Cross-species biomarkers of cerebellar injury in acute sepsis: integrated metabolomics of mouse cerebellum and plasma identify conserved human plasma biomarkers and therapeutic modulation by human MSC-sEVs.

Septic encephalopathy (SE) is a severe complication of sepsis, characterized by neuroinflammation and metabolic dysfunction, with the cerebellum among the most vulnerable brain regions. Advances in the field have been constrained by the lack of reliable biomarkers for SE detection, incomplete mapping of cerebellar metabolic alterations in SE, and limited insight into the therapeutic mechanisms of human mesenchymal stem cell (MSC)-derived small extracellular vesicle (sEV) therapy. To overcome these challenges, we used a murine sepsis model and conducted integrated metabolomic analyses of cerebellar tissue and plasma, with and without MSC-sEV administration. Cross-compartment analyses identified six plasma metabolites with strong diagnostic potential in mice, three of which (n-acetylputrescine, aspartic acid, and cystathionine) were also observed in the plasma of human septic patients, supporting their promise as translatable biomarker candidates. Sepsis triggered profound cerebellar metabolic dysfunction, suppression of oxidative energy metabolism, and redox imbalance. MSC-sEVs attenuated these disturbances via their bioactive cargo, restoring cellular energetics and reestablishing antioxidant balance. Collectively, these results highlight cross-species plasma biomarkers for SE diagnosis, delineate key cerebellar metabolic mechanisms in SE, and demonstrate therapeutic modulation by human MSC-sEVs.