Journal of Neuroinflammation(2024) 21:184
Oft et al. Journal of Neuroinflammation
https://doi.org/10.1186/s12974-024-03177-6

Open Access

REVIEW

New insights into metabolism dysregulation
after TBI
Helena C. Oft1,2, Dennis W. Simon3,4,5,6 and Dandan Sun1,2,7*Abstract
Traumatic brain injury (TBI) remains a leading cause of death and disability that places a great physical, social,and financial burden on individuals and the health system. In this review, we summarize new research into the metabolic changes described in clinical TBI trials, some of which have already shown promise for informing injury classification and staging. We focus our discussion on derangements in glucose metabolism, cell respiration/mitochondrial
function and changes to ketone and lipid metabolism/oxidation to emphasize potentially novel biomarkers for clinical outcome prediction and intervention and offer new insights into possible underlying mechanisms from preclinicalresearch of TBI pathology. Finally, we discuss nutrition supplementation studies that aim to harness the gut/microbiome-brain connection and manipulate systemic/cellular metabolism to improve post-TBI recovery. Taken together,
this narrative review summarizes published TBI-associated changes in glucose and lipid metabolism, highlighting
potential metabolite biomarkers for clinical use, the cellular processes linking these markers to TBI pathology as wellas the limitations and future considerations for TBI “omics” work.
Keywords Glucose metabolism, Gut-brain axis, Ketometabolism, Lipid oxidation, Mitochondrial metabolism,
Microbiome
Overview of traumatic brain injury management
and limited therapies
In 2015, the United States Center for Disease Control(CDC) delivered its first report on traumatic brain injury*Correspondence:
Dandan Sun
sund@upmc.edu
1
Department of Neurology, University of Pittsburgh, 3501 Fifth Avenue,
Pittsburgh, PA 15213, USA
2
Pittsburgh Institute for Neurodegenerative Disorders, Universityof Pittsburgh, Pittsburgh, PA 15213, USA
3
Department of Critical Care Medicine, School of Medicine, Universityof Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
4
Department of Pediatrics, University of Pittsburgh School of Medicine,
Pittsburgh, PA, USA
5
Safar Center for Resuscitation Research, University of Pittsburgh Schoolof Medicine, Pittsburgh, PA, USA
6
Children’s Neuroscience Institute, Children’s Hospital of Pittsburgh,
Pittsburgh, PA, USA
7
Geriatric Research, Educational and Clinical Center, Veterans Affairs
Pittsburgh Health Care System, Pittsburgh, PA 15213, USA(TBI) to the United States Congress, citing critical challenges related to injury detection and treatment [1]. Preventative measures, such as infrastructure improvementsthat reduce motor vehicle accidents, have contributed todecreases in TBI worldwide. The most recent Global Burden of Diseases, Injuries, and Risk Factors (GBD) study
reported an age-standardized prevalence rate of 448.6
per 100,000 people in 2021 compared to the 2019 edition’s cited rate of 599 cases per 100,000 people [2–4].
However, these numbers do not capture the extent towhich TBI affects those who do not seek immediate
medical attention, those with masking comorbidities
or poly-trauma and those with unclear mechanisms of
injury [5]. The CDC estimates that between 3.2–5.3 million people in the US are living with a TBI-related disability that can include pain, cognitive, emotional andmotor disturbances and secondary neurological disorders such as posttraumatic epilepsy and mood disorders,dementia syndromes, chronic traumatic encephalopathy,
etc. [1, 6]. The GBD estimated that TBI resulted in 5.490© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​
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Oft et al. Journal of Neuroinflammation(2024) 21:184

