Parkinson’s disease-associated alterations of the gut microbiome predict disease-relevant changes in metabolic functions

Abstract

Background Parkinson’s disease (PD) is a systemic disease clinically defined by the degeneration of dopaminergic neurons in the brain. While alterations in the gut microbiome composition have been reported in PD, their functional consequences remain unclear. Herein, we addressed this question by an analysis of stool samples from the Luxembourg Parkinson’s Study (n = 147 typical PD cases, n = 162 controls). Results All individuals underwent detailed clinical assessment, including neurological examinations and neuropsychological tests followed by self-reporting questionnaires. Stool samples from these individuals were first analysed by 16S rRNA gene sequencing. Second, we predicted the potential secretion for 129 microbial metabolites through personalised metabolic modelling using the microbiome data and genome-scale metabolic reconstructions of human gut microbes. Our key results include the following. Eight genera and seven species changed significantly in their relative abundances between PD patients and healthy controls. PD-associated microbial patterns statistically depended on sex, age, BMI, and constipation. Particularly, the relative abundances of Bilophila and Paraprevotella were significantly associated with the Hoehn and Yahr staging after controlling for the disease duration. Furthermore, personalised metabolic modelling of the gut microbiomes revealed PD-associated metabolic patterns in the predicted secretion potential of nine microbial metabolites in PD, including increased methionine and cysteinylglycine. The predicted microbial pantothenic acid production potential was linked to the presence of specific non-motor symptoms. Conclusion Our results suggest that PD-associated alterations of the gut microbiome can translate into substantial functional differences affecting host metabolism and disease phenotype.

Gut Microbial Ecosystem in Parkinson Disease: New Clinicobiological Insights from Multi‐Omics

“…Increased abundance of Akkermansia has also been associated with slow colonic transit, 9,34 a frequent problem in neurological disorders. Nevertheless, as the single most consistent signature observed in PD (≥10 studies), the role of Akkermansia deserves further investigation, particularly in view of it now being one of several “newly explored” microorganisms being seriously considered as a probiotic treatment for metabolic and inflammatory disorders 18,37 …”

“…Some studies inferred microbiota function based on predicted functional gene profiling, 14 but the majority of genes in the human microbiome cannot yet be functionally assigned, and their dynamic transcriptional and translational activities remain to be elucidated 15 . The need for a multi‐omics approach has been highlighted 2,16–18 . In a recent PD microbiome study, serum metabolomics (which primarily reflects host metabolites) was performed in a subset of subjects, with correlations found between 2 protein‐degradation byproducts and several bacterial genera 9 .…”

Akkermansia muciniphila secretome promotes α-synuclein aggregation in enteroendocrine cells

“…However, we cannot rule out recent reports showing that alteration in gut microbiota is associated with PD. Several lines of evidence suggest that PD patients present strong gut dysbiosis with remarkable abundance of A. muciniphila which is consistently high in PD stool samples (Baldini et al, 2020; Bedarf et al, 2017; Desai et al, 2016; Heintz-Buschart et al, 2018; Hill-Burns et al, 2017; Li et al, 2017; Lin et al, 2019; Mertsalmi et al, 2017; Nishiwaki et al, 2020; Unger et al, 2016; Vidal-Martinez et al, 2020). Additionally, emerging studies have described increased abundance of A. muciniphila in multiple sclerosis (MS), one of which enrolled monozygotic twins discordant for MS diagnosis, therefore excluding genetic confounders (Berer et al, 2017; Cekanaviciute et al, 2017).…”

“…The mucin-degrading microorganism A. muciniphila (Derrien, 2004) comprehends about 1-4% of the fecal microbiome in humans (Naito et al 2018). While numerous diseases have been associated with a decrease in A. muciniphila abundance (Grander et al, 2018; Schneeberger et al, 2015), an increase of this microorganism has been consistently reported in PD patients (Baldini et al, 2020). In addition, it was shown that A. muciniphila abundance had the largest contribution to the significantly altered metabolite secretion profiles of sporadic PD patients (Baldini et al, 2020).…”

Integration of constraint-based modelling with faecal metabolomics reveals large deleterious effects ofFusobacteriaspecies on community butyrate production

“…Seven species (Copprococcus comes, Eubacterium rectale, Eubacterium siraeum, Eubacterium ventriosum, Faecalibacterium prausnitzii, Roseburia intestinales, and Roseburia inulinivorans) fulfilled these criteria. Then, we fitted a series of seven fractional logistic regressions (Baldini et al, 2020) with the abundance of the seven species as response variables, the presence of Fusobacteria sp. (binary: present vs. not present) as predictor of interest, while adjusting for age, sex, BMI, and study group.…”