Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms Original paper

What was studied?

This study investigated the gut microbiome’s role in Parkinson’s disease (PD) by conducting a large-scale, high-resolution metagenomic analysis. The researchers employed deep shotgun sequencing of fecal DNA from PD patients and neurologically healthy controls, followed by rigorous metagenome-wide association studies (MWAS) using two independent statistical methods (MaAsLin2 and ANCOM-BC) to identify disease-associated microbial taxa, genes, and metabolic pathways. The study also incorporated network analyses to uncover co-occurring and competing microbial clusters and performed extensive functional profiling to examine the potential mechanistic contributions of the gut microbiome to PD pathogenesis, including inflammation, neurotransmitter metabolism, and neurodegeneration.

Who was studied?

The cohort consisted of 490 individuals diagnosed with Parkinson’s disease and 234 neurologically healthy controls, all newly enrolled from a single geographic region in the Deep South of the United States. The controls were predominantly elderly, with 55% being spouses of PD patients, thus sharing environmental exposures. The majority of participants were over 50 years of age (97% of PD, 93% of controls), and both sexes were nearly equally represented. Extensive metadata, including dietary habits, medication use, gastrointestinal symptoms, and demographic information, were collected via standardized questionnaires to ensure comprehensive characterization and to control for potential confounders.

Most important findings

The study found that over 30% of microbial species, genes, and pathways tested exhibited differential abundance in PD, reflecting widespread gut dysbiosis. Notably, 84 species (55 enriched, 29 depleted in PD) and 34 genera (23 enriched, 11 depleted) were robustly associated with PD across both statistical methods. Key taxa elevated in PD included Bifidobacterium dentium, Actinomyces oris, Streptococcus mutans, various Lactobacillus and Actinomyces species, and opportunistic pathogens such as Escherichia coli and Klebsiella pneumoniae. Conversely, short-chain fatty acid (SCFA)-producing bacteria—including Roseburia intestinalis, Blautia wexlerae, Faecalibacterium prausnitzii, Eubacterium, and Ruminococcus—were significantly reduced.

Network analysis revealed that these PD-associated species formed polymicrobial clusters that co-occurred or competed, suggesting complex microbial interactions in disease states. For example, a cluster of SCFA producers was depleted, while clusters of pathogens and pro-inflammatory species were expanded in PD. Functional profiling showed enrichment of gene families and pathways promoting inflammation, neuroactive signaling disruption (e.g., altered dopamine, glutamate, and serotonin metabolism), and the production of neurotoxic metabolites (e.g., trimethylamine). Genes related to the amyloidogenic protein curli, which can induce alpha-synuclein aggregation, were also elevated. Conversely, pathways for polysaccharide degradation and SCFA production, as well as neuroprotective molecule synthesis (e.g., nicotinamide, trehalose), were depleted.

These findings validate, at species-level resolution, previous observations from human and animal models, reconcile inconsistencies in PD microbiome literature, and provide an extensive list of validated microbial signatures and functional pathways for PD.

Key implications

The study establishes a comprehensive, high-resolution landscape of gut microbiome dysbiosis in Parkinson’s disease, highlighting specific microbial species and functional pathways likely contributing to disease mechanisms. The observed overabundance of pro-inflammatory and neurotoxic microbes, coupled with depletion of neuroprotective and anti-inflammatory taxa, suggests that the PD gut microbiome is “disease-permissive.” These microbiome signatures may serve as potential biomarkers for PD diagnosis and progression, and as targets for therapeutic interventions, such as microbiome modulation or probiotic/prebiotic strategies. The extensive publicly available dataset also provides a valuable resource for future research, including biomarker discovery and mechanistic studies.

Citation

Wallen ZD, Demirkan A, Twa G, et al. Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms. Nature Communications. 2022;13:6958. doi:10.1038/s41467-022-34667-x