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: (1) the incomplete characterization of cerebellar metabolic disruption in SE, (2) the limited understanding of the therapeutic mechanisms of mesenchymal stem cell (MSC)-derived small extracellular vesicle (sEV) treatments in SE, and (3) 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 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.