Cerebellum and Plasma Metabolomics Identify Sepsis Biomarkers and MSC-sEV-Mediated Rescue.

Septic encephalopathy (SE) is a devastating complication of sepsis, marked by neuroinflammation and metabolic dysfunction, with the cerebellum being among the most affected brain regions. Progress in the field has been hindered by the incomplete characterization of cerebellar metabolic disruption in SE, a limited understanding of the therapeutic mechanisms of mesenchymal stem cell (MSC)-derived small extracellular vesicle (sEV) treatment, and the absence of reliable biomarkers for detecting SE. To address these gaps, we employed a murine sepsis model and performed metabolomic analyses of cerebellar tissue and plasma with and without MSC-sEV treatment. Sepsis induced profound cerebellar metabolic dysfunction, suppression of oxidative energy metabolism, and redox imbalance. MSC-sEVs mitigated these effects through their bioactive cargo, restoring cellular energetics and rebalancing antioxidant pathways. Cross-compartment analyses identified six plasma metabolites with strong diagnostic potential. These findings define key cerebellar metabolic mechanisms of SE and MSC-sEV treatment and propose plasma biomarkers for SE diagnostics.