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 PICRUSt2.

RESULTS

Three gut microbiota species were protective against IgAN: (OR = 0.64,  = .002), (OR = 0.75,  = .040), and (OR = 0.68,  = .040). Six species were associated with increased IgAN risk, including (OR = 1.32,  = .030) and (OR = 1.52,  = .040). After multiple-testing correction, significant associations persisted for ( = .043), ( = .035), and ( = .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.