Exploring the Possible Role of Gut Microbiota with Ischemic Stroke Subtypes: A Mendelian Randomization Study with...

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.

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.

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%.

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.

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.