The Mediating Role of Plasma Inflammatory Proteins in Gut Microbiota-Driven Valvular Heart Disease: A Mendelian Randomization Study.

Abstract

This study investigates the causal relationships between gut microbiota (GM), plasma inflammatory proteins (PIPs), and valvular heart disease (VHD) using two-sample Mendelian Randomization (MR) analysis. We also assess whether PIPs mediate the link between GM and VHD. We conducted bidirectional MR analyses to explore causal associations between GM, PIPs, and VHD, and used multivariable MR to test the independence of associations. Genome-wide association study (GWAS) data on 196 GM taxa, 91 PIPs, and VHD were analyzed. MR methods including inverse-variance weighted (IVW), MR-Egger regression, and weighted median approaches were applied. Sensitivity analyses ensured robustness. Actinobacteria and Defluviitaleaceae were associated with lower VHD risk, while Oxalobacteraceae increased risk. At the genus level, Intestinibacter, Lachnospiraceae NC2004 group, Oscillospira, and Ruminococcaceae UCG004 were protective, whereas Oscillibacter increased risk. Among PIPs, Interleukin-10, Interleukin-17C, Leukemia inhibitory factor receptor (LIFR), and monocyte chemoattractant protein 2 were protective, while TNF-beta elevated risk. Multivariable MR confirmed the independent roles of TNF-beta, LIFR, and MCP-2. Actinobacteria's protective effect appeared partially mediated through increased LIFR expression, accounting for 14% of the effect. Our findings suggest that modulating gut microbiota, particularly enhancing Actinobacteria, may serve as a novel strategy for VHD prevention and treatment.