Anatomizing causal relationships between gut microbiota, plasma metabolites, and epilepsy: A mendelian randomization study

Background: Epilepsy causes a heavy disease burden, and the gut microbiota (GM) influences the progression of epilepsy, while plasma metabolites directly or indirectly associated with GM may play a mediating role. However, the causal relationships between epilepsy, GM, and potential metabolite mediators are lack of investigation. Methods: Mendelian randomization (MR) analysis was applied to estimate the effects of GM and plasma metabolites on epilepsy. Genetic instruments were obtained from large-scale genome-wide meta-analysis of GM (n = 5959), plasma metabolites (n = 136,016), and epilepsy (Cases/controls = 12891/312803) of European ancestry. Epilepsy phenotypes included all epilepsy, generalized epilepsy and focal epilepsy from the Finn Gen R10 database. And two-step MR (TSMR) to discover the potential mediating metabolites. Results: In total, we found 19 gut microbial taxa to be causally associated with the risk of epilepsy, among which Omnitrophota phylum had the strongest association (OR, 2.3; P = 0.009) with promoting effect. We also identified 21 plasma metabolites associated with epilepsy, the strongest ones of which are eastotal fatty acids (OR, 1.12; P = 0.001) that exhibited a facilitating effect. We observed indirect effects of free cholesterol to total lipids ratio in large LDL in associations between Fournierella massiliensis species and epilepsy, with a mediated proportion of -3.64% (95%CI, -7.22%similar to-0.06%; P = 0.046). Conclusion: This study supports a causal link between Fournierella massiliensis species, free cholesterol to total lipids ratio in large LDL and epilepsy, as well as a mediating effect of free cholesterol to total lipids ratio in large LDL in epilepsy.