Metabolomic Analysis of Metabolic Syndrome and Effects of Wharton's Jelly Mesenchymal Stem Cell Small Extracellular Vesicles Therapy in Rat Models Using Nuclear Magnetic Resonance Spectroscopy

Long‐term management of metabolic syndrome (MetS) often involves polypharmacy, which may lead to undesirable outcomes. Regenerative approaches such as mesenchymal stem cell–derived small extracellular vesicles (MSC‐sEVs) have gained attention due to their paracrine effects, lower immunogenicity, and safer profile compared to whole‐cell therapies. Previous studies suggest that MSC‐sEVs improve insulin sensitivity, reduce inflammation, and support cardiovascular health, yet their precise mechanisms remain unclear. This study aimed to compare fecal and serum metabolic profiles of healthy, MetS, and MSC‐sEVs‐treated MetS rats using NMR‐based metabolomics and to identify metabolic pathways underlying the therapeutic effects of Wharton's jelly MSC‐sEVs (WJMSC‐sEVs). 18 Sprague Dawley rats were divided into three groups: healthy controls, MetS + saline, and MetS + WJMSC‐sEVs. After 16 weeks of MetS induction, rats received intravenous saline or WJMSC‐sEVs every 3 weeks for 12 weeks. Multivariate analysis revealed clear separations between groups. MetS was associated with reduced serum isoleucine, acetate, and propionic acid, and elevated lactate, threonine, and glucose; fecal samples showed increased valine, alanine, leucine, glutamate, and fructose but reduced threonine and SCFAs. Pathway analysis highlighted disturbances in starch and sucrose metabolism, pyruvate metabolism, and alanine, aspartate and glutamate metabolism. WJMSC‐sEVs partially restored these imbalances, suggesting their therapeutic potential by targeting key metabolic pathways in MetS.