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image of Causal Relationships Between Specific Gut Microbiota Taxa, Plasma 
Metabolites, and Cerebral Small Vessel Disease Risk: A Mendelian 
Randomization Analysis

Abstract

Aims

This study investigates causal relationships between gut microbiota (GM), plasma metabolites, and cerebral small vessel disease (CSVD), with a focus on identifying GM taxa and metabolites that mediate disease risk.

Methods

Summary data from genome-wide association studies on GM (MiBioGen), 1,400 plasma metabolites, and CSVD were analyzed using a two-step Mendelian randomization (MR) approach. The primary analysis utilized inverse-variance weighting, complemented by weighted median, weighted mode, and MR-Egger methods for robustness.

Results

The MR analysis identified 12 GM taxa associated with CSVD risk, including 7 taxa linked to increased risk (Veillonellaceae, Hungatella, Ruminococcus2, Lachnospiraceae UCG010, Streptococcus, Cyanobacteria, Verrucomicrobia) and 5 taxa linked to decreased risk (Faecalibacterium, Alphaproteobacteria, Eubacterium nodatum group, Fusicatenibacter, Rhodospirillales). Additionally, 10 plasma metabolites were causally associated with CSVD risk, with sphingomyelin (d18:2/14:0, d18:1/14:1), nicotinamide, 3-ethylcatechol sulfate (2), sphingosine, and phenylpyruvate-to-4 hydroxyphenylpyruvate ratio linked to increased risk, while phosphate-to-uridine ratio, adenosine 5'-diphosphate (ADP)-toflavin adenine dinucleotide (FAD) ratio, arginine, caffeine-to-theobromine ratio and N-succinylphenylalanine were linked to decreased risk. Mediation analysis identified 8 causal pathways through which plasma metabolites connect GM taxa to CSVD.

Conclusion

These findings underscore the substantial influence of GM and plasma metabolites on CSVD risk, highlighting potential therapeutic targets. Further investigation is needed to elucidate the biological mechanisms underlying these associations.

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2025-05-20
2025-09-19

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Causal Relationships Between Specific Gut Microbiota Taxa, Plasma 
Metabolites, and Cerebral Small Vessel Disease Risk: A Mendelian 
Randomization Analysis
Bentham Science Publishers ; https://doi.org/10.2174/0113892010373952250510105002
/content/journals/cpb/10.2174/0113892010373952250510105002
/content/journals/cpb/10.2174/0113892010373952250510105002
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  • Article Type:     Research Article
Keywords: gut microbiota ; mendelian randomization ; genetics ; genome-wide association studies ; Cerebral small vessel disease ; metabolites

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