Metabolomics Profiling of Serum Small Extracellular Vesicle-Enriched Fractions Across Early Post-Injury Intervals Following Severe Traumatic Brain Injury

Abstract Severe traumatic brain injury (sTBI) induces metabolic disturbances that remain difficult to assess non-invasively. This exploratory study compared metabolomics profiles of serum small extracellular vesicle-enriched fractions from healthy controls and patients with sTBI sampled at days 1, 3, and 5 post-injury. Using high-resolution liquid chromatography−mass spectrometry (LC−MS), we identified metabolite differences associated with each sampled post-injury interval. Principal component analysis showed group-level separation between controls and the individual post-injury interval groups, with the largest separation observed in the day 1 comparison. N-Acetyl-l-aspartic acid, a canonical marker of neuronal integrity, showed lower abundance in the day 1 group relative to controls, whereas PGF2α ethanolamide showed lower abundance relative to controls in all three interval-specific comparisons. Glu−ser and tryptophan also met the differential-abundance criteria in more than one interval vs. control comparison. Ingenuity pathway analysis (IPA) linked the day 1 metabolite alterations to literature-curated neurological functions, including demyelination and neurodegeneration; however, these associations are presented as hypothesis-generating. Collectively, these findings identify serum small extracellular vesicle-enriched fraction metabolite alterations associated with sTBI for further investigation in fully longitudinal sTBI cohorts.