Alterations of fecal microbiota and plasma metabolome in patients with Parkinson's disease with rapid eye movement sleep disorder

Abstract

Patients with Parkinson's disease (PD) with probable rapid eye movement sleep behavior disorder (RBD) (PD-RBD), a specific subtype of PD, are characterized by the presence of more severe motor and non-motor symptoms. This study aimed to elucidate the characteristics and interactions of gut microbiota and plasma metabolic characteristics of PD-RBD, thus screening for the disease mechanisms. A total of 100 PD patients, 50 healthy controls (HCs) and 16 probable idiopathic RBD (iRBD) patients were collected. There were 33 PD-RBD and 67 patients without probable RBD (PD-nRBD) in PD patients. DNA extraction, PCR amplification, and high-throughput sequencing were used for intestinal microbiota analysis, and ultra-high liquid chromatography tandem mass spectrometry was used for metabolome analysis. Spearman analysis was applied to investigate the correlation of fecal microbiota and plasma metabolome. Our findings revealed Lactobacillaceae (P = 0.017), Christensenellaceae (P = 0.017), Fusobacteriaceae (P = 0.018), Lactobacillus (P = 0.035), Christensenellaceae R-7 group (P = 0.035), and Fusobacterium (P = 0.035) were significantly different in PD-RBD, PD-nRBD, and HC. Moreover, the differential metabolites identified in both PD-nRBD and PD-RBD were 3-hydroxy-2-methylpyridine-4,5-dicarboxylate (VIP = 5.802) and 3-methoxy-4-hydroxyphenylglycol sulfate (VIP = 5.732). Furthermore, our analysis revealed that 3-methoxy-4-hydroxyphenylglycol sulfate showed a positive correlation with Lactobacillus (r = 0.197, P = 0.049). Finally, functional analysis indicated that these distinctive microbiota and metabolites were primarily associated with phenylalanine metabolism and vitamin B6 metabolism. We managed to show that the differential microbiota, differential metabolites, and their interactions in PD-RBD compared to PD-nRBD and HC. This furthers our understanding of disease pathogenesis, and offers fresh perspectives on its detection and treatment.

Importance: There are currently fewer investigations on the intestinal microbiota and metabolites of probable rapid eye movement sleep behavior disorder (PD-RBD) and idiopathic RBD (iRBD). Our findings indicate that PD-RBD exhibits an increase in Christensenellaceae and 3-methoxy-4-hydroxyphenethyleneglycol sulfate, and that iRBD exhibits a similar trend. This suggests that the PD prodromal stage may have seen this alteration. Furthermore, functional analysis indicated that these distinctive microbiota and metabolites were primarily associated with phenylalanine metabolism and vitamin B6 metabolism. Basic experiments and multi-center, large-cohort clinical researches are worth conducting to confirm this, since they may offer insights for treating individuals with PD-RBD.

Keywords: Parkinson’s disease; fecal microbiota; metabolome; rapid eye movement sleep behavior disorder.

Fig 1

The flow chart of Materials and Methods.

Fig 2

(A) Principal coordinates analysis (PCoA) diagram based on the Bray-Curtis distance. Each point on the plot represents a sample, where samples from the same group are assigned the same color. The proximity of two sample points reflects the similarity in species composition between them. (B) Visual circle diagram showing species-sample correspondence at the phylum and genus levels. (C) Lefse multilevel species hierarchical tree diagram with different colored nodes representing significantly enriched microbial taxa in their respective groups, thus contributing to intergroup differences. (D) LDA discriminant bar chart, drawn with a cutoff of 3, which indicates the relative impact of each species' abundance on the differential effect.

Fig 3

Plots of PLS-DA scores under cationic (A) and anionic (B) conditions, respectively. Greater sample separation between groups denotes a more profound classification effect. The first two principal components, Component 1 and Component 2, explain the degree of variance observed. Differential metabolite abundances in PD-nRBD and PD-RBD were shown in (C) and (D).

Fig 4

Plots of KEGG pathway differential abundance scores in HC and PD-RBD (A) and PD-nRBD and PD-RBD (B). The horizontal axis represents the differential abundance score (DA Score), while the vertical axis shows the KEGG metabolic pathway names. The length of the line segment corresponds to the absolute value of the DA score, and the dot’s size indicates the number of differential metabolites annotated in the pathway.

Fig 5

Correlation heatmap of differential species or metabolites and clinical characteristics. *P value < 0.05, **P value < 0.01, ***P value < 0.001.