Background PD may begin with the intestinal accumulation of α‐synuclein fibrils, which can be causally associated with gut dysbiosis. The variability of gut microbiota across countries prevented us from identifying shared gut dysbiosis in PD. Objectives To identify gut dysbiosis in PD across countries. Methods We performed 16S ribosomal RNA gene sequencing analysis of gut microbiota in 223 patients with PD and 137 controls, and meta‐analyzed gut dysbiosis by combining our dataset with four previously reported data sets from the United States, Finland, Russia, and Germany. We excluded uncommon taxa from our analyses. For pathway analysis, we developed the Kyoto Encyclopedia of Genes and Genomes orthology set enrichment analysis method. Results After adjusting for confounding factors (body mass index, constipation, sex, age, and catechol‐O‐methyl transferase inhibitor), genera Akkermansia and Catabacter, as well as families Akkermansiaceae, were increased, whereas genera Roseburia, Faecalibacterium, and Lachnospiraceae ND3007 group were decreased in PD. Catechol‐O‐methyl transferase inhibitor intake markedly increased family Lactobacillaceae. Inspection of these bacteria in 12 datasets that were not included in the meta‐analysis revealed that increased genus Akkermansia and decreased genera Roseburia and Faecalibacterium were frequently observed across countries. Kyoto Encyclopedia of Genes and Genomes orthology set enrichment analysis revealed changes in short‐chain fatty acid metabolisms in our dataset. Conclusions We report that intestinal mucin layer‐degrading Akkermansia is increased and that short‐chain fatty acid–producing Roseburia and Faecalibacterium are decreased in PD across countries. © 2020 International Parkinson and Movement Disorder Society

Twenty studies on gut microbiota in PD have been reported, whereas only one study has been reported on iRBD from Germany. iRBD has the highest likelihood ratio to develop PD. Our meta-analysis of iRBD in Japan and Germany revealed increased mucin-layer-degrading genus Akkermansia in iRBD.

Gut dysbiosis has been reported repeatedly in Parkinson's disease (PD), but once in rapid-eye-movement sleep behavior disorder (RBD) from Germany. Abnormal aggregation of α-synuclein fibrils causing PD possibly starts from the intestine. RBD patients frequently develop PD. Initial gut dysbiosis causally associated with PD is thus expected to be observed in RBD. We here analyzed gut microbiota in 26 RBD patients and 137 controls by 16S rRNA-seq, and meta-analyzed our dataset with the German dataset. Unsupervised clustering of gut microbiota by LIGER, a topic model-based tool for single-cell RNA-seq analysis, revealed enterotypes A-D. Enterotypes were shifted from A-to-D with transition from controls, RBD, to the disease progression of PD. Seven taxa were increased in RBD in Japan, and six of them were also increased in RBD in Japan and Germany. Among the six taxa, genus Akkermansia and family Akkermansiaceae were consistently increased in PD in five countries, and the other four taxa were also variably changed in PD. No short-chain fatty acid (SCFA)-producing bacteria were significantly changed in RBD in the meta-analysis. In contrast, we previously reported that recognized and putative SCFA-producing genera Faecalibacterium, Roseburia, and Lachnospiraceae ND3007 group were consistently decreased in PD in five countries. Increased mucin-layer-degrading genus Akkermansia possibly accounts for the development of RBD, and an additional decrease of SCFA-producing genera may be associated with the transition from RBD to PD.