Investigating causal associations of gut microbiota and blood metabolites on stroke and its subtypes: A Mendelian randomization study

Ruijie Zhang; Liyuan Han; Liyuan Pu; Guozhi Jiang; Qiongfeng Guan; Weinv Fan; Huina Liu

doi:10.1016/j.jstrokecerebrovasdis.2025.108233

Investigating causal associations of gut microbiota and blood metabolites on stroke and its subtypes: A Mendelian randomization study

J Stroke Cerebrovasc Dis. 2025 Jan 9;34(4):108233. doi: 10.1016/j.jstrokecerebrovasdis.2025.108233. Online ahead of print.

Authors

Ruijie Zhang¹, Liyuan Han², Liyuan Pu², Guozhi Jiang³, Qiongfeng Guan⁴, Weinv Fan⁴, Huina Liu⁵

Affiliations

¹ 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.
² 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.
³ School of Public Health, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China; School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China.
⁴ Department of Neurology, Ningbo No.2 Hospital, Ningbo, Zhejiang, China.
⁵ 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. Electronic address: liuhuina@ucas.ac.cn.

PMID: 39798630
DOI: 10.1016/j.jstrokecerebrovasdis.2025.108233

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Blood metabolites; Causal effects; Gut microbiota; Mendelian randomization; Stroke.