Regulatory effects of leflunomide on gut microecology during IgA nephropathy treatment

Growing evidence suggests that the gut-kidney axis may contribute to the pathogenesis of IgA nephropathy (IgAN). However, the effects of immunosuppressants on the intestinal microbiome remain unclear. We investigated how different therapeutic strategies influence gut microbial composition in IgAN patients. We enrolled 46 patients with IgAN and 37 healthy controls (HC). Patients were stratified by treatment regimen into a supportive care group or an immunosuppressive therapy group, with subgroups defined by the use of leflunomide and systemic glucocorticoids. Fecal samples from patients in clinical remission were analyzed and 16S rRNA gene sequencing was performed. We examined microbial α- and β-diversity, taxonomic differences, and predicted functional pathways using Linear Discriminant Analysis Effect Size and Kyoto Encyclopedia of Genes and Genomes (KEGG)-based annotation. Compared with HCs, IgAN patients showed significantly reduced microbial α-diversity, depletion of beneficial taxa such as Faecalibacterium, and enrichment of potential pathogens, including Enterobacteriaceae. Neither supportive care and systemic glucocorticoid therapy were not associated with an apparent restoration of overall microbial diversity or community structure. Conversely, leflunomide treatment was associated with higher microbial diversity and a taxonomic profile that showed a trend toward similarity with healthy controls. Notably, anti-inflammatory bacteria, including Dysosmobacter welbionis, Ruthenibacterium lactatiformans, and Intestinimonas butyriciproducens were significantly enriched (all p < 0.01). KEGG-based predictions revealed downregulation of pro-inflammatory pathways, accompanied by reduced levels of inflammatory markers (p < 0.05). Overall, the therapeutic efficacy of leflunomide in IgA nephropathy is associated with specific characteristics of the patients' gut microbiota, which may be linked to its potential to reverse dysbiosis and enhance anti-inflammatory effects.