Zhang Ruijie, Han Liyuan, Pu Liyuan, Jiang Guozhi, Guan Qiongfeng, Fan Weinv, Liu Huina
School of Public Health, Southeast University, Nanjing, Jiangsu, China; Department of Clinical Epidemiology, Ningbo No.2 Hospital, Ningbo, Zhejiang, China; Center for Cardiovascular and Cerebrovascular Epidemiology and Translational Medicine, Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang, China.
Department of Clinical Epidemiology, Ningbo No.2 Hospital, Ningbo, Zhejiang, China; Center for Cardiovascular and Cerebrovascular Epidemiology and Translational Medicine, Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang, China.
J Stroke Cerebrovasc Dis. 2025 Apr;34(4):108233. doi: 10.1016/j.jstrokecerebrovasdis.2025.108233. Epub 2025 Jan 9.
The causal relationships between gut microbiota, blood metabolites, and stroke and its subtypes remain unclear. This study aims to uncover the causal associations using Mendelian randomization.
We initially identify Single-Nucleotide Polymorphisms (SNPs) correlated with gut microbiota and blood metabolites as instrumental variables (IVs) from the summary statistics in Genome-Wide Association Study (GWAS) to evaluate their potential causal associations with stroke and its subtypes. We proceed with a two-step Mendelian randomization analysis aiming to determine whether blood metabolites mediate the relationships between gut microbiota and stroke or its subtypes.
We identified the genetic predictions of 12, 11, and 10 particular gut microbiota were associated with stroke, ischemic stroke, and intracerebral hemorrhage respectively. Inverse variance weighted (IVW) analysis disclosed Alistipes (OR [95%CI]: 1.11[1.00,1.23]), Streptococcus (OR [95%CI]: 1.17[1.05,1.30]), and Porphyromonadaceae (OR [95%CI]: 2.41[1.09,5.31]) as the primary causal effects on stroke, ischemic stroke, and ICH, respectively. We determined that 8, 11, and 1 blood metabolites were causally related to stroke, ischemic stroke, and ICH, respectively. Among these metabolites, Citrate (OR [95%CI]: 2.39[1.32,4.34]) and Beta-hydroxyisovalerate (OR [95%CI]: 2.54[1.62,3.97]) had the foremost causal effect on stroke and ischemic stroke, respectively, whereas Glutaroyl carnitine evidenced a causal effect on ICH. Furthermore, our study revealed that Tetradecanedioate marginally mediated the causal effects of Paraprevotella on stroke and ischemic stroke.
This study established a causal link between gut microbiota, plasma metabolites, and stroke. It revealed a marginal pathway, shedding new light on the intricate interactions among gut microbes, blood metabolites, stroke, and their underlying mechanisms.
肠道微生物群、血液代谢物与中风及其亚型之间的因果关系仍不清楚。本研究旨在利用孟德尔随机化揭示因果关联。
我们首先从全基因组关联研究（GWAS）的汇总统计中确定与肠道微生物群和血液代谢物相关的单核苷酸多态性（SNP）作为工具变量（IV），以评估它们与中风及其亚型的潜在因果关联。我们进行了两步孟德尔随机化分析，旨在确定血液代谢物是否介导肠道微生物群与中风或其亚型之间的关系。
我们确定分别有12种、11种和10种特定肠道微生物群的遗传预测与中风、缺血性中风和脑出血相关。逆方差加权（IVW）分析显示，阿利斯氏菌属（比值比[95%置信区间]：1.11[1.00,1.23]）、链球菌属（比值比[95%置信区间]：1.17[1.05,1.30]）和卟啉单胞菌科（比值比[95%置信区间]：2.41[1.09,5.31]）分别是对中风、缺血性中风和脑出血的主要因果效应。我们确定分别有8种、11种和1种血液代谢物与中风、缺血性中风和脑出血存在因果关系。在这些代谢物中，柠檬酸（比值比[95%置信区间]：2.39[1.32,4.34]）和β-羟基异戊酸（比值比[95%置信区间]：2.54[1.62,3.97]）分别对中风和缺血性中风具有最主要的因果效应，而戊二酰肉碱对脑出血有因果效应。此外，我们的研究表明，十四烷二酸对中风和缺血性中风的因果效应起到了微弱的中介作用。
本研究建立了肠道微生物群、血浆代谢物与中风之间的因果联系。它揭示了一条微弱的途径，为肠道微生物、血液代谢物、中风及其潜在机制之间的复杂相互作用提供了新的见解。