million years lived with disability across surveyed countries in 2021 alone [3]. In addition to the physical costfor patients, those diagnosed with nonfatal TBI in the US
may accumulate an average of $19,598 per person annually in additional healthcare costs [7]. Moreover, theseburdens are not distributed equally; vulnerable populations, unhoused or incarcerated individuals, marginalized racial and ethnic groups, victims of interpersonalor combat violence, young children or older adults are at
greater risk for TBI and associated disability. They also
experience unique barriers to TBI detection and care [5,8, 9]. Since the CDC’s TBI report to the US Congress,
federal agencies have invested more than two billion dollars in improving TBI research and treatment aimed ataddressing this global priority [10].
Despite the proliferation of research that has expanded
our understanding of TBI epidemiology and pathogenesis, the updated consensus for clinical management in
the hospital setting does not define reliable biomarkers or
drug therapies aimed at directly limiting secondary brain
injury [11, 12]. Briefly, patients with TBI exposure aretriaged based on clinical factors including the presenceof other life-threatening injuries, neurologic exam (asassessed by Glasgow Coma Scale, GCS) and neuroimaging. In addition to routine medical management, monitoring of glucose and/or lactate levels has been describedin some TBI protocols [5, 11–13]. Patients may receive a
CT scan according to the center’s policy, and though thisdecision-making is typically guided by the New Orleans
Criteria or Canadian Head CT rules, they may varyacross clinical sites [14]. Precise clinical decision-making
remains challenging despite recent advances informedby data from multisite observational studies including
TRACK-TBI [15–17], CENTER-TBI [18, 19] and the
CREACTIVE project [20] to name a few. These challenges highlight a need for new research aimed at better
understanding TBI pathogenesis and identifying specificbiomarkers corresponding to underlying cellular, structural and secretomic changes that can improve clinicaldecision making. In this review, we focus on the body ofclinical and preclinical research aimed at identifying such
TBI-induced alterations in cellular metabolism. Emphasizing the overlap and differences between bench andbedside research findings, we examine the translational
potential of proposed metabolic biomarkers for improving TBI management and as therapeutic targets.

Blood and brain biomarkers for TBI‑mediatedchanges in metabolism
Differences in TBI management protocols and a lack of
drug options to target underlying TBI pathology demonstrate a need for biomarkers that can improve diagnosis
and prognosis determination for patients with TBI. The

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utility of putative blood biomarkers, including glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminalhydrolase L1 (UCH-L1), S100 calcium-binding protein B(S100B) and Neurofilament-light (NF-L), has been evaluated by multicenter studies such as ALERT, CENTERTBI, TRACK-TBI and BIO-AX-TBI [5, 21]. Among thesecandidates, GFAP most consistently predicts CT anomalies, and to date, only GFAP/UCH-L1 testing has been
approved for clinical use by the FDA [16, 20, 22]. However, these tests have limitations, including nonspecificreadings in the context of polytrauma, limited availability
in the acute care setting and minimal mechanistic insight[23, 24]. This led to expanded research on the contributions of metabolic dysfunction to TBI in the last decadeusing blood samples and cerebral microdialysis (CMD)[25]. Microdialysis utilizes a catheter and a semipermeable membrane inserted into the brain parenchyma (frequently in the frontal lobe, proximal to existing ICP or
PbtO2 monitors) to detect changes in brain metabolites
with high temporal and spatial resolution [26]. This precision microdialytic sampling may provide more insight
into the mechanisms underlying TBI pathogenesis andsecondary injury than systemic indicators in blood or
cerebrospinal fluid (CSF). CMD may be especially useful in cases where invasive neuromonitoring of the ICP
is already needed. Nuclear magnetic resonance and mass
spectrometry with gas or liquid chromatography are themost commonly used methods for analyzing CMD samples [27]. Reviews of the growing CMD data pool havesuggested the importance of including cellular metabolism markers in TBI classification and prognosis [28]. The
most recent consensus statement from the International
Microdialysis Forum, released in 2015, summarized key
advances in the CMD clinical usage and contributions toneurocritical care since 2004 [25]. Although continuous
monitoring with CMD might allow for greater temporal
resolution, there are still limitations. CMD studies are
more invasive than serum collection, limiting large scale
sampling, generalizability of conclusions and increasing
the impact of study design discrepancies (sample collection times, outcome follow-up, etc.) on reported values[28]. More so than in serum sampling, parenchymal fluid
samples are small in volume, perhaps explaining why
the published literature has not explored as comprehensive a metabolite profile as is reported in serum metabolomics work. As CMD collects local parenchymal fluid,
interpatient variation and minor regional differencesin probe placement (to the site of primary injury) can
also increase the sample size required to achieve statistical significance [29]. The following sections highlight
key metabolites implicated by several studies as putative
high-yield targets for CMD/serum detection or therapeutic intervention.

