Metagenomics of the Gut Microbiome in Parkinson’s Disease: Prodromal Changes Original paper

What was studied?

This study investigated the gut microbiome in Parkinson’s disease (PD), with a particular focus on identifying microbial changes that occur during the prodromal (premotor) phase, before a formal PD diagnosis. Utilizing shotgun metagenomic sequencing, the researchers conducted a nested case–control study within two large, well-characterized epidemiological cohorts: the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study. By profiling stool samples from participants with recent onset PD, prodromal PD features, constipation controls, and healthy controls, the research aimed to discern taxonomic and functional microbial signatures that could serve as early biomarkers for PD. The study evaluated both the composition of gut bacterial species and their metabolic functional pathways, seeking to determine whether microbiome alterations precede the clinical onset of PD and could therefore be implicated in disease pathogenesis or serve as diagnostic indicators.

Who was studied?

The study population comprised 420 participants drawn from the NHS and HPFS cohorts. Four groups were included: 75 individuals with recently diagnosed PD, 101 with features of prodromal PD (PPS, defined as the combined presence of constipation, probable REM sleep behavior disorder, and hyposmia), 113 controls with constipation but no PD or prodromal symptoms, and 131 healthy controls. Participants were frequency-matched on age and sex/cohort to minimize confounding. All had completed detailed questionnaires assessing lifestyle, dietary habits, medication use, and relevant prodromal symptoms. Stool samples were collected using standardized protocols and processed for shotgun metagenomic sequencing to ensure robust, high-resolution microbial profiling.

Most important findings

The study revealed a continuum of gut microbiome changes across healthy controls, constipation controls, prodromal PD (PPS), and recently diagnosed PD cases. Notably, PD and PPS participants showed significant depletion of several strict anaerobic bacterial species associated with anti-inflammatory properties and short-chain fatty acid (SCFA) production, including Faecalibacterium prausnitzii, Eubacterium rectale, Roseburia faecis, and others. These depletions followed a stepwise gradient from healthy to constipated to PPS to PD, suggesting that microbiome alterations begin before clinical PD onset. There was also an increased abundance of certain species, such as Bifidobacterium dentium and Hungatella hathewayi, previously implicated in PD. Functionally, metagenomic pathway analysis identified reduced abundance of microbial carbohydrate utilization pathways (notably those involved in glucuronide, mannan, galacturonate, and fructuronate degradation) in both PPS and PD, alongside increased pathways related to glycogen degradation and altered B-vitamin metabolism. A microbiome-based classifier achieved moderate accuracy in discriminating PD and PPS from controls (AUC 0.76 and 0.67, respectively), underscoring the potential of gut microbial profiles as early biomarkers. The findings were robust to adjustment for lifestyle, dietary, and demographic confounders.

Key implications

This study provides compelling evidence that gut microbiome alterations not only characterize clinical Parkinson’s disease but are also detectable during the prodromal phase, years before diagnosis. The identification of a taxonomic and functional shift in anti-inflammatory, SCFA-producing bacteria and carbohydrate metabolism pathways supports a link between gut microbial dysbiosis, inflammation, and PD pathogenesis. These microbiome changes could reflect both causal and responsive processes. Importantly, the results suggest that microbiome-based biomarkers may aid in early PD detection, potentially enabling preventative interventions. Furthermore, the study’s robust design and large, well-characterized cohorts strengthen the validity of these findings, which have direct relevance for microbiome-targeted therapeutic strategies and the ongoing development of a comprehensive microbiome signatures database for neurodegenerative diseases.

Citation

Palacios N, Wilkinson J, Bjornevik K, Schwarzschild MA, McIver L, Ascherio A, Huttenhower C. Metagenomics of the Gut Microbiome in Parkinson’s Disease: Prodromal Changes. Ann Neurol. 2023;94(3):486-501. doi:10.1002/ana.26719