INTRODUCTION: Certain observational studies have indicated a link between gut microbiota, metabolites, and synucleinopathies, but the causal relationship mediated by metabolites remains un-proven. METHODS: To examine potential causal relationships among gut microbiota, plasma metabolites, and synucleinopathies, we utilized Mendelian randomization (MR), with the inverse variance weighted (IVW) approach serving as the main analytical method. Additionally, we investigated whether plasma metabolites function as mediators via two-step/mediation MR analysis. RESULTS: We observed indirect effects of the taurine-to-cysteine ratio in associations between genus DefluviitaleaceaeUCG011 and the risk of Parkinson's disease (PD), with a mediated proportion of 26.4% (p = 0.043). Besides, the pregnenediol sulfate (C21H34O5S) mediated the causal pathway from species Odoribacter_laneus to dementia with Lewy bodies (DLB), with a mediated proportion of 28.4% (p=0.028). DISCUSSION: Our findings indicate that the taurine-to-cysteine ratio and pregnenediol sulfate (C21H34O5S) serve as key mediating factors connecting the gut microbiota and synucleinopathies. Given that cysteine, taurine, and neurosteroids exert neuroprotective effects, targeting these meta-bolic pathways emerges as a potential therapeutic strategy for synucleinopathies. CONCLUSIONS: In the present study, we revealed that gut microbiota is essential to the development and progression of synucleinopathies with the involvement of cysteine, taurine, and the pregnenedi-ol sulfate (C21H34O5S), establishing an axis among gut microbiota, metabolites, and synucleinopa-thies. The comprehensive exploration uncovers new insights into synucleinopathy mechanisms and could support efforts in prevention and treatment.