Causal Relationship Between Gut Microbiota and Parkinson’s Disease

Academic Background

Parkinson’s Disease (PD) is a common neurodegenerative disorder characterized by motor dysfunction (such as bradykinesia, muscle rigidity, and resting tremors) and non-motor symptoms (such as olfactory impairment, cognitive decline, and sleep disturbances). Although the etiology of Parkinson’s disease is not fully understood, research suggests that a combination of genetic, environmental, and aging factors may contribute to its development. In recent years, the relationship between intestinal microbiota and Parkinson’s disease has garnered significant attention. The gut microbiota interacts with the central nervous system through the “gut-brain axis,” potentially influencing neuroinflammation and metabolic processes, thereby playing a role in the pathogenesis of Parkinson’s disease.

However, the causal relationship between gut microbiota and Parkinson’s disease has not been fully elucidated. To explore this issue, researchers employed Mendelian Randomization (MR) methods, combined with Genome-Wide Association Study (GWAS) data, to systematically analyze the causal relationships and potential mechanisms between gut microbiota, inflammatory cytokines, peripheral immune cells, plasma metabolites, and Parkinson’s disease.

Source of the Paper

This paper was completed by a research team from the Department of Neurosurgery, Affiliated Chuzhou Hospital of Anhui Medical University, and the Health Examination Center. The primary authors include Chengcheng Wang, Yuhang Tang, and Tao Yang, among others. The paper was published in 2025 in the European Journal of Neuroscience, titled “Causal relationship between intestinal microbiota, inflammatory cytokines, peripheral immune cells, plasma metabolome and Parkinson’s disease: a mediation Mendelian randomization study.” The study was supported by the Anhui Provincial Key Research and Development Plan.

Research Process and Results

1. Study Design

This study utilized a two-step Mendelian Randomization (Two-step MR) analysis to explore the potential causal pathways through which gut microbiota may influence Parkinson’s disease via inflammatory cytokines, peripheral immune cells, and plasma metabolites. The research process included the following steps:

1. Data Sources: The study used publicly available data from the GWAS Catalog, including 473 gut microbiota traits (n=5959), 91 inflammatory cytokine traits (n=14,824), 118 peripheral immune cell count traits (n=3757), 1400 plasma metabolite traits (n=8299), and Parkinson’s disease traits (n=482,730).
2. Instrumental Variable Selection: Single nucleotide polymorphisms (SNPs) meeting the following criteria were selected as instrumental variables (IVs): (1) significant association with exposure factors (e.g., gut microbiota) (p < 1×10⁻⁵); (2) exclusion of linkage disequilibrium (r² < 0.001, window size of 10,000 kb); (3) F-statistic greater than 10 to ensure the strength of the instrumental variables.
3. Two-step MR Analysis: First, a two-sample MR analysis was conducted to assess the causal relationship between gut microbiota and Parkinson’s disease. Second, mediation analysis was used to explore the potential mediating roles of inflammatory cytokines, immune cells, and plasma metabolites in the relationship between gut microbiota and Parkinson’s disease.

2. Key Findings

a) Causal Relationship Between Gut Microbiota and Parkinson’s Disease

The study identified 19 causal relationships between gut microbiota and Parkinson’s disease. Among them, the Demequina genus (p=0.0408, OR=1.7142) was positively associated with Parkinson’s disease, while Bifidobacterium adolescentis (p=0.0101, OR=0.8686) and the Actinomycetales order (p=0.0208, OR=0.7469) were negatively associated with Parkinson’s disease. Additionally, several species within the Lachnospiraceae family were associated with Parkinson’s disease risk, such as Blautia a sp002159835 (p=0.0223, OR=1.4256) and Kle1615 sp900066985 (p=0.0202, OR=1.2545), which may increase the risk of Parkinson’s disease, whereas the Lachnospiraceae family (p=0.0132, OR=0.6642) and Rug147 sp900315495 (p=0.0474, OR=0.4808) may reduce the risk.

b) Causal Relationship Between Inflammatory Cytokines and Parkinson’s Disease

The study found that Tumor Necrosis Factor Receptor Superfamily Member 9 (TNFRSF9) was negatively associated with Parkinson’s disease (p=0.0005, OR=0.8190). However, no significant causal relationship was found between peripheral immune cell count traits and Parkinson’s disease.

c) Causal Relationship Between Plasma Metabolites and Parkinson’s Disease

The study identified 12 causal relationships between plasma metabolites and Parkinson’s disease. Among them, tryptophan (p=0.0025, OR=0.8256) was negatively associated with Parkinson’s disease, suggesting that reduced tryptophan levels may increase the risk of Parkinson’s disease. Additionally, mannose (p=0.0078, OR=1.1543) and cholesterol (p=0.0356, OR=1.1678) were positively associated with Parkinson’s disease.

d) Mediation Analysis

Mediation analysis revealed that the Demequina genus influenced Parkinson’s disease by reducing tryptophan levels, with a mediation proportion of 17.51% (p=0.0393). This indicates that the Demequina genus may promote the occurrence of Parkinson’s disease by decreasing tryptophan levels.

3. Conclusions and Significance

This study, through Mendelian Randomization methods, systematically evaluated for the first time the causal relationships between gut microbiota, inflammatory cytokines, peripheral immune cells, plasma metabolites, and Parkinson’s disease. The study identified significant causal relationships between 19 gut microbiota traits, 1 inflammatory cytokine, and 12 plasma metabolites with Parkinson’s disease. Notably, the Demequina genus mediated its effect on Parkinson’s disease by reducing tryptophan levels, providing new insights into the pathogenesis of Parkinson’s disease.

4. Research Highlights

• Innovative Methodology: This study is the first to employ a two-step Mendelian Randomization approach, combined with large-scale GWAS data, to systematically analyze the causal relationships and potential mechanisms between gut microbiota and Parkinson’s disease.
• Key Findings: The study found that the Demequina genus influences Parkinson’s disease risk through tryptophan metabolism, offering new directions for early diagnosis and prevention of Parkinson’s disease.
• Broad Applicability: This research not only provides new perspectives for the study of Parkinson’s disease etiology but also offers methodological references for research on other neurodegenerative diseases.

Summary

The findings of this study provide important scientific evidence for understanding the etiology of Parkinson’s disease, particularly the mechanisms by which gut microbiota influences Parkinson’s disease risk through metabolic pathways. Future research can further validate these findings and explore intervention strategies based on gut microbiota, offering new approaches for the prevention and treatment of Parkinson’s disease.