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Gut Microbiota, Plasma Metabolites, and Synucleinopathies: A Mendelian Randomization Study
Xiafei Long1,2, Linlin Wan1,2,3,4,5, Zhao Chen1,2,3,6
1Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Current Neuropharmacology
|May 15, 2026
Summary
Gut microbiota metabolites, like the taurine-to-cysteine ratio and pregnenediol sulfate, causally link to synucleinopathies such as Parkinson's disease. Targeting these metabolic pathways may offer new therapeutic strategies.
Area of Science:
- Microbiome Research
- Metabolomics
- Neurodegenerative Diseases
Background:
- Observational studies suggest a link between gut microbiota, metabolites, and synucleinopathies.
- The causal role of metabolites in this relationship remains unproven.
Purpose of the Study:
- To investigate potential causal relationships between gut microbiota, plasma metabolites, and synucleinopathies.
- To examine the mediating role of plasma metabolites in these associations.
Main Methods:
- Utilized Mendelian randomization (MR) analysis, primarily employing the inverse variance weighted (IVW) approach.
- Conducted two-step/mediation MR analysis to assess metabolite mediation.
- Examined associations between specific gut bacteria (DefluviitaleaceaeUCG011, Odoribacter_laneus) and synucleinopathies (Parkinson's disease, dementia with Lewy bodies).
Main Results:
- The taurine-to-cysteine ratio mediated 26.4% of the association between genus DefluviitaleaceaeUCG011 and Parkinson's disease risk (p=0.043).
- Pregnenediol sulfate (C21H34O5S) mediated 28.4% of the causal pathway from species Odoribacter_laneus to dementia with Lewy bodies (p=0.028).
Conclusions:
- The taurine-to-cysteine ratio and pregnenediol sulfate are key mediators linking gut microbiota to synucleinopathies.
- These findings establish a gut microbiota-metabolite-synucleinopathy axis.
- Targeting these metabolic pathways presents a potential therapeutic strategy for synucleinopathies.
