Lai Yupei, Liu Yike, Chen Jiahao, Cao Yu, Zhang Xiangsheng, Li Lu, Zhou Pengyu, Sun Peng, Zhou Jun
The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Shunde Hospital of Guangzhou University of Chinese Medicine, Foshan, China.
Brain Behav. 2025 Jul;15(7):e70693. doi: 10.1002/brb3.70693.
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.
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.
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.
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.
偏头痛给经济和社会带来了沉重负担，但其潜在机制仍知之甚少。虽然观察性研究表明肠道微生物群失调、免疫表型改变与偏头痛风险之间存在关联，但缺乏因果证据。本研究利用孟德尔随机化方法来研究肠道微生物群与偏头痛之间的因果关系，同时探讨免疫特征在这种关联中的中介作用。
我们采用两样本、两步孟德尔随机化方法，以检验免疫细胞表型对肠道微生物群与偏头痛结局（包括伴先兆偏头痛和无先兆偏头痛）之间关系的中介作用。主要分析采用逆方差加权估计，并辅以敏感性分析以确保稳健性。肠道微生物群的汇总统计数据来自MiBioGen联盟和NHGRI-EBI，免疫细胞表型来自GWAS目录，偏头痛数据来自芬兰基因组计划联盟。接下来，我们通过qPCR评估组胺普雷沃氏菌水平。
我们的分析确定了34种肠道微生物分类群与偏头痛亚型之间存在提示性关联。值得注意的是，双歧杆菌科（id.433，PIVW：1.51×10⁻⁵，ORIVW：0.861，95%CI：0.765-0.970）和双歧杆菌目（id.432，PIVW：1.51×10⁻⁵，ORIVW：0.861，95%CI：0.765-0.970）与偏头痛风险降低之间存在强烈的因果关系。中介分析显示，单核细胞上的HLA-DR介导了从普雷沃氏菌属9（id.11183，PIVW：0.002，ORIVW：0.834，95%CI：0.744-0.936）到伴先兆偏头痛的因果路径的7.74%。
本研究为双歧杆菌科与偏头痛风险降低之间的因果关系提供了有力证据。此外，我们确定单核细胞上的HLA-DR是普雷沃氏菌对伴先兆偏头痛保护作用中的关键炎症介质。这些发现突出了肠道微生物群调节和免疫靶向治疗在偏头痛预防和治疗中的潜力，为偏头痛发病机制中的肠-脑-免疫轴提供了新的见解。
