Systematic analysis of gut microbiome reveals the role of bacterial folate and homocysteine metabolism in Parkinson’s disease Original paper

What was studied?

This study systematically analyzed the gut microbiome in Parkinson’s disease (PD), focusing on the functional and compositional changes associated with disease severity, gastrointestinal dysfunction, and patient age. Through a combination of shotgun metagenomics, serum metabolomics, and advanced systems biology approaches, particularly genome-scale metabolic modeling (GEMs), the researchers sought to unravel how bacterial metabolic pathways, especially those involved in folate and homocysteine metabolism, contribute to PD pathophysiology. The study integrated metagenomic data with personalized community-level metabolic models to predict microbial contributions to host metabolism and validated selected predictions with targeted serum metabolomics. The ultimate goal was to identify microbial metabolic signatures—particularly those linked to folate deficiency and hyperhomocysteinemia that could serve as hallmarks of PD, thereby informing both mechanistic understanding and potential clinical interventions.

Who was studied?

The study utilized a German cohort comprising 26 early-stage, L-DOPA-naive male patients with PD and 25 age- and sex-matched controls. The control group included 11 healthy individuals and 14 disease controls with cardiovascular risk factors. Fecal samples from all participants were subjected to deep shotgun metagenomic sequencing, while serum samples from a subset (8 PD, 5 healthy controls, 5 disease controls) were analyzed using targeted metabolomics. Clinical metadata, including Unified Parkinson’s Disease Rating Scale (UPDRS) scores (disease severity), GI Symptom Rating Scale scores, and age, were collected to correlate microbiome features with clinical states. All participants provided informed consent, and the study was approved by the University of Bonn ethics committee.

Most important findings

The study found profound alterations in the gut microbiome composition of PD patients. Notably, 132 metagenome species pangenomes showed significant abundance differences: 73 increased and 59 decreased in PD versus controls. Key increases were observed in Akkermansia muciniphila, Alistipes shahii, and certain Methanobrevibacter smithii strains, while short-chain fatty acid (SCFA) producers like Prevotella copri, Clostridium saccharolyticum, Faecalibacterium prausnitzii, and Roseburia intestinalis were depleted. Functionally, PD-associated microbiomes exhibited enhanced mucin and host glycan degradation capability, linking to increased gut permeability. The abundance of pro-inflammatory and amyloidogenic species (e.g., Escherichia coli) was positively correlated with disease severity, GI dysfunction, and age.

Metabolic modeling revealed that microbial pathways for folate biosynthesis and riboflavin metabolism were diminished in PD, especially among elderly patients and those with severe disease. In contrast, microbial production of homocysteine, indole, glycine, and certain biogenic amines was predicted and confirmed to be elevated in PD. Serum metabolomics validated higher levels of indole derivatives (notably indolepropionic acid, IPA) and lower folate levels in PD, consistent with model predictions. Microbial species driving these changes included increased A. muciniphila, Erysipelatoclostridium spp., and Eubacterium spp. (for tryptophan/indole), and decreased Paraprevotella clara, Prevotella spp., and R. intestinalis (for folate production). The findings suggest a mechanistic link between PD gut dysbiosis, reduced microbial folate production, and hyperhomocysteinemia, both implicated in neurodegeneration.

Key implications

This study provides compelling evidence that the gut microbiome in PD is functionally reprogrammed toward increased mucin degradation, pro-inflammatory metabolite production, and impaired folate biosynthesis. The depletion of SCFA producers and folate-synthesizing bacteria, alongside the enrichment of species favoring homocysteine and indole production, may exacerbate neuroinflammation and neuronal vulnerability. These microbiome-derived metabolic signatures—especially those related to folate and homocysteine—could serve as diagnostic or therapeutic targets. The integration of multi-omics data with metabolic modeling sets a new standard for unraveling host-microbiome interactions in neurodegenerative diseases, supporting the rationale for microbiota- and metabolism-targeted interventions in PD.

Citation

Rosario D, Bidkhori G, Lee S, Bedarf J, Hildebrand F, Le Chatelier E, Uhlen M, Ehrlich SD, Proctor G, Wüllner U, Mardinoglu A, Shoaie S. Systematic analysis of gut microbiome reveals the role of bacterial folate and homocysteine metabolism in Parkinson’s disease. Cell Reports. 2021;34(9):108807. doi:10.1016/j.celrep.2021.108807