Causal effect of gut microbiota and its metabolites on cerebral small vessel disease: A multivariable Mendelian randomization analysis

Emerging evidence suggests a strong relationship between cerebral small vessel disease (CSVD), gut microbiota (GM), and their secreted metabolites. The major subtypes of CSVD include lacunar stroke, cerebral microbleeds, perivascular spaces (PVSs), and white matter hyperintensity (WMH) volume. However, their causal relationship remains unknown. A 2-sample Mendelian randomization (MR) analysis was undertaken on summarized data from genome-wide association studies. Univariable MR and multivariable MR were used to find the possible causal link between CSVD, GM, and their metabolites. The causal association was determined through the inverse variance weighted, weighted median, maximum likelihood, MR-Egger regression, and MR-PRESSO approaches. Multiple sensitivity tests were employed to evaluate the presence of horizontal pleiotropy and heterogeneity. A reverse MR analysis determined the potential for reverse causality. Finally, enrichment analyses were carried out to elucidate relevant biological functions. Overall, 1505 host single-nucleotide polymorphisms related to 119 GM features and 1873 related to 81 GM-derived metabolites (GMDMs) were identified as exposure variables. Two intestinal bacteria were linked with raised likelihood of WMH volume, 1 with cerebral microbleeds, 2 with lacunar stroke, and 7 with PVSs. However, 3 bacterial species were correlated with decreased WMH volume risk, 2 to lacunar stroke, and 8 to PVSs. Moreover, the possible causal link between 28 GMDMs and CSVD was observed. Enrichment analysis revealed the crucial involvement of multiple key regulatory pathways. This study provided new insights into gut biomarkers and specialized prevention and therapy for CSVD by demonstrating evidence of the causal link between GM, GMDMs, and CSVD.