (HR, 0.75; 95% CI: 0.62-0.91) and mediated 20.51% of the protective effect of lifestyle. Furthermore, neuroimaging analysis revealed that a healthy lifestyle correlated with larger volumes in specific brain structures, such as the hippocampus. Specifically, hippocampal volume partially mediated the link between the metabolic signature and epilepsy. SEM revealed that lifestyle influences epilepsy through metabolic and structural brain alterations. A healthy lifestyle is a robust protective factor against epilepsy, even in genetically susceptible individuals. This protection is mechanistically linked to metabolic signature and brain structure, offering novel targets for prevention.