Human umbilical cord mesenchymal stem cell–derived exosomes are associated with changes in renal injury markers, gut microbiota composition, and inflammatory signaling in IgA nephropathy

Background IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a leading cause of end-stage kidney disease, yet disease-specific therapeutic options remain limited. Emerging evidence implicates gut microbiota dysbiosis and innate immune activation, particularly NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome-related signaling, in IgAN pathogenesis. However, whether human umbilical cord mesenchymal stem cell–derived exosomes (hUCMSC-Exos) are associated with changes in renal injury and gut–immune-related parameters in IgAN remains unclear. Methods hUCMSC-Exos were isolated and administered to an IgAN-like mouse model. Renal function, histopathological changes, and systemic inflammatory markers were assessed. Gut microbiota composition was analyzed using 16S rRNA sequencing, and exploratory microbial co-occurrence networks were constructed. In vitro , podocytes stimulated with galactose-deficient IgA1 (Gd-IgA1) were used to evaluate inflammasome-related markers following exosome exposure. Transcriptomic data from human IgAN glomeruli (GSE93798) were analyzed to explore inflammatory and immune-related gene signatures. Results hUCMSC-Exos were associated with changes in renal injury markers in IgAN-like mice, along with alterations in gut microbial composition. Microbiome analysis showed a shift toward a microbial profile closer to controls, with enrichment of bacterial taxa previously reported in association with gut metabolic homeostasis in other cohorts, including Anaerostipes, Dorea, and Ruminococcus. These taxa showed correlations with renal dysfunction indicators and inflammatory markers and were identified as hub taxa in an exploratory co-occurrence network. Transcriptomic analysis of human IgAN glomeruli revealed altered expression of NLRP3 inflammasome-related genes and aryl hydrocarbon receptor (AhR)-related signaling components, suggesting context-dependent inflammatory activity requiring further validation. In vitro , hUCMSC-Exos were associated with reduced levels of NLRP3, IL-1β, and IL-18 in Gd-IgA1–stimulated podocytes. Conclusions hUCMSC-Exos were associated with changes in renal injury markers in an IgAN-like model, accompanied by alterations in gut microbiota composition and inflammasome-related inflammatory markers. These findings are consistent with a potential association between gut microbiota, innate immune-related signaling, and renal injury in IgAN. hUCMSC-Exos may represent a cell-free candidate for further investigation in IgAN. However, these observations are descriptive and associative in nature, and causal mechanisms cannot be inferred from the present study.