Table 2.
Human metabolome database (HMDB) classification of collected metabolites by class (bolded)
| HMDB class | Metabolite | Sample type | Change identified | Supplemental | Refs. |
|---|---|---|---|---|---|
| Fatty acyls | |||||
| Isobutyrylcarnitine | Serum/Plasma | Decrease | Significant decrease in sTBI patients compared to healthy volunteers, orthopedic patients and mTBI | Jeter et al. [27] | |
| Isoleucine | Serum/Plasma | Decrease | Significant decrease in sTBI patients compared to healthy volunteers, orthopedic patients and mTBI | Jeter et al. [27] | |
| Propionylcarnitine | Serum/Plasma | Decrease | Decent reduction in sTBI patients compared to healthy volunteers | Jeter et al. [27] | |
| Succinylcarnitine | Serum/Plasma | Decrease | Only differed by a decrease in sTBI patients compared to orthopedic injury patients | Jeter et al. [27] | |
| Hydroxyisovaleryl carnitine | Serum/Plasma | Decrease | Found decreased exclusively in sTBI patients compared to healthy volunteers | Jeter et al. [27] | |
| Octanoic acid | Serum/Microdialysate | Increase | Found upregulated in sTBI patients and remained high in most patients | Oresic et al. [33] | |
| Decanoic acid | Serum/Microdialysate | Increase | Found upregulated in sTBI patients and remained high in most patients | Oresic et al. [33] | |
| Octanoic acid | Serum/Plasma | Increase | As TBI severity increased, octanoic acid increased | Thomas et al. [32] | |
| Decanoic acid | Serum/Plasma | Increase | As TBI severity increased, decanoic acid increased | Thomas et al. [32] | |
| 2-methylbutyrylcarnitine | Serum/Plasma | Decrease | Significant decrease in sTBI patients compared to healthy volunteers and mTBI | Jeter et al. [27] | |
| Isovalerylcarnitine | Serum/Plasma | Decrease | Significant decrease in sTBI patients compared to healthy volunteers, orthopedic controls, and mTBI | Jeter et al. [27] | |
| Keto acids and derivatives | |||||
| α-ketobutyrate | Serum/Plasma | Increase | Found significantly increased in the plasma of sTBI patients | Dash et al. [29] | |
| Methylglutarylcarnitine | Serum/Plasma | Increase | Plasma levels were found significantly increased in sTBI patients compared to healthy volunteers, orthopedic controls, and mTBI | Jeter et al. [27] | |
| 4-methyl-2-oxopentanoate | Serum/Plasma | Decrease | Decreased in sTBI patients compared to healthy volunteers | Jeter et al. [27] | |
| 3-methyl-2-oxovalerate | Serum/Plasma | Decrease | Significant decrease in sTBI patients compared to healthy volunteers, orthopedic patients, and mTBI | Jeter et al. [27] | |
| Carboxylic acids and derivatives | |||||
| Methionine | Serum/Plasma | Decrease | Significant reduction in plasma relative to healthy volunteers | Dash et al. [29] | |
| Betaine | Serum/Plasma | Decrease | Significantly reduced compared to mTBI group and healthy volunteers | Dash et al. [29] | |
| Dimethylglycine | Serum/Plasma | Decrease | Significant decrease in sTBI patients relative to healthy volunteers | Dash et al. [29] | |
| Cysteine | Serum/Plasma | Decrease | Showed a significant reduction in sTBI patients | Dash et al. [29] | |
| Glycine | Serum/Plasma | Decrease | Significantly reduced in sTBI and mTBI | Dash et al. [29] | |
| Gamma-glutamylvaline | Serum/Plasma | Decrease | Relative levels were found significantly decreased in sTBI patients | Dash et al. [29] | |
| Gamma-glutamylleucine | Serum/Plasma | Decrease | Relative levels were found significantly decreased in sTBI patients | Dash et al. [29] | |
| Gamma-glutamylisoleucine | Serum/Plasma | Decrease | Relative levels were found significantly decreased in sTBI patients | Dash et al. [29] | |
| Gamma-glutamyltyrosine | Serum/Plasma | Decrease | Relative levels were found significantly decreased in sTBI patients | Dash et al. [29] | |
| Gamma-glutamylphenylalanine | Serum/Plasma | Decrease | Relative levels were found significantly decreased in sTBI patients | Dash et al. [29] | |
| 5-oxoproline | Serum/Plasma | Decrease | Significantly reduced in sTBI patients compared to mTBI and healthy volunteers | Dash et al. [29] | |
| 2-Aminobutyric acid | Serum/Plasma/Microdialysate | Decrease | Found lower concentrations in patients with detectable CT features following TBI | Dickens et al. [36] | |
| Citrulline | Serum/Plasma | Decrease | Significantly reduced in the plasma of sTBI patients | Jeter et al. [26] | |
| Ornithine | Serum/Plasma | Decrease | Significant decrease in the plasma of sTBI patients compared to healthy volunteers, orthopedic controls, and mTBI patients | Jeter et al. [26] | |
