Abstract
BACKGROUND: Migraines impose a substantial economic and societal burden, yet their underlying mechanisms remain poorly understood. While observational studies suggest associations between gut microbiota dysbiosis, immunophenotypic alterations, and migraine risk, causal evidence is lacking. This study leverages Mendelian Randomization to investigate the causal relationship between gut microbiota and migraine while exploring the mediating role of immune traits in this association. METHODS: We employed a two-sample, two-step Mendelian Randomization approach to examine the mediating effects of immunocyte phenotypes on the relationship between gut microbiota and migraine outcomes, including migraine with aura and migraine without aura. The primary analysis utilized inverse-variance weighted estimation, supplemented by sensitivity analyses to ensure robustness. Summary statistics for gut microbiota were sourced from the MiBioGen consortium and NHGRI-EBI, immunocyte phenotypes from the GWAS catalog, and migraine data from the FinnGen consortium. Next, we evaluated Prevotella histicola level by qPCR. RESULTS: Our analysis identified suggestive associations between 34 gut microbiota taxa and migraine subtypes. Notably, Family Bifidobacteriaceae (id.433, PIVW: 1.51×10⁻⁵, ORIVW: 0.861, 95% CI: 0.765-0.970) and Order Bifidobacteriales (id.432, PIVW: 1.51×10⁻⁵, ORIVW: 0.861, 95% CI: 0.765-0.970) demonstrated strong causal links to a reduced risk of migraine. Mediation analysis revealed that HLA-DR on monocytes mediated 7.74% of the causal pathway from Genus Prevotella9 (id.11183, PIVW: 0.002, ORIVW: 0.834, 95% CI: 0.744-0.936) to MA. CONCLUSIONS: This study provides robust evidence of a causal relationship between Bifidobacteriaceae and a decreased risk of migraine. Furthermore, we identify HLA-DR on monocytes as a key inflammatory mediator in the protective effect of Prevotella against migraine with aura. These findings highlight the potential of gut microbiota modulation and immune-targeted therapies in migraine prevention and treatment, offering novel insights into the gut-brain-immune axis in migraine pathogenesis.