Oft et al. Journal of Neuroinflammation(2024) 21:184

GlucoseIn the last few years, “omics” analyses in larger multicenter studies, such as CENTER-TBI, CanTBI, and TBICare, have significantly expanded our understanding of
the metabolic landscape after TBI. Glucose metabolism
substrates and metabolites are among the best characterized biomarkers in these studies. Researchers have sought
to identify specific patterns among these variables corresponding to specific disease etiology, pathogenesis, andprognosis [18, 24, 28, 30–33]. These signatures or “fingerprints” vary across trials but demonstrate the utility of
metabolomics for prognostication as well as certain overarching traits when individual metabolites do not reachsignificance. Åkerlund et al.’s analysis of 1728 patientswith TBI enrolled in the CENTER-TBI study during
their intensive care unit (ICU) stay identified clusters ofpatients with lower GCSs and a “deranged metabolism”
pattern defined by acidosis, elevated lactate and glucose[18]. They found that metabolic derangements were associated with increased risk of mortality in both moderate and severe TBI clusters. Generally, the detection ofincreased serum levels of sugar derivatives, including gluconates [30], pyruvate, lactate, d-( +)-galacturonic acidand (myo-)inositol [31], 2,3-bisphosphoglyceric acid (2,3BPG) and pentitol-3-desoxy [34], particularly in the first
24 h after TBI, corresponded to poorer clinical outcomes
and increased mortality (Table 1). Although these analyses are not specific to the central nervous system (CNS),
they do offer clues to ongoing brain injury pathogenesis,as the increased permeability of the blood–brain barrier (BBB) after TBI allows for greater exchange of CNS/
peripheral solutes, and many of these metabolites arealso detected in the brain parenchyma [34]. For instance,
Banoei et al. reported that more extreme changes inserum metabolite profiles from days 1 to 4 after severe
TBI corresponded to unfavorable clinical outcomes andthat serum metabolites on day 4 could better predict outcomes than serum metabolites collected on day 1 [27].
They suggested that this alludes to the impact of secondary injuries on metabolism over the days after injury but
called for additional studies to expand the data to additional timepoints [27]. A smaller pilot study also revealed
that cerebral glucose delivery was determined by plasma
glucose concentration and cerebral blood flow, withinjured brains exhibiting less glucose uptake and utilization around lesions but increased utilization at distal
hyperglycolytic sites in the brain [32]. This overall reduction in glucose utilization detected by 18F-fluorodeoxyglucose-PET (positron emission tomography) imaging
persists in the context of chronic cognitive impairment
after TBI [35]. However, in studies exploring TBI in polytrauma patients, serum glucose metabolites have yet
to show any significant patterns corresponding to brain

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injury or the thawed plasma response [24, 36]. Venturini
et al. and others [37] suggested that substrate levels may
also represent a new clinical target, citing trials that indicated that both high [38] and low parenchymal glucose(< 1 mmol/L) [33] corresponded to worse clinical outcomes, although others found no statistically significant
relationship between outcomes and glucose levels [26].
This discrepancy may also reflect the impact of sample
collection timing and catheter placement since proximity to lesion or “hyperglycolytic” regions may significantly
alter metabolite levels/utilization [32].
The lactate to pyruvate ratio

Stratification of metabolites for TBI most commonly
relies on the lactate to pyruvate ratio (LPR) to capture
the metabolic redox state [39]. Although serum sampling
offers a broader picture of metabolism after TBI andlacks the specificity of cerebral microdialysis approaches,it clearly shows promise as a feasible enhancement toestablished models of prognostication based on clinicalfeatures. The addition of metabolic biomarkers improved
the predictive ability of models using IMPACT and
CRASH parameters to estimate severity/prognosis [18,30, 31]. Serum-based analyses may also prove useful forearly clinical decision making, most critically in determining the need for a head CT after TBI [40]. Dickens
et al. identified several metabolites (including the sugar
derivatives pentitol 3-desoxy, inositol, isovaleryl glucuronide, and ribonic acid) that outperformed the FDAapproved biomarkers GFAP/UCH-L1 in predicting
positive CT findings [41]. It has been reported that serum
levels of several sugar derivatives (e.g. inositol) may predict TBI outcomes and directly reflect levels within the
cerebral parenchyma after injury [34].
Broadly, the literature consensus from cerebral microdialysate defines “metabolic crisis” as a post-TBI elevationin LPR beyond a certain threshold (Table 1) [28, 42]. A
highly elevated LPR is associated with more unfavorable
outcomes several months after injury and increased mortality in several clinical groups [26, 28, 33, 42]. A recent
trial reported a significant association between elevated
LPR during the first 96 h after injury and increased graymatter volume loss at 12 months after TBI (Table 1)[43]. Substrate levels can be used to further distinguishmetabolic “fingerprints” corresponding to ischemic andanaerobic conditions (with elevated LPR in the absenceof substrate/pO2) or mitochondrial dysfunction (elevated
LPR despite normal substrate levels/perfusion). Evidence
for these categories varies widely; however, a lower LPR(elevated pyruvate and lower lactate levels) was found to
be protective [26, 43]. In general, glycemic control is anaccepted concept in TBI management [27, 38], and supplementation with additional substrates such as lactate

