Abstract
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.
Importance Nineteen studies have been reported on gut microbiota in PD, whereas only one study has been reported in RBD from Germany. RBD has the highest likelihood ratio to develop PD. Our meta-analysis of RBD in Japan and Germany revealed increased mucin-layer-degrading genus Akkermansia in RBD, which was not conspicuous in the German study. Genus Akkermansia may increase the intestinal permeability, as we previously observed in PD patients, and make the intestinal neural plexus exposed to oxidative stress, which can lead to abnormal aggregation of prion-like α-synuclein fibrils in the intestine. In contrast to PD, SCFA-producing bacteria were not decreased in RBD. As SCFA induces Treg cells, a decrease of SCFA-producing bacteria may be a prerequisite for the development of PD. We propose that prebiotic and/or probiotic therapeutic strategies to increase the intestinal mucin layer and to increase intestinal SCFA potentially retard the development of RBD and PD.