Exploring the Possible Role of Gut Microbiota with Ischemic Stroke Subtypes: A Mendelian Randomization Study with Insights into Immune Cell Mediators

Introduction: Ischemic Stroke (IS) is a complex cerebrovascular disorder in which the gut microbiota has been identified as a key modulator. This study aims to explore the potential causal relationships between gut microbiota and three IS subtypes— Large-Artery Atherosclerosis (LAA), Small-Artery Stroke (SAS), and Cardiogenic Stroke (CES)—and to elucidate the mediating role of immune cells. Methods: We performed a two-sample bidirectional Mendelian Randomization (MR) analysis using multi-cohort data to examine the associations of 207 gut microbial taxa and 205 metabolic pathways with IS subtypes, further incorporating immune phenotypes as mediating factors. Results: Specific gut microbial taxa and metabolic pathways showed significant associations with the three IS subtypes. Thirty immune cell phenotypes were identified as mediators in the gut microbiota-IS relationship. Among these, 14 mediating pathways explained more than 10% of the observed effects; for example, Parabacteroides johnsonii influenced LAA via HLA-DR on CD33-HLA-DR+ cells, with a mediation proportion of 11.34%. Discussion: These findings reveal distinct immune-mediated mechanisms linking the gut microbiota to different IS subtypes, highlighting the complex tripartite interactions among the microbiota, immunity, and cerebrovascular pathology. Conclusion: This study provides evidence supporting immune-mediated associations between gut microbiota and IS subtypes. The results clarify potential mechanisms through which the microbiota contribute to different IS subtypes and offer new insights for developing therapeutic targets.