Meta-analysis of shotgun sequencing of gut microbiota in Parkinson’s disease Original paper

What was studied?

This meta-analysis investigated gut microbiome alterations in Parkinson’s disease (PD) using shotgun metagenomic sequencing. The primary aim was to identify microbial signatures and metabolic pathway changes consistent across geographically and ethnically diverse populations. The authors combined their own Japanese cohort (94 PD patients, 73 controls) with five previously published shotgun metagenomic datasets from the USA, Germany, China (two cohorts), and Taiwan. They examined global and species-level microbial diversity, taxonomic profiles, functional pathways (particularly those involved in vitamin and polyamine biosynthesis), and fecal metabolite profiles—including short-chain fatty acids (SCFAs) and polyamines. By correlating metagenomic data with metabolomic measurements, the study explored potential mechanistic links between microbial changes and PD pathogenesis, focusing on the roles of riboflavin (vitamin B2), biotin (vitamin B7), SCFAs, and polyamines. The comprehensive analysis sought to discern both globally shared and region-specific microbiome alterations relevant to PD and to inform the development of robust microbiome signatures for clinical and research applications.

Who was studied?

The study encompassed a total of 813 PD patients and 558 controls. The Japanese cohort consisted of PD patients diagnosed according to Movement Disorder Society criteria and their healthy, cohabiting spouses (serving as controls), recruited between 2015 and 2018. Exclusion criteria included chronic illnesses and recent antibiotic use to minimize confounding effects. The meta-analysis incorporated five additional cohorts from the USA, Germany, China (Shanghai and Xiangyang), and Taiwan, with similar inclusion criteria and available demographic data. All datasets used shotgun metagenomic sequencing and, where available, included metadata such as age, sex, BMI, constipation status, and medication use. The analysis adjusted for demographic and clinical confounders where feasible, ensuring the observed microbiome alterations were robust across different populations and backgrounds.

Most important findings

The meta-analysis revealed several microbiome features consistently altered in PD across countries. Notably, alpha diversity (Shannon index) at the species level was increased in PD, a finding that contrasts with many other diseases where decreased diversity is typical. Taxonomically, the mucin-degrading species Akkermansia muciniphila was significantly increased, while SCFA-producing species Roseburia intestinalis and Faecalibacterium prausnitzii were decreased in PD. Functionally, metagenomic pathway analyses showed marked reductions in genes involved in riboflavin and biotin biosynthesis in PD, after adjusting for confounding factors. Five of six carbohydrate-active enzyme (CAZyme) categories were also significantly decreased, indicating impaired bacterial carbohydrate metabolism.

Metabolomic analyses of fecal samples from the Japanese cohort demonstrated significantly lower levels of SCFAs (acetate, propionate, butyrate) and polyamines (putrescine, spermidine, spermine) in PD patients. There was a positive correlation between the abundance of metagenomic genes for riboflavin and biotin biosynthesis and fecal levels of SCFAs and polyamines, suggesting interconnected microbial metabolic deficits. Importantly, the bacterial taxa responsible for these deficits varied by country: in Japan, the USA, and Germany, Faecalibacterium prausnitzii was the main contributor to reduced riboflavin biosynthesis, whereas in Chinese and Taiwanese cohorts, Phocaeicola vulgatus played this role. Similar geographic differences were seen for biotin biosynthesis, implicating distinct taxa such as Blautia obeum and Phocaeicola vulgatus.

Key implications

This study highlights a reproducible microbiome signature in PD characterized by increased alpha diversity, enrichment of Akkermansia muciniphila, and depletion of SCFA-producing species and functional pathways for riboflavin and biotin biosynthesis. The concomitant reduction in fecal SCFAs and polyamines suggests a mechanistic link to impaired intestinal barrier function, increased neuroinflammation, and possibly the propagation of alpha-synuclein pathology—a key feature of PD. The observation that different taxa drive similar functional deficits in different regions underscores the necessity of focusing on microbial functions (rather than taxa alone) for biomarker development and intervention strategies. Clinically, supplementation with riboflavin, biotin, or interventions to restore SCFA/polyamine production may be therapeutically beneficial in PD, particularly in patients with evidence of gut dysbiosis. These findings support the inclusion of microbial metabolic pathway alterations as core elements in microbiome signature databases for PD, reinforcing the potential for precision microbiome-targeted interventions (MBTIs).

Citation

Nishiwaki H, Ueyama J, Ito M, et al. Meta-analysis of shotgun sequencing of gut microbiota in Parkinson’s disease. npj Parkinson’s Disease. 2024;10:106. doi:10.1038/s41531-024-00724-z