Mendelian Randomization Study on Lactobacillus salivarius, CD62L⁻ pDCs, and Luminal cerebral infarction Risk

Background: Lacunar cerebral infarction (LCI) is a common subtype of ischemic stroke. Emerging evidence links the gut microbiota to cerebrovascular diseases through immune-mediated pathways, but causal relationships remain unclear. Methods: Genetic instruments for gut microbiota (n = 473 traits), immune cells (n = 731 traits), and LCI were obtained from large-scale GWAS datasets of European ancestry. Bidirectional MR and mediation MR analyses were conducted to evaluate directionality and immune mediation. Results: Genetically predicted Lactobacillus salivarius abundance was positively associated with LCI risk (OR = 2.123, 95% CI: 1.3045-3.4567, P =0.002/OR = 1.6427, 95% CI: 1.1379-2.3714, P =0.008). Among immune cell traits, CD62L⁻ plasmacytoid dendritic cells (pDCs) were identified as a significant mediator, showing a causal link with both L. salivarius and LCI. Mediation analysis revealed that 7.6% of the effect of L. salivarius on LCI risk was mediated through CD62L⁻ pDCs. Conclusions: This study provides genetic evidence that Lactobacillus salivarius may increase the risk of lacunar stroke via proinflammatory immune activation. These findings highlight the importance of gut–immune–brain interactions in stroke pathogenesis and suggest potential microbiota-targeted strategies for prevention.