Causal relationships between gut microbiota and IgA nephropathy: evidence from Mendelian randomization and microbiome validation.

Background: Emerging evidence links gut microbiota strongly with IgA Nephropathy (IgAN). However, the causal role of specific gut microbiota in IgAN remains unclear. This study used a two-sample Mendelian randomization (MR) approach, validated with 16S rRNA datasets, to identify these causal relationships.

Methods: We performed MR analysis using genetic instruments for 412 gut microbiota taxa from genome-wide association studies (GWAS) as exposures and IgAN GWAS data as outcomes. The inverse-variance weighted method was used as the primary analysis, supplemented by MR-Egger regression, weighted median methods, and Cochran's Q test to assess pleiotropy and heterogeneity. Significant findings were validated using reverse, multivariable, and mediation MR analyses. Results were validated using genus-level 16S rRNA datasets with batch correction (ConQuR), and microbial function was inferred via PICRUSt2.

Results: Three gut microbiota species were protective against IgAN: s_Alistipes_senegalensis (OR = 0.64, p = .002), s_Ruminococcus_bromii (OR = 0.75, p = .040), and s_Bilophila_unclassified (OR = 0.68, p = .040). Six species were associated with increased IgAN risk, including g_Barnesiella (OR = 1.32, p = .030) and s_Rothia_mucilaginosa (OR = 1.52, p = .040). After multiple-testing correction, significant associations persisted for s_Alistipes_senegalensis (p = .043), s_Bacteroides_clarus (p = .035), and s_Bilophila_unclassified (p = .002). Sensitivity analyses confirmed robust results without pleiotropy or heterogeneity. Genus-level validation confirmed consistent microbial shifts. Functional predictions showed upregulation of carbohydrate/fatty acid metabolism and downregulation of the urea cycle.

Conclusions: This study reveals specific gut microbes and metabolic pathways potentially driving IgAN, offering novel biomarkers and therapeutic targets for microbiome-based interventions.