To elucidate the relevance of gut dysbiosis in Parkinson’s disease (PD) in disease progression, we made random forest models to predict the progression of PD in two years by gut microbiota in 165 PD patients. The area under the receiver operating characteristic curves (AUROCs) of gut microbiota-based models for Hoehn & Yahr (HY) stages 1 and 2 were 0.799 and 0.705, respectively. Similarly, gut microbiota predicted the progression of Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) III scores in an early stage of PD with AUROC = 0.728. Decreases of short-chain fatty acid-producing genera, Fusicatenibacter, Faecalibacterium, and Blautia, as well as an increase of mucin-degrading genus Akkermansia, predicted accelerated disease progression. The four genera remained unchanged in two years in PD, indicating that the taxonomic changes were not the consequences of disease progression. PD patients with marked gut dysbiosis may thus be destined to progress faster than those without gut dysbiosis.

We aimed to identify gut microbial features in Parkinson’s disease (PD) across countries by meta-analyzing our fecal shotgun sequencing dataset of 94 PD patients and 73 controls in Japan with five previously reported datasets from USA, Germany, China1, China2, and Taiwan. GC-MS and LC-MS/MS assays were established to quantify fecal short-chain fatty acids (SCFAs) and fecal polyamines, respectively. α-Diversity was increased in PD across six datasets. Taxonomic analysis showed that species Akkermansia muciniphila was increased in PD, while species Roseburia intestinalis and Faecalibacterium prausnitzii were decreased in PD. Pathway analysis showed that genes in the biosyntheses of riboflavin and biotin were markedly decreased in PD after adjusting for confounding factors. Five out of six categories in carbohydrate-active enzymes (CAZymes) were decreased in PD. Metabolomic analysis of our fecal samples revealed that fecal SCFAs and polyamines were significantly decreased in PD. Genes in the riboflavin and biotin biosyntheses were positively correlated with the fecal concentrations of SCFAs and polyamines. Bacteria that accounted for the decreased riboflavin biosynthesis in Japan, the USA, and Germany were different from those in China1, China2, and Taiwan. Similarly, different bacteria accounted for decreased biotin biosynthesis in the two country groups. We postulate that decreased SCFAs and polyamines reduce the intestinal mucus layer, which subsequently facilitates the formation of abnormal α-synuclein fibrils in the intestinal neural plexus in PD, and also cause neuroinflammation in PD.

Gut microbiota and fecal bile acids were analyzed in 278 patients with α-synucleinopathies, which were comprised of 28 patients with dementia with Lewy bodies (DLB), 224 patients with Parkinson’s disease (PD), and 26 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD). Similarly to PD, short-chain fatty acids-producing genera were decreased in DLB. Additionally,Ruminococcus torquesandCollinsellawere increased in DLB, which were not changed in PD. Random forest models to differentiate DLB and PD showed that highRuminococcus torquesand highCollinsella, which presumably increase intestinal permeability, as well as lowBifidobacterium, which are also observed in Alzheimer’s disease, were predictive of DLB. AsRuminococcus torquesandCollinsellaare also major secondary bile acids-producing bacteria, we quantified fecal bile acids and found that the production of ursodeoxycholic acid (UDCA) was high in DLB. Increased UDCA in DLB may mitigate neuroinflammation at the substantia nigra, whereas neuroinflammation may not be critical at the neocortex. Theraeutic intervention to increaseBifidobacteirumand its metabolites may retard the development and progression of DLB.

We aimed to investigate the prevalence and severity of nonmotor symptoms (NMSs) and to identify factors affecting NMSs and the health-related quality of life of Japanese patients with Parkinson's disease (PD). A total of 1021 patients with PD who had one or more NMS and showed wearing-off under anti-parkinsonian treatment were enrolled from 35 medical centers in Japan for this observational study. The primary measurements were the Movement Disorder Society unified Parkinson's disease rating scale (MDS-UPDRS) part I and the Parkinson's Disease Questionnaire (PDQ-8). The relationships of MDS-UPDRS and PDQ-8 with the patient's clinical background and undertaken medical interventions were determined. Here, we report baseline data of our 52-week ongoing study. The mean MDS-UPDRS part I and PDQ-8 scores were 10.9 and 7.3, respectively. The most common NMSs were constipation problems (85.4%), sleep problems (73.7%), pain and other sensations (72.7%) and daytime sleepiness (72.0%). Fatigue was an NMS that affected 79.6% of females but only 72.6% of males, whereas features of dopamine dysregulation syndrome affected only 5.6% of females and 10.8% of males. Positive correlations were found between the MDS-UPDRS part I and the PDQ-8 (p < 0.0001, r = 0.56) and between the number of NMSs and the PDQ-8 score (p < 0.0001, r = 0.47). This study revealed distinctive patterns of NMSs in Japanese patients with PD and suggested that the prevalence and severity of NMSs vary between sexes, and that the NMSs are important factors affecting the long-term quality of life of PD patients.