Abstract
Background：IgA nephropathy (IgAN) is an immune-inflammatory glomerulonephritis mediated by both genetic and environmental factors. Recent research indicates a close association between gut microbiota dysbiosis and IgAN development. Additionally, circulating inflammatory proteins also play a significant role in the progression of IgAN.However, the causal relationship among gut microbiota, circulating inflammatory proteins, and IgAN remains unclear.
Methods：This study utilized publicly available genome-wide association study (GWAS) data for Mendelian randomization (MR) analysis to investigate the causal relationship among gut microbiota circulating inflammatory proteins and IgAN, as well as to examine the mediating role of circulating inflammatory proteins in the association between gut microbiota and IgAN. The primary analytical method employed in this study was inverse variance-weighted (IVW) analysis with specific attention given to Bayesian-weighted MR results and supported by MR-Egger regression, weighted median, median model and simple model approaches. Several sensitivity analyses were performed to evaluate the robustness of MR analysis findings.
Results：(1)MR analysis of gut microbiota and IgAN indicates negative associations between g_Roseburia, g_Faecalibacterium, s_Odoribacter_splanchnicus, and s_Roseburia_unclassified with IgAN risk, while positive associations exist between s_Paraprevotella_unclassified and s_Lachnospiraceae_bacterium_7_1_58FAA with IgAN risk.(2) Circulating inflammatory proteins to IgAN in MR analysis showed that IL-10RA was negatively correlated with the risk of IgAN, while TSGP-CD5, FGF23, LIF, and TGF-α levels were positively correlated with the risk of IgAN.(3)Mediation analysis suggests that TGF-αserves as a mediator between s_Odoribacter_splanchnicus and the causality of IgAN. (4) The results of the reverse MR analysis suggest no significant causal effect of IgAN on gut flora and circulating inflammatory proteins.Sensitivity analyses consistently support the reliability of the study results.
Conclusion：Our research findings, obtained through genetic methods, substantiate the causal link between gut microbiota, circulating inflammatory proteins, and IgAN. The identification of biomarkers offers novel insights into the potential mechanisms underlying IgAN, which can be advantageous for early diagnosis and the development of more effective treatment strategies.