Oft et al. Journal of Neuroinflammation(2024) 21:184

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Table 1 Glucose metabolism marker findings from select TBI metabolomics sets
Biomarker

Finding

Model

Reference

Glucose- Increased ɑ-ketoglutaric acid in a biosignature at 4 days post injury predicts poorer GOSE outcomes at 12 months and predicts 30-day mortality

sTBI (Serum)

Banoei et al. [30]

TBI (m/mod/s) (Serum)

Thomas et al. [31]

TBI (m/mod/s) (Serum

Orešič et al. [34]TBI (m/mod/s) (Serum)

Dickens et al. [41]- Median CMD glucose 0–96 h after TBI is strongly correlated with total grey matter volume
change, parietal grey matter volume change, cortical grey matter volume change and catheter
region volume change (but not white matter volume change) over 12 months after injury

sTBI (CMD)

Bernini et al. 2023

- CMD glucose was associated with outcomes when averaged over 7 days after injury

TBI (CMD)

Guilfoyle et al. [33]- Increased glucose, citrate & fumarate at 24 h post injury predict 3 month mortality- Increasing levels of glucose, ribose & maltose predict increasing TBI severity- Increased glucose or mannose & sorbitol is associated with positive CT findings- Increased levels of glucose, mannose, inositol & myoinositol predict unfavorable GOSE outcomesat 6 months- Glucose derivatives, including 2,3-bisphosphoglyceric acid, are increased in sTBI patient sera (andto a lesser degree in mTBI patients) within 12 h after injury- Increases in 4 unknown sugar derivatives predict unfavorable GOSE outcomes at 6–12 months
Increased sugar derivatives inositol, ribonic acid and 3-desoxy pentitol at 12 h after admission
for TBI predicted positive CT findings- Increased Isovaleryl glucuronide is associated with mass lesion rather than diffuse lesion on CT- Glucose was elevated from days 5–11 after injury in patients with unfavorable GOS outcomes
relative to those with favorable outcomes
Lactate- Elevated CMD Glucose predicted mortality

TBI (m/mod/s) (CMD)

Timofeev et al. [26]- Increased lactate in a biosignature at 24 h and 4 days post injury predict poorer GOSE outcomesat 3 months

sTBI (Serum)

Banoei et al. [30]

TBI (m/mod/s) (Serum

Thomas et al. [31]- No relationship between median CMD glutamate, pyruvate or lactate 0–96 h after TBI and brain
volume changes observed

sTBI (CMD)

Bernini et al. 2023

- CMD LPR was associated with outcomes when averaged over 72 h after injury

TBI (CMD)

Guilfoyle et al. [33]TBI (m/mod/s) (CMD)

Timofeev et al. [26]- Increased galactose is associated with positive CT findings- Increased galacturonic acid predicts unfavorable GOSE outcomes at 6 months- Median CMD LPR 0–96 h after TBI strongly correlates with total grey matter volume change (butnot white matter volume change) over 12 months after injury- Following an initial decrease during the first 48 h, LPR increases until day 14 after injury. LPR
was elevated for about 10 days after injury in patients with unfavorable GOS outcomes relative
to those with favorable outcomes- Following an initial decrease during the first 48 h, Lactate increases until day 10 after injury.
Lactate was elevated in patients with unfavorable outcomes relative to those with favorable
outcomes- CMD Lactate and LPR were elevated in patients who died and those with unfavorable GOS
outcomes relative to those with favorable outcomes- CMD LPR was elevated in pericontusional tissue relative to uninjured tissue- Elevated CMD LPR predicted mortality
Pyruvate

Glutamate- Increased pyruvate at 24 h post injury predicts 3-month mortality

sTBI (Serum)

Banoei et al. [30]

- Increased levels of pyruvic acid predict unfavorable GOSE outcomes at 6 months

TBI (m/mod/s) (Serum)

Thomas et al. [31]- Pyruvate gradually increases over 14 days after injury. Levels do not differ between unfavorable
or favorable GOS outcomes

TBI (CMD)

Guilfoyle et al. [33]- Decreased CMD pyruvate predicted mortality

TBI (m/mod/s) (CMD)

