The Dysbiosis of Gut Microbiota and Dysregulation of Metabolites in IgA Nephropathy and Membranous Nephropathy

Lei Zhang¹Lan Hu²Li Tan³Zhenjie Zhang³Mengying Chen¹Wenbo Gan¹Li Chen¹Yan Zou¹Shi Wang¹Yu Pang³Zhenxin Fan^3*Junjie Liu^1*

• ¹Guang’an People’s Hospital, Guan’an, China
• ²Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
• ³Sichuan University, Chengdu, China

Immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) are primary glomerular diseases with increasing incidence, yet their pathogenesis and noninvasive diagnostic approaches remain insufficiently understood. In this study, we integrated metagenomic and untargeted metabolomic profiling to explore gut microbiota alterations and metabolic disturbances in 24 IgAN patients, 20 MN patients, and 17 healthy controls. Metagenomic analysis showed that both the IgAN and MN groups had significantly reduced α-diversity. Although β-diversity analysis did not reveal significant differences between the three groups, the IgAN and MN groups exhibited higher sample dispersion than the control group. Notably, both IgAN and MN patients showed a decrease in the abundance of certain specific microbial taxa. A total of 34 and 28 differentially abundant microbial species were identified in IgAN and MN, respectively, compared to healthy controls, with 16 taxa consistently downregulated in both disease groups. Notably, Streptococcus oralis was significantly enriched in the MN group, while [Clostridium] innocuum was markedly depleted. Metabolomic profiling identified 307 and 209 differentially abundant metabolites in IgAN and MN, respectively. Dipeptides (e.g., prolylleucine) were consistently upregulated, while the levels of certain short-chain fatty acids (SCFA) were reduced. Multivariate biomarker models demonstrated excellent diagnostic performance, achieving area under the curve (AUC) of 0.919 (IgAN vs. control) ,0.897( MN vs. control) and 0.912 (IgAN vs.MN), surpassing individual metabolite markers. Microbiota-metabolite correlation networks further linked specific microbes, including Oscillibacter hominis, to SCFA depletion, suggesting microbiota-driven metabolic dysregulation. Together, these findings underscore the contribution of the gut-kidney axis to IgAN and MN pathogenesis and propose novel non-invasive biomarkers for improved differential diagnosis and precision medicine.