| Proline | Serum/Plasma | Decrease | Significantly reduced in the plasma of sTBI patients compared to healthy volunteers, orthopedic controls, and mTBI patients | Jeter et al. [26] | |
| 4-Hydroxyproline | Serum/Plasma | Decrease | Significantly reduced in the plasma of sTBI patients compared to healthy volunteers, orthopedic controls, and mTBI patients | Jeter et al. [26] | |
| Creatine | Serum/Plasma | Increase | Significantly increased in sTBI patients compared to HC and orthopedic controls | Jeter et al. [26] | |
| Valine | Serum/Plasma | Decrease | Significantly decreased during the first week post sTBI compared to controls | Vuille-Dit-Bille [35] | |
| Valine | Serum/Plasma | Decrease | Reduction in valine levels detected in the plasma of sTBI patients compared to all other groups | Jeter et al. [27] | |
| Serine | Serum/Microdialysate | Decrease | Found downregulated in all TBIs, more strongly in sTBI | Oresic et al. [33] | |
| Leucine | Serum/Plasma | Decrease | Significantly decreased during the first week post sTBI compared to controls | Vuille-Dit-Bille [35] | |
| Isoleucine | Serum/Plasma | Decrease | Significantly decreased during the first week post sTBI compared to controls | Vuille-Dit-Bille [35] | |
| Leucine | Serum/Plasma | Decrease | Decrease in patients with sTBI compared to healthy volunteers and mTBI patients | Jeter et al. [27] | |
| Alanine | Serum/Microdialysate | Decrease | Found downregulated in all TBIs, more strongly in sTBI | Oresic et al. [33] | |
| Glutamine | CSF | Increase | Statistically increasing trend in moTBI and sTBI patients compared to non-injured controls | Glenn et al. [37] | |
| Creatinine | CSF | Decrease | Significantly decreased concentrations of total creatinine in moTBI and sTBI patients | Glenn et al. [37] | |
| Proline | Serum/Plasma | Decrease | ≤ 60% the conc. in arterial plasma and jugular blood compared to HC | Wolahan et al. [34] | |
| Hydroxyproline | Serum/Plasma | Decrease | ≤ 60% the conc. in jugular blood compared to HC | Wolahan et al. [34] | |
| Serine | Serum/Plasma | Decrease | ≤ 60% the conc. in jugular blood compared to HC | Wolahan et al. [34] | |
| Citrulline | Serum/Plasma | Decrease | ≤ 60% the conc. in jugular blood compared to HC | Wolahan et al. [34] | |
| eNAA | Microdialysate | Decrease | Steep decline of extracellular NAA seen in 8 patients early on | Shannon et al. [28] | |
| Phenylalanine | Serum/Plasma | Increase | Significantly increased during the first posttraumatic week following TBI | Vuille-Dit-Bille [35] | |
| Methionine | Urine | Increase | Significant negative correlation (increase) to patients decreasing GCS scores | Bykowski et al. [30] | |
| NAA | MR Imaging | Decrease | Decrease in patients with differing degrees of TBI, including sTBI | Marino et al. [25] | |
| L-arginine | Serum/Plasma | Decrease | Significant reduction compared to healthy volunteers, orthopedic injury patients, and mTBI | Jeter et al. [26] | |
| Serine | Serum/Plasma | Decrease | Found decreased in TBI patients overall | Thomas et al. [32] | |
| Alanine | Serum/Plasma | Decrease | Found decreased in TBI patients overall | Thomas et al. [32] | |
| Glutamate | CSF | Increase | Significantly increased compared to control and survival groups | Stefani et al. [38] | |
| Tyrosine | Serum/Plasma | Increase | Significantly increased for both posttraumatic weeks following TBI | Vuille-Dit-Bille [35] | |
| Asparagine | Serum/Plasma | Decrease | TBI blood had less than or equal to 60% the concentration of HC in jugular blood | Wolahan et al. [34] | |
| Threonine | Serum/Plasma | Decrease | Found decreased in TBI patients overall | Thomas et al. [32] | |
| Hydroxy acids and derivatives | |||||
| 2-hydroxybutyrate | Serum/Plasma | Increase | Found significantly increased in sTBI | Dash et al. [29] | |
| 2-hydroxybutyric acid | Serum/Microdialysate | Increase | Found upregulated in sTBI patients | Oresic et al. [33] | |
| 3-hydroxybutyric acid | Serum/Microdialysate | Increase | Found upregulated in sTBI patients | Oresic et al. [33] | |
| Lactate | CSF | Increase | A slight increase compared to non-injured controls in moTBI and sTBI patients | Glenn et al. [37] | |
| Lactate | CSF | Increase | Significantly increased compared to control and survival groups | Stefani et al. [38] | |
| Lactate | MR Images | Increase | Diffusely high signal of lactate resonance intensity in patients with acute TBI | Marino et al. [25] | |
