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

Abstract

Parkinson’s disease (PD) may start in the gut and spread to the brain. To investigate the role of gut microbiome, we conducted a large-scale study, at high taxonomic resolution, using uniform standardized methods from start to end. We enrolled 490 PD and 234 control individuals, conducted deep shotgun sequencing of fecal DNA, followed by metagenome-wide association studies requiring significance by two methods (ANCOM-BC and MaAsLin2) to declare disease association, network analysis to identify polymicrobial clusters, and functional profiling. Here we show that over 30% of species, genes and pathways tested have altered abundances in PD, depicting a widespread dysbiosis. PD-associated species form polymicrobial clusters that grow or shrink together, and some compete. PD microbiome is disease permissive, evidenced by overabundance of pathogens and immunogenic components, dysregulated neuroactive signaling, preponderance of molecules that induce alpha-synuclein pathology, and over-production of toxicants; with the reduction in anti-inflammatory and neuroprotective factors limiting the capacity to recover. We validate, in human PD, findings that were observed in experimental models; reconcile and resolve human PD microbiome literature; and provide a broad foundation with a wealth of concrete testable hypotheses to discern the role of the gut microbiome in PD.

Metagenome-assembled microbial genomes from Parkinson’s disease fecal samples

“…Coverage depth helps to understand the abundance of a microorganism, and comparing abundance between PD and control group might indicate association of a microorganism to the disease. A MAG that was annotated as Alistipes onderdonkii had significantly (p < 0.1) more coverage depth in the PD group, which was similarly reported in other studies with high abundance of Alistipes in the PD group [ 51,52,53 ].…”

“…A MAG that was annotated as Alistipes onderdonkii had significantly (p < 0.1) more coverage depth in the PD group, which was similarly reported in other studies with high abundance of Alistipes in the PD group [ 51,52,53 ].…”

Role of Microbiota-Modified Bile Acids in the Regulation of Intracellular Organelles and Neurodegenerative Diseases

“…Moreover, a recent study using shotgun metagenomic sequencing of Parkinson’s disease patients has shown that eighty-four species were associated with Parkinson’s disease, with 55 species more and 29 species less exist in Parkinson’s disease compared to healthy subjects. In addition, 34 genera more and 1 genus less present in Parkinson’s disease compared to healthy controls [ 48 ].…”

Forging the microbiome to help us live long and prosper

“…Furthermore, a recent preprint demonstrates that gut bacteria can also influence the production of host amyloids, as bacterial nitrate reduction stimulates the intestinal aggregation of α-synuclein [ 106 ]. These results, combined with the growing amount of metagenomic data from patients with Parkinson’s disease and healthy individuals, suggest that multiple, distinct microbiome-dependent cellular and molecular mechanisms may combine to drive disease in patients with Parkinson’s disease [ 107 ].…”