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, and 3-ethylcatechol sulfate (2) linked to increased risk, while phosphate-to-uridine ratio, adenosine 5'-diphosphate (ADP)-toflavin adenine dinucleotide (FAD) ratio, arginine, caffeine-to-theobromine ratio, N-succinylphenylalanine, sphingosine, and phenylpyruvate-to-4-hydroxyphenylpyruvate ratio 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.