Traumatic brain injury (TBI) remains a leading cause of death and long-term disability in children worldwide (Dewan et al., 2016). Despite its impact, clinical management is still largely limited to supportive care, leaving a critical gap in therapies that can actually reduce mortality or mitigate lasting brain damage (Haydel et al., 2024).
To address this, Michigan State University, in collaboration with Corewell Health and our analytical team at VUGENE, set out to map the pediatric biological response to trauma. To our knowledge, this study is the first to apply multi-omics, integrating longitudinal transcriptomics and metabolomics, to track the systemic response in the days following a severe injury in children. The collaborative effort contributed to the discovery of several key findings:
Deep Molecular Integration
Our analysis showed 345 significant transcripts that clustered into distinct signatures over time. This temporal mapping revealed 50 potential biomarkers that differentiate the body’s immediate trauma response from its recovery phase.
Targeting S100A8/A9
While S100β is a known biomarker of pediatric TBI, we identified S100A8/A9 as a mechanistic driver of neuroinflammation and oxidative stress. As a druggable candidate shown to reduce neuronal death in preclinical models, this pathway could serve as a future therapeutic target.
Polyamine-ODC Disruption
We identified increased Ornithine Decarboxylase (ODC) gene expression linked to elevated plasma putrescine, creating a neurotoxic environment. This mismatch drives secondary injury and vasogenic edema, suggesting that ODC inhibition may be a promising therapeutic approach.
Metabolic Reprogramming
The analysis revealed a “lipid burst” and shifts in amino acid metabolism, representing the systemic cost of the brain’s attempt to repair neural membranes and manage acute energy failure.
The Gut-Brain Axis Connection
A significant drop in indole-3-propionic acid (a microbiome-related metabolite) levels in TBI patients relative to controls correlated with clinical severity, suggesting the involvement of the gut-brain axis in trauma processing.
The Bioinformatics Behind the Breakthrough
To identify individual transcript and metabolite level changes, we used mixed-effects linear regression via the limma statistical framework (Ritchie et al., 2015). Our models were adjusted for key covariates, including age, sex, and time point, to isolate the specific biological signals of trauma. Similar linear regression modeling was carried out for the integrated multi-omic analysis, assessing transcript-metabolite associations across TBI timepoints relative to controls. This approach pinpointed specific molecular pairs uniquely disrupted by the injury.
Further functional enrichment analysis, including gene-set and metabolite-set enrichment analysis and over-representation analysis (ORA), was carried out to gain systematic insight into biomolecular pathways. This transformed extensive data points into a functional map of the biomolecular processes defining the biology of pediatric TBI progression.
Why does this matter?
This single- and multi-omic analysis shows that pediatric TBI is characterized by dynamic molecular changes, where both gene expression and metabolic alterations are observed. This study suggests that by characterizing the molecular alterations in a time-dependent manner, we can identify potential windows for personalized, targeted interventions.
Elora Hussain, Jeremy W. Prokop, Emily Nonnemacher, Nadia Ashrafi, Ali Yilmaz, Romana Ashrafi Mimi, Abdullah Khalid, Karolis Krinickis, Vilija Lomeikaite, Lena Sanfilippo, Kylie Maxton, Jacob Charron, Charitha Subrahmanya, Austin Goodyke, Annie Needs, Daniel R. Woldring, Caleb P. Bupp, Nicholas Hartog, Juozas Gordevičius, Stewart F. Graham & Surender Rajasekaran. The molecular architecture of severe pediatric traumatic brain injury: integrated omics reveal therapeutic pathways. Crit Care, 2026, 30(23).
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Written by: Kotryna Meilūnaitė
Cover image credits: Satjawat / Adobe Stock
