Gut Microbiota Affects Cardiovascular Diseases via Inflammatory Cytokines: a Bidirectional Two-sample Mendelian Randomization Study and Mediation Analysis

Abstract

Background: Cardiovascular diseases (CVDs) arise from complex interactions between genetic predisposition and environmental exposures, manifesting as persistent inflammatory disorders. Although accumulating evidence has implicated gut microbiota in the pathogenesis of CVDs, whether this association reflects a causal relationship remains to be firmly established. Therefore, the present study sought to examine the potential causal links between gut microbiota composition, circulating inflammatory cytokines, and susceptibility to CVDs.
Methods: Summary statistics for 196 gut microbiota taxa, 91 cytokines, and 8 CVD subtypes were extracted from the largest published genome-wide association studies (GWAS) to conduct bidirectional two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method was used as the primary statistical approach. We investigated the causal associations between gut microbiota and 8 CVD subtypes, including coronary artery disease (CAD), coronary atherosclerosis (CAS), heart failure (HF), stroke, atrial fibrillation (AF), angina pectoris (AP), calcific aortic valve stenosis (CAVS), and aortic aneurysm. Multivariable MR (MVMR) analysis was further performed to explore the potential mediating role of cytokines in the causal pathways from gut microbiota to CVDs.
Results: MR analysis identified causal associations between 58 gut microbiota taxa, 46 inflammatory cytokines, and CVDs. Specifically, 34 positive and 24 negative causal effects were observed between gut microbiota and CVDs, along with 16 positive and 30 negative causal effects between cytokines and CVDs. Additionally, mediation analysis identified C-C motif chemokine 25 (CCL25) level as a key mediator in the causal relationship from gut microbiota to CVDs.
Conclusions: Our findings support a causal link between gut microbiota, inflammatory cytokines, and CVDs, with CCL25 mediating the protective effect of specific gut taxa against CAVS. These identified biomarkers offer novel insights into the pathophysiological mechanisms of CVDs and may inform the development of novel strategies for CVD prevention, diagnosis, and treatment.