Investigating the Relationships Among Gut Microbiota, Inflammatory Cytokines, Cerebrovascular Diseases, and the Mediation Pathways.

Objectives: Cerebrovascular disease (CeVD), the second leading global cause of death, has an incompletely understood pathogenesis. This study aimed to investigate causal relationships among gut microbiota, inflammatory cytokines, and CeVD, specifically examining inflammatory cytokine-mediated pathways. Methods: Genome-wide association study (GWAS) summary statistics for 209 gut microbial taxa, 91 inflammatory cytokines, and three CeVD subtypes were obtained from publicly available datasets. Causal effects were estimated by applying four complementary two-sample Mendelian randomization (MR) methods. Reverse MR and comprehensive sensitivity analyses were performed to validate the robustness of the findings. Multivariable MR (MVMR) analyses were conducted to account for potential confounders. Mediation analysis was conducted to elucidate the pathways from gut microbiota to CeVD, mediated by inflammatory cytokines. Results: Our study identified 33 gut microbiota significantly associated with CeVD, including nine with ischemic stroke (IS), 14 with intracerebral hemorrhage (ICH), and 10 with subarachnoid hemorrhage (SAH). Eighteen inflammatory cytokines showed significant associations with different CeVD subtypes. Mediation analysis revealed 10 causal pathways from gut microbiota to CeVD mediated by inflammatory cytokines; among these, three inflammatory cytokines mediated more than two pathways. Conclusions: This study demonstrated that inflammatory cytokines mediated the gut microbiota-CeVD causal pathway through genetic evidence, elucidating novel disease mechanisms, thereby providing actionable insights for developing CeVD prevention and treatment strategies.