Abstract Background Alterations in gut microbiota are observed in Parkinson's disease (PD). Previous studies on microbiota‐derived metabolites in PD were small‐scale and post‐diagnosis, raising concerns about reverse causality. Objectives Our goal was to prospectively investigate the association between plasma microbial metabolites and PD risk within a metabolomics framework. Methods A nested case–control study within the prospective EPIC4PD cohort, measured pre‐diagnostic plasma microbial metabolites using untargeted metabolomics. Results Thirteen microbial metabolites were identified nominally associated with PD risk ( P ‐value &lt; 0.05), including amino acids, bile acid, indoles, and hydroxy acid, although none remained significant after multiple testing correction. Three pathways were implicated in PD risk: valine, leucine, and isoleucine degradation, butanoate metabolism, and propanoate metabolism. PD‐associated microbial pathways were more pronounced in men, smokers, and overweight/obese individuals. Conclusion Changes in microbial metabolites may represent a pre‐diagnostic feature of PD. We observed biologically plausible associations between microbial pathways and PD, potentially influenced by individual characteristics. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Gut Microbial Metabolites and Future Risk of Parkinson's Disease: A Metabolome‐Wide Association Study