Gut Microbiota Across Early Stages of Alpha-Synucleinopathy: From High-Risk Relatives, REM Sleep Behavior Disorder to Early Parkinson's Disease

Background: Gut microbiota disturbances are well established in α-synucleinopathies, such as Parkinson’s disease (PD). However, the emergence of gut microbiota changes in the long prodromal period of PD is largely unknown. This study aimed to characterize gut microbiota at different prodromal preclinical stages of PD, which simulated a staging concept of early α-synucleinopathy. Methods: We performed 16S rRNA gene analysis of fecal samples from 441 subjects, including 36 early PD, 170 REM sleep behavior disorder (RBD, pre-PD), 127 first-degree relatives of RBD (RBD-FDR, pre-RBD) and 108 controls. All subjects completed the assessments of neurodegenerative markers, gastrointestinal symptoms, and lifestyle features. Findings: In RBD, the overall microbiota composition shifted close to early PD, with depletion of short-chain fatty acids (SCFA)-producing bacteria and overabundance of bacteria inducing gut barrier disruptions (e.g., Christensenellaceae R-7 group and Akkermansia). In RBD-FDR, an even earlier prodromal stage, there were emerging PD-like microbial changes, with regard to shifted microbial composition and decreased abundance of SCFA-producing bacteria. These results remained robust even after stratifying potential confounders, such as obesity and constipation symptoms. Utilizing random forest classifier, gut microbiota could differentiate early PD, RBD and RBD-FDR from controls with area under the receiver operating curve [95% CI] of 0.78 [0.69, 0.87], 0.71 [0.65, 0.78] and 0.63 [0.56, 0.70], respectively. Interpretation: PD-like gut dysbiosis are already present at an even earlier prodromal stage before the onset of RBD and PD. Interventions targeting at specific gut microbes will open up possibilities for future prevention and disease-modifying therapies of PD.Trial Registration Details: The study was registered at clinicaltrial.gov as NCT03645226. Funding Information: Health and Medical Research Fund (05162876), Hong Kong; Centre for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. Declaration of Interests: Y.K.W. received personal fees from Eisai Co., Ltd for lecture, travel support from Lundbeck HK Limited and J.W.Y.C. received personal fees from Eisai Co.,Ltd., which are outside the submitted work. Y.K.W., H.M.L., B.H., P.K.S.C., V.C.T.M., and F.K.L.C. are inventors of a pending patent (under application) related to this work. Other co-authors reported no competing interests.Ethics Approval Statement: The study was approved by the Joint CUHK-NTEC Clinical Research Ethics Committee (CRE-2017.670). Written informed consent was obtained from all subjects in accordance with the Declaration of Helsinki.