Supplementary Material for: The Impact of Gut Microbiota on IgA Nephropathy Through the Mediation of Specific Immune Cells: A Mendelian Randomization Study

Introduction: Gut microbiota alterations had been implicated in the pathogenesis of IgA nephropathy (IgAN). However, how did the gut microbiota participated in the onset and development of IgAN was unclear. This study investigated the causal effects of gut microbiota on IgAN and identifies potential mediators, including lipids, inflammatory factors, metabolites, and immune cells. Methods: Genome-wide association study (GWAS) data for gut microbiota, IgAN, and mediators were analyzed. Two-sample Mendelian randomization (MR) assessed the causal relationship between gut microbiota and IgAN, followed by two-step MR mediation analysis to identify indirect effects via mediators. Mediation effects were quantified using the coefficient product method. Results: MR analysis identified six genera and one phylum of gut microbiota with potential causal linked to IgAN. Two-step MR revealed one lipid, two inflammatory factors, ten metabolites, and sixteen immune cell types as mediators. Specifically, Oscillospira, Clostridium innocuum group, and Actinobacteria exerted effected via IgD+CD24− B cells, CD24 on IgD+CD38+ B cells, and CD4 on naïve CD4+ T cells, respectively. Conclusion: Gut microbiota alterations could causally influence IgAN, with specific immune cell subsets mediating these effects. Specific subsets of B cells and T cells could be involved in the development of IgAN, which would need our attention in the future.