Associations between gut microbiota and multiple system atrophy: a Mendelian randomization study.

backgroundMultiple system atrophy (MSA) is a rare and progressive neurodegenerative disorder characterized by Parkinsonism, cerebellar dysfunction, and autonomic failure. Emerging evidence suggests that gut microbiota may contribute to neurodegeneration, but whether these associations are causal remains unclear.

methodsWe conducted a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics of gut microbiota (n = 18,340) from the MiBioGen consortium and MSA (888 cases, 7,128 controls) from a recent European study. Single nucleotide polymorphisms associated with 196 bacterial taxa were selected as instrumental variables. The primary MR method was inverse-variance weighting, complemented by weighted median, MR-Egger, and MR-PRESSO. Sensitivity analyses assessed pleiotropy, heterogeneity, and robustness.

resultsSix taxa showed nominal associations with MSA risk. Lentisphaeria (OR = 1.57, p = 0.035), Oscillospira (OR = 1.76, p = 0.034), Victivallales (OR = 1.57, p = 0.035), and Peptococcus (OR = 1.46, p = 0.025) were positively associated with increased risk, whereas Veillonella (OR = 0.40, p = 0.004) and Erysipelotrichaceae UCG-003 (OR = 0.60, p = 0.041) were associated with reduced risk. No evidence of pleiotropy or heterogeneity was found. None survived multiple-testing correction.

conclusionsThis MR study provides hypothesis-generating evidence suggesting potential causal relationships between gut microbiota and MSA. These taxa nominate candidate microbial targets for future mechanistic and translational studies.