Department of Neurology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Pediatric Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Front Immunol. 2024 Sep 9;15:1438645. doi: 10.3389/fimmu.2024.1438645. eCollection 2024.
Previous studies have suggested that gut microbiota (GM) may be involved in the pathogenesis of epilepsy through the microbiota-gut-brain axis (MGBA). However, the causal relationship between GM and different epilepsy subtypes and whether circulating inflammatory proteins act as mediators to participate in epileptogenesis through the MGBA remain unclear. Therefore, it is necessary to identify specific GM associated with epilepsy and its subtypes and explore their underlying inflammatory mechanisms for risk prediction, personalized treatment, and prognostic monitoring of epilepsy.
We hypothesized the existence of a pathway GM-inflammatory proteins-epilepsy. We found genetic variants strongly associated with GM, circulating inflammatory proteins, epilepsy and its subtypes, including generalized and partial seizures, from large-scale genome-wide association studies (GWAS) summary data and used Multivariate Mendelian Randomization to explore the causal relationship between the three and whether circulating inflammatory proteins play a mediating role in the pathway from GM to epilepsy, with inverse variance weighted (IVW) method as the primary statistical method, supplemented by four methods: MR-Egger, weighted median estimator (WME), Weighted mode and Simple mode.
16 positive and three negative causal associations were found between the genetic liability of GM and epilepsy and its subtypes. There were nine positive and nine negative causal associations between inflammatory proteins and epilepsy and its subtypes. Furthermore, we found that C-X-C motif chemokine 11 (CXCL11) levels mediated the causal association between Genus Family XIII AD3011 group and epilepsy.
Our study highlights the possible causal role of specific GM and specific inflammatory proteins in the development of epilepsy and suggests that circulating inflammatory proteins may mediate epileptogenesis through the MGBA.
先前的研究表明，肠道微生物群（GM）可能通过微生物群-肠-脑轴（MGBA）参与癫痫的发病机制。然而，GM 与不同癫痫亚型之间的因果关系，以及循环炎症蛋白是否通过 MGBA 作为介质参与癫痫发生尚不清楚。因此，有必要确定与癫痫及其亚型相关的特定 GM，并探讨其潜在的炎症机制，以进行风险预测、个性化治疗和癫痫的预后监测。
我们假设 GM-炎症蛋白-癫痫存在一条通路。我们从大规模全基因组关联研究（GWAS）汇总数据中发现了与 GM、循环炎症蛋白、癫痫及其亚型（包括全面性和部分性发作）强烈相关的遗传变异，并使用多变量孟德尔随机化来探索三者之间的因果关系，以及循环炎症蛋白是否在 GM 向癫痫的通路中发挥中介作用，以逆方差加权（IVW）法作为主要统计方法，并辅以四种方法：MR-Egger、加权中位数估计器（WME）、加权模式和简单模式。
在 GM 遗传易感性与癫痫及其亚型之间发现了 16 个阳性和 3 个阴性因果关联。在炎症蛋白与癫痫及其亚型之间发现了 9 个阳性和 9 个阴性因果关联。此外，我们发现 C-X-C 基序趋化因子 11（CXCL11）水平介导了属科 XIII AD3011 组与癫痫之间的因果关联。
我们的研究强调了特定 GM 和特定炎症蛋白在癫痫发生发展中的可能因果作用，并表明循环炎症蛋白可能通过 MGBA 介导癫痫发生。