| Organooxygen compounds | |||||
| Inositol | Serum/Plasma/Microdialysate | Increase | Found to increase in patients with detectable pathology on a CT scan or the presence of a mass lesion | Dickens et al. [36] | |
| (2,3-BPG) | Serum/Microdialia | Increase | Found upregulated in sTBI patients and a strong association with TBI severity, roughly a 100-fold upregulation compared to controls | Oresic et al. [33] | |
| Propylene glycol | CSF | Increase | Significantly higher concentrations in moTBI and sTBI patients | Glenn et al. [37] | |
| Gluconate | Serum/Plasma | Decrease | TBI blood had less than or equal to 60% the concentration of HC in arterial plasma | Wolahan et al. [34] | |
| Glucose-6-phosphate | Serum/Plasma | Decrease | Significant decrease in jugular venous blood from arterial levels | Wolahan et al. [34] | |
| Glycerol | Microdialysis | Increase | Significant positive conc. correlations between extracellular NAA and glycerol of 8 patients | Shannon et al. [28] | |
| Ribonic acid | Serum/Plasma | Increase | Found to increase in patients with detectable pathology on a CT scan or the presence of a mass lesion following TBI | Dickens et al. [36] | |
| Kynurenine | CSF | Increase | Displayed median levels similar to control days 0–3, but at days 4 and 5 showed significant elevation over controls post sTBI | Yan et al. [62] | |
| Myo-inositol | Serum/Plasma | Increase | Found elevated in TBI patients and proportional to differing severity | Thomas et al. [32] | |
| Organic carbonic acids and derivatives | |||||
| Urea | Serum/Plasma | Decrease | Significant decrease in plasma of sTBI patients compared to healthy volunteers, orthopedic controls, and mTBI patients | Jeter et al. [26] | |
| Quinolines and derivatives | |||||
| Kynurenic acid | CSF | Increase | Increased post sTBI compared to controls and reached a plateau after day 2 which lasted until day 5 | Yan et al. [62] | |
| Pyridines and derivatives | |||||
| Niacinamide | Serum/Plasma | Decrease | TBI blood had less than or equal to 60% the concentration of HC in jugular blood | Wolahan et al. [34] | |
| Quinolinic acid | CSF | Increase | Concentration significantly increased between days 1 and 5 compared to controls | Yan et al. [62] | |
| Imidazopyrimidines | |||||
| Xanthine | Serum/Plasma | Increase | Significant net cerebral release or increase in jugular venous blood | Wolahan et al. [34] | |
| Xanthine | Urine | Increase | Increased levels following recovery | Bykowski et al. [30] | |
| Hypoxanthine | Urine | Increase | Found increased following recovery | Bykowski et al. [30] | |
| Diazines | |||||
| Thymine | Urine | Increase | Significant negative correlation (increase) to patients decreasing GCS scores | Bykowski et al. [30] | |
| Purine nucleosides | |||||
| Adenosine | Urine | Increase | Found to be significantly upregulated over recovery | Bykowski et al. [30] | |
| Inosine | Urine | Increase | Found upregulated in urine | Bykowski et al. [30] | |
| Deoxyinosine | Urine | Increase | Found upregulated after recovery | Bykowski et al. [30] | |
| Guanosine | Urine | Increase | Found upregulated in urine | Bykowski et al. [30] | |
| Indoles and derivatives | |||||
| Indole-3-propionic acid | Serum/Microdialysis | Decrease | Found downregulated in all TBIs, more strongly in sTBI | Oresic et al. [33] | |
| Tryptophan | CSF | Increase | Increased in CSF compared to controls between days 0 to 5 in sTBI, however, median concentrations did not change much | Yan et al. [62] | |
| Tryptophan | Plasma/Serum | Decrease | Decreased post sTBI in serum from days 0 to 4 | Yan et al. [62] | |
| Organonitrogen compounds | |||||
| Choline | Serum/Plasma | Decrease | Significantly reduced compared to mTBI and healthy volunteers | Dash et al. [29] | |
| Choline | Serum/Plasma | Increase | Net cerebral release or increase in jugular venous blood | Wolahan et al. [34] | |
| Choline | MR Imaging | Increase | From patients with differing degrees of TBI including sTBI | Marino et al. [25] | |
| Spermidine | Serum/Plasma | Decrease | Significantly lower levels post moTBI and sTBI | Huang et al. [65] | |
CSF cerebrospinal fluid; CT computed tomography; GCS Glasgow Coma Scale; HC healthy controls; HMDB Human Metabolome Database; mTBI minor traumatic brain injury; moTBI moderate traumatic brain injury; NAA N-acetylaspartate; sTBI severe traumatic brain injury; TBI traumatic brain injury