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The Mediating Role of Plasma Inflammatory Proteins in Gut Microbiota-Driven Valvular Heart Disease: A Mendelian
Jiajing Zhao1, Yuhan Wang1, Chuxin Lv1
1Internal Medicine of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing City, Jiangsu Province, China.
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.
Insights
Modulating gut microbiota, like enhancing Actinobacteria, may prevent and treat valvular heart disease (VHD). Certain gut bacteria and plasma inflammatory proteins show causal links to VHD risk.
Area of Science:
- Microbiology
- Cardiovascular Medicine
- Immunology
Background:
- Valvular heart disease (VHD) is a significant cardiovascular condition.
- The interplay between gut microbiota (GM), plasma inflammatory proteins (PIPs), and VHD is not fully understood.
- Investigating these relationships can reveal novel therapeutic targets.
Purpose of the Study:
- To investigate the causal relationships between GM, PIPs, and VHD.
- To determine if PIPs mediate the association between GM and VHD.
- To identify specific microbial taxa and inflammatory proteins influencing VHD risk.
Main Methods:
- Two-sample Mendelian Randomization (MR) analysis using genome-wide association study (GWAS) data.
- Bidirectional MR for causal associations and multivariable MR for independence testing.
- Analysis of 196 GM taxa, 91 PIPs, and VHD data with sensitivity analyses.
Main Results:
- Specific GM taxa (e.g., Actinobacteria, Defluviitaleaceae) were linked to reduced VHD risk, while others (e.g., Oxalobacteraceae) increased risk.
- Certain PIPs showed protective effects (e.g., Interleukin-10, LIFR), while others (e.g., TNF-beta) elevated risk.
- Actinobacteria's protective effect was partially mediated by increased Leukemia inhibitory factor receptor (LIFR).
Conclusions:
- Gut microbiota composition significantly influences valvular heart disease risk.
- Targeting specific gut bacteria, such as increasing Actinobacteria, could be a novel strategy for VHD prevention and treatment.
- Plasma inflammatory proteins like LIFR and TNF-beta play independent roles in VHD pathogenesis.
