Metabolomics of cerebrospinal fluid following traumatic brain injury: Exploration of biomarkers for secondary injuries and severity

Traumatic brain injury (TBI) constitutes a major global public health concern associated with substantial mortality and long-term disability, while its diagnostic approaches and underlying pathophysiological mechanisms remain to be fully elucidated. In this study, we conducted longitudinal metabolomic profiling of cerebrospinal fluid (CSF) from 23 TBI patients (9 mild, 14 severe) and 5 uninjured controls using high-resolution mass spectrometry. Comprehensive quantification of metabolites was performed at three critical post-injury time points (days 1, 3, and 7), revealing distinct temporal metabolic patterns. Our results demonstrated significant alterations in the CSF metabolome following TBI. Early-phase changes (day 1) predominantly involved energy-related metabolites, including sphingosine, glucose, and dl-lactate. More pronounced metabolic shifts were observed by day 3, characterized by marked variations in amino acids (l-glutamine, l-histidine) and medium-chain fatty acids (caprylic acid, octanoic acid), suggesting the transition from primary to secondary injury mechanisms. The day 7 profile revealed accumulation of repair-associated metabolites such as 2'-deoxyuridine 5'-monophosphate and 1,2-dihexadecanoyl-sn-glycerol, potentially indicative of processes occurring in the chronic phase, which may include both reparative mechanisms and ongoing pathology. Notably, we identified significant alterations in established biomarkers (trimethylamine N-oxide) and novel small peptides (e.g., Gly-His-Lys), with distinct metabolic signatures differentiating mild versus severe TBI cases. These findings delineate temporally dynamic and severity-dependent metabolic reprogramming in TBI, providing mechanistic insights into the progression from acute injury through secondary pathogenesis to chronic recovery phases. The identified metabolic signatures may serve as potential biomarkers for injury staging and therapeutic monitoring.