Exploring Causal Links Among Proton Pump Inhibitors, Gut Microbiota and Ischemic Stroke: A Mediation Mendelian Randomization Study
Abstract
Recent studies have highlighted a significant association between the use of proton pump inhibitors (PPIs) and an increased risk of cardiovascular diseases, with alterations in gut microbiota—induced by PPIs—potentially influencing the pathogenesis of ischemic stroke (IS). To investigate the causal relationship between PPI use and IS, we employed Mendelian Randomization (MR), utilizing single nucleotide polymorphisms (SNPs) associated with commonly used PPIs, including esomeprazole, lansoprazole, omeprazole, and rabeprazole, as instrumental variables. A two-step MR approach was further employed to examine the potential mediating effect of gut microbiota on these relationships. Our findings revealed a significant causal association between the use of esomeprazole and lansoprazole and the risk of large artery atherosclerotic stroke (LAS). Although specific shifts in gut microbiota were observed following the administration of these PPIs, these changes did not mediate the increased LAS risk, suggesting that the association between PPI use and LAS is not primarily driven by microbiota alterations. This study establishes a direct causal link between certain PPIs and the risk of specific IS subtypes, providing important insights into the cardiovascular risks associated with PPI use and underscoring the need for cautious clinical application, particularly in individuals at heightened risk of cardiovascular events.
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