hucMSC-sEVs restores intestinal epithelial homeostasis in inflammatory bowel disease via CKB-dependent creatine metabolism.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by intestinal barrier dysfunction, excessive immune activation, and impaired epithelial homeostasis. Emerging evidence suggests that metabolic dysregulation contributes to disease progression. This study investigated whether human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (hucMSC-sEVs) alleviate IBD by regulating creatine metabolism through creatine kinase B (CKB)-mediated creatine/phosphocreatine (Cr/PCr) conversion. A dextran sulfate sodium (DSS)-induced murine colitis model and lipopolysaccharide (LPS)-stimulated IEC-6 intestinal epithelial cells were used to evaluate the effects of hucMSC-sEVs on inflammation, apoptosis, barrier integrity, and creatine metabolism. hucMSC-sEVs treatment markedly alleviated colitis and restored intestinal epithelial homeostasis in both in vivo and in vitro settings. Mechanistically, hucMSC-sEVs significantly increased the expression of the creatine metabolism-related molecules SLC6A8 and GATM, while normalizing the inflammation-induced elevation of the Cr/PCr ratio by recovering CKB function. Furthermore, pharmacological inhibition or knockdown of CKB aggravated inflammation, apoptosis, and barrier dysfunction and substantially diminished the protective effects of hucMSC-sEVs. These findings demonstrate that CKB-mediated creatine metabolism is a critical regulator of intestinal epithelial homeostasis during inflammatory injury. hucMSC-sEVs exerts its protective effects, at least in part, by restoring creatine metabolic balance through CKB, highlighting a previously unrecognized metabolic mechanism and a potential therapeutic target for IBD.