Gut microbiome signatures of risk and prodromal markers of Parkinson's disease.

OBJECTIVES: Alterations of the gut microbiome in Parkinson's disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they relate to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition. METHODS: Established risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function and medication were studied in relation to bacterial α-/β-diversity, enterotypes, and differential abundance in stool samples of 666 elderly TREND study participants. RESULTS: Among risk and prodromal markers, physical activity, occupational solvent exposure, and constipation showed associations with α-diversity. Physical activity, sex, constipation, possible REM-sleep behavior disorder (RBD), and smoking were associated with β-diversity. Subthreshold parkinsonism and physical activity showed an interaction effect. Amongst other factors, age and urate-lowering medication were associated with α- and β-diversity. Physical inactivity and constipation were highest in individuals with the Firmicutes-enriched enterotype. Constipation was lowest and subthreshold parkinsonism least frequent in individuals with the Prevotella-enriched enterotype. Differentially abundant taxa were linked to constipation, physical activity, possible RBD, smoking, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history and the prodromal PD probability showed no significant microbiome associations. INTERPRETATION: Several risk and prodromal markers of PD are associated with gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome-dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases. This article is protected by copyright. All rights reserved.