(1762) Metabotranscriptomic Signatures in Pediatric Severe Traumatic Brain Injury: A Role for IPA?

Introduction: Traumatic brain injury (TBI) is a leading cause of childhood death and disability. Current care is primarily supportive with no therapies shown to improve outcomes. We hypothesized that a multi-omics approach could reveal unique metabolic patterns supported by transcriptomics that may have therapeutic implications in pediatric severe TBI.

Methods: After IRB approval (CWH 2021-096) and informed consent, seventeen pediatric severe TBI patients ages ≥ 1 and ≤ 21 years were prospectively enrolled. Serial blood samples were collected at 24±12 hours, 48±12 hours, and on day 9±12 hours. Demographics and clinical variables were extracted from the medical record. Blood samples from ten control patients were obtained at a single timepoint. RNA expression was extrapolated using matching reads to human genes using Salmon quasi-alignments. Metabolomic profiling was performed using 1H NMR spectroscopy, and direct injection/liquid chromatography coupled with mass spectrometry. High quality transcripts from RNA-expression data were assessed for association with metabolite abundance, using linear regression models and adjustment for individual age and sex, and potential unknown and unwanted variation inferred from the data.

Results: Severe TBI patients revealed unique metabolite patterns with timepoint 3 (recovery phase) being the most unique, with 21.5 % of all RNA to metabolite associations. Serum Indole-3-prioprionic acid (IPA) was significantly reduced in TBI patients compared to controls (1.74 uM in controls to 0.12uM at timepoint 3; P< 0.05). The IPA signature correlated with multiple genes associated with IPA production. These genes were also related to production of multiple lipids such as triglycerides and ceramides. Some examples include: ATXN7L3,ICAM2, BTNL8, and genes regulating lipid pathways.

Conclusions: We found a significant decrease in serum IPA levels in pediatric severe TBI in the acute period, compared to a later time point and controls. IPA is a deamination product of tryptophan formed by gut flora, demonstrating antioxidant effects and enhanced axonal recovery. Further studies are needed to examine the relationship between potential gut dysbiosis after severe TBI, and potential therapeutic implications of this novel finding in a pediatric cohort.