Exploring the mediating role of immune cells in the pathogenesis of IgA nephropathy through the inflammatory axis of gut microbiota from a genomic perspective.

IgA nephropathy (IgAN) is a chronic glomerular disease characterized by the deposition of IgA antibodies in the kidney's mesangium. Its pathogenesis involves genetic, immune, and environmental factors, particularly within the mucosal immune system and gut microbiota. Immune cells play a central role in mediating these processes, which this study investigates using Mendelian Randomization (MR) to explore causal relationships among gut microbiota, inflammatory markers, blood cells, and immune cells in IgAN pathogenesis. We conducted a two-sample MR analysis using Genome-Wide Association Study (GWAS) summary data to assess the causal effects of gut microbiota, inflammatory markers, and blood cell traits on IgAN. Data sources included the FinnGen dataset for IgAN and relevant GWAS datasets for immune traits, blood cells, and inflammatory markers. Inverse variance weighting (IVW) was the primary MR method, supported by sensitivity analyses. We particularly examined the mediation effect of immune cells on these exposures' influence on IgAN. Significant associations were found between several factors and IgAN. Gut microbiota traits, such as Firmicutes E and Sporomusales, increased IgAN risk, while Citrobacter A and Herbinix reduced it. Inflammatory markers, including Interleukin-10 and Fibroblast Growth Factor 23, promoted IgAN onset. Blood cell traits like red blood cell perturbation response increased risk, while monocyte perturbation response was protective. Immune traits played a key mediating role, with Transitional %B cells reducing IgAN risk and CD28- CD25 +  + CD8br %T cells increasing it. This study highlights the pivotal mediating role of immune cells in the interactions between gut microbiota, inflammatory markers, and IgAN risk. These findings identify potential biomarkers and therapeutic targets, providing new insights into the immune mechanisms underlying IgAN and opportunities for intervention.