Parkinson's Disease and the Gut Microbiome

Parkinson's disease (PD) is a neurodegenerative disorder affecting approximately 10 million people worldwide, with a steadily increasing incidence. Previous research has suggested a clear link between the gut microbiome and PD, particularly in patients with the "gut-first" subtype of the disease. In this context, we aimed to assess differences in the gut microbiome of PD patients compared to healthy controls (HC), and also to compare an early stage of PD—idiopathic REM sleep behavior disorder (iRBD)—with both PD and HC groups.

The design

In this study, we employed a multi-layered meta-omics approach, including metagenomics, meta-transcriptomics, meta-proteomics, and meta-metabolomics, to gain a deeper understanding of the gut microbiome in these individuals. We enrolled 46 healthy controls, 27 iRBD patients, and 49 PD patients, all with no recent history of antibiotic use or other known confounding factors.

How we did it

Given the vast number of potential features generated by a multi-omics approach, we chose to use meta-metabolomics as the primary driver of our statistical analysis. This decision was based on two factors: first, metabolomics data were not influenced by confounders, and second, metabolites represent one of the final outputs of microbiome activity. Through this approach, we identified several compounds—such as β-glutamate, bile acids, isovalerate & isobutyrate, and glycerol—that were differentially abundant in PD and iRBD patients compared to healthy controls. In addition, thanks to this approach we also simplified the statistical proceedings by reducing the amount of comparisons.

Chemotaxis, flagellar assembly and taxonomy.

Interestingly, β-glutamate remains poorly understood, with only one known enzyme capable of metabolizing it. To explore the potential functions associated with these metabolomic differences, we retrieved all KEGG orthologs (KOs) known to interact with the differentially present compounds and their related metabolites. This analysis revealed that many KOs were less expressed in PD patients, particularly those involved in chemotaxis and flagellar assembly (FA).
We observed a significant reduction in the expression of genes related to chemotaxis and flagellar assembly in the PD gut microbiome, with over 50% of these genes showing decreased expression in the PD group. Notably, these differences were not reflected in gene abundance or potential, suggesting that the microbial community retains the genetic capacity for these functions but no longer expresses them. We then investigated which microbial taxa were responsible for this decrease and found a complex picture: some bacterial clusters expressed FA genes predominantly in healthy controls, one cluster was specific to HC, and another expressed FA genes only in PD patients. This highlights the importance of identifying not just which functions are present, but which microbes are actively expressing them.

Function and Taxonomy: Both Matter

This study reinforces the importance of examining the functional activity of the gut microbiome, rather than focusing solely on its taxonomic composition. However, it also underscores that the identity of the microbes expressing specific functions is crucial and appears to be linked to disease status. We strongly believe that understanding microbiome functionality will be key to unraveling its role in disease and improving microbiome-targeted interventions. Reactivating or enhancing specific missing functions within a given microbiome may be the key to restoring balance and improving patient outcomes.

Related work

We published a little earlier a paper on the same cohort, but using a co-expression network on the ratio of meta-transcriptomic/metagenomics data. This approach led us to find a disrupted network in the gut microbiome of PD individuals and an apparent discontinuation of the cross-feeding between commensals. The paper can be found here: Very nice paper