Explore the relationships between gut microbiota and cardiomyopathies with the potential mediating effect of cytokines: A univariable and multivariable Mendelian randomization study

Emerging evidence suggests a potential link between gut microbiota and cardiomyopathies, but the causal relationships and the mediating role of cytokines remain unclear. We performed a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary data for 211 gut microbiota taxa, 41 cytokines, and cardiomyopathy subtypes. Instrumental variables were selected at a genome-wide significance threshold (P < 1 × 10-5). Primary causal estimates were derived via inverse-variance weighted (IVW) regression, supplemented by sensitivity analyses. Multivariable MR was utilized to reduce bias from confounders. Mediation analysis tested whether cytokines linked gut microbiota to cardiomyopathies. Genetic liability in gut microbiota showed significant associations with cardiomyopathy risk. For dilated cardiomyopathy (DCM), genus Ruminococcaceae (OR = 1.24, 95% CI: 1.00-1.54, P = .045) and genus Flavonifractor (OR = 1.66, 95% CI: 1.15-2.35, P = .0067) increased risk, while family Peptostreptococcaceae was protective (OR = 0.71, 95% CI: 0.51-0.99, P = .041). For hypertrophic cardiomyopathy (HCM), genus Enterorhabdus raised risk (OR = 1.53, 95% CI: 1.00-2.33, P = .049), whereas order Methanobacteria lowered it (OR = 0.69, 95% CI: 0.52-0.93, P = .013). For myocarditis, genus Faecalibacterium reduced risk (OR = 0.53, 95% CI: 0.33-0.85, P = .009), but genus Family XIII UCG001 increased it (OR = 2.06, 95% CI: 1.15-3.69, P = .015). Cytokines including IL-9 and MIP-1β showed protective effects for DCM, while pro-inflammatory cytokines TNF-α and VEGF elevated myocarditis risk. Mediation analysis revealed cytokines did not mediate gut microbiota-cardiomyopathy pathways. Specific gut microbiota and cytokines exert causal effects on cardiomyopathy subtypes, independent of cytokine mediation. These findings highlight potential therapeutic targets and underscore the need to explore alternative mechanistic pathways.