Plasma Metabolites as Mediators Between Gut Microbiota and Parkinson's Disease: Insights from Mendelian Randomization

Recent evidence supports the causal role of both plasma metabolites and gut microbiota (GM) in Parkinson's disease (PD). However, it remains unclear whether GM are responsible for causing PD through plasma metabolites. Here, we used Mendelian randomization (MR) to investigate the intrinsic causal relationships among GM, plasma metabolites, and PD. Summary statistics were derived from a GWAS of 1400 metabolites (N = 8299), GM (N = 18,340), and PD (Ncase = 33,674 and Ncontrol = 449,056). We used two-step/mediation MR (TSMR) to study the mediating effect of plasma metabolites on the association between GM and the risk of developing PD. We detected 54 genetic traits that were causally associated with PD development. According to the TSMR analysis, ceramide had a mediating effect on the relationship between the genus Clostridium sensu stricto 1 and the risk of developing PD (15.35% mediation; 95% CI = 1.29-32.75%). 7-Alpha-hydroxy-3-oxo-4-cholestenoate had a mediating effect on the relationship between the genus Eubacterium xylanophilum group and the risk of developing PD (11.04% mediation; 95% CI = 0.11-27.07%). In the present study, we used MR analysis to investigate the connections among GM, plasma metabolites, and PD. This comprehensive investigation offers insights into the pathogenic mechanisms of PD and the roles of the intestinal microbiota and metabolites in this disease.