Mesenchymal stem cells protect against diabetic nephropathy through gut microbiota-butyrate-mediated inhibition of neutrophil extracellular traps

Mesenchymal stem cells (MSCs) have demonstrated therapeutic potential in diabetic nephropathy (DN), yet the underlying mechanisms remain incompletely understood, limiting strategies to enhance their efficacy. This study aimed to elucidate whether MSCs exert renoprotective effects by modulating the gut microbiota and its metabolite short-chain fatty acids (SCFAs). DN was induced in rats via a high-fat diet (HFD) combined with streptozotocin (STZ) injection. MSCs were administered via tail vein infusion. Therapeutic efficacy was evaluated by renal function parameters, urine biochemistry, and renal histopathology. Neutrophil extracellular trap (NET) formation was assessed using immunofluorescence staining and ELISA. Alterations in gut microbial composition and SCFA profiles were analyzed through 16S rRNA gene sequencing and targeted metabolomics, respectively. The causal role of the gut microbiota was validated using fecal microbiota transplantation (FMT). Administration of MSCs, as well as FMT from MSC-treated donors, significantly ameliorated renal injury and suppressed NET formation in DN rats. Notably, pharmacological induction of NETs abolished the protective effects conferred by MSC-FMT. 16S rRNA sequencing revealed that MSC intervention enriched beneficial bacterial populations, particularly within the family Muribaculaceae . Targeted metabolomic analysis identified a significant elevation of butyrate among fecal SCFAs in MSC-treated rats. Furthermore, exogenous butyrate supplementation recapitulated the inhibitory effects on NET formation and attenuated DN progression. MSC therapy alleviates diabetic nephropathy via a gut-kidney axis mechanism, driven by the enrichment of butyrate-producing microbiota and the subsequent inhibition of neutrophil extracellular trap formation.