The molecular architecture of severe pediatric traumatic brain injury: integrated omics reveal therapeutic pathways.

INTRODUCTION: Traumatic brain injury (TBI) remains a leading cause of death and long-term disability in children worldwide. Despite its impact, current clinical management is limited to supportive care, with no FDA-approved therapies to reduce mortality or mitigate lasting neurological consequences. This study presents, to our knowledge, the first integrated multi-omics analysis combining transcriptomic and metabolomic data from pediatric patients with severe TBI spanning both acute and subacute phases offering novel insights into the molecular pathways underlying injury and recovery. METHODS: In this prospective, observational cohort study seventeen severe pediatric TBI patients (median age of 13.1 years, median Glasgow Coma Scale (GCS) of 3, and median Injury Severity Score (ISS) of 29) with no pre-existing neurological comorbidities or non-accidental trauma, and corresponding sex and age-matched controls were enrolled between May 2022 and November 2023. The longitudinal bulk transcriptomic analysis of whole blood and metabolomic profiling of serum were performed at three distinct timepoints. The resulting multi-omics datasets were subsequently integrated with validated clinical severity scoring systems to assess changes over a nine-day period of care in the pediatric intensive care unit (PICU). RESULTS: We showed that despite the heterogeneity of mechanism and presentation, there was overlap in the transcriptomic and metabolic signatures at each timepoint. There were immediate signs of inflammatory and immune activation, metabolic dysregulation, disturbance of the gut-brain axis in the acute phase. Early markers of T-cell infiltration, such as TRAV35 and ANXA2R, are highly correlated with GCS, and lysophosphatidylcholine 18:0 is highly correlated with NK-cell activation. Multiple gut metabolites, such as indole-3-propionic acid (IPA), and RNA signatures of gut flora are elevated in blood early after TBI. Putrescine elevation at time point one highly correlates with Day 9 red blood cell stimulation. At Day9, multiple lipid species in the metabolome are associated with length of stay and Glasgow Outcome Scale-Extended (GOS-E Peds). By Day 9, both the metabolome and transcriptome show incomplete recovery, marked by highly specific TBI IGH, IGK, and IGL clonal expansion. CONCLUSIONS: Despite the heterogeneity in injury mechanisms and clinical presentations, our findings reveal a convergent host response, characterized by shared transcriptomic and metabolic signatures across all time points. This convergence highlights potentially targetable biological pathways and opens the door to the development of novel therapeutic strategies for severe pediatric TBI.