Timofeev et al. [26]- Reduced Glutamic acid was associated with “healthier” CMD state and was among the top 10
most relevant metabolites for Therapy Intensity Level (TIL) prediction

sTBI (CMD)

Eiden et al. [46]- Reduced Glutamic acid and increased glutamate in a biosignature at 24 h and 4 days post injury
predict poorer GOSE outcomes at 3 months

sTBI (Serum)

Banoei et al. [30]

- CMD Glutamate and glycerol were elevated in patients who died and those with unfavorable
GOS outcomes relative to those with favorable outcomes

TBI (m/mod/s) (CMD)

Timofeev et al. [26]- Glutamate and glycerol trended higher in patients with unfavorable GOS outcomes relative
to those with favorable outcomes

TBI (CMD)

Guilfoyle et al. [33]- Decreased glutamine at 24 h post injury predicts 3-month mortality

CMD: Cerebral microdialysate; CT: Computed Tomography Scan; GOS(E): Glasgow Outcome Scale (Extended); LPR: Lactate Pyruvate Ratio; TBI: sTBI: severeTBI; modTBI:
moderate TBI; mTBI: mild TBI); TIL: Therapy Intensity Level

Oft et al. Journal of Neuroinflammation(2024) 21:184(intravenously or via CMD) may also show some clinicalutility in reducing complications, like intracranial hypertension [44], when metabolic targets are better defined.
Lipids, fatty acids, and ketogenic amino acids

In addition to the glucose metabolites explored above,
several clinical trials and preclinical studies have revealedchanges in lipid metabolism after TBI [30, 31]. Alteredmetabolites encompass a variety of lipid classes as wellas metabolites associated with lipid metabolism, including fatty acids, phospholipids, ketone bodies, ketogenic
amino acids (AAs), and branched-chain amino acids(BCAAs), which are derived from a variety of cellular andsystemic compartments/processes [45]. A pilot study of
cerebral dialysate from 26 ICU patients with TBI defined
two clinically relevant metabolic states based on distinct
changes in glucose, lactate and pyruvate as well as metabolites related to ketone metabolism [46]. The “healthier
metabolic state” was defined by higher glucose metabolism substrate levels and corresponded to higher levels of
ketogenic AAs/BCAA metabolite derivatives (tyrosine,
threonine, valine, 4-methyl-2-oxovaleric acid and propionylcarnitine), ketone bodies (3-hydroxybutyrate and2-hydroxybutyrate), and butyrylcarnitine (a metabolite
involved in fatty acid metabolism; Table 2). This state
was also associated with lower levels of the medium
straight chain fatty acids, decanoic acid and octanoic
acid (p = 0.06721) [46]. This study generated a metabolite
model that could predict clinical outcomes, quantified by
Therapy Intensity Level (TIL), in the initial and validation
cohorts based on the levels of the ketogenic AA isoleucine, ketone bodies (β-hydroxybutyrate and acetoacetate), medium chain fatty acids (dodecanoic acid, subericacid, 2-hydroxyoctanoic acid), medium chain fatty acidderivatives (10-hydroxydecanoic acid, 8-hydroxyoctanoicacid), and butyrylcarnitine (Table 2) [46]. Taken together,
these findings indicate that TBI induces changes in key
ketometabolic pathways, particularly fatty acid oxidation and ketogenic/BCAA metabolism [46]. However, thesmall cohort size contributed to underpowered statistical analysis and marked heterogeneity among patients,emphasizing the need for additional CMD trials in
expanded cohorts.
Serum analyses of patients with TBI have also revealedchanges in lipid metabolites, although these studies areless common than trials focused on glucose metabolism.
Serum metabolomic studies, including some describedin the prior sections, identified lipid metabolite clusters
associated with TBI at 24 h [30, 31, 47] and 4 days [30]after injury using sera from TBI and control patients(Table 2). Several metabolites related to lipid metabolism
ranked among the most robust metabolic markers fordiscrimination between moderate/severe TBI, mild TBI,

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and healthy controls (highest AUC, 0.665–0.9311) andwere the best predictors of TBI outcomes according tologistic regression models [31]. These markers included
four unidentified lipids, lysophosphatidylcholines (LPCs,
16:0, 18:0, 18:2, and 20:5), phosphatidylethanolamines(PEPs, P-18:0/22:5 and 20.1:20.4), cholesterol, an ether
LPC (O-LPC 16:0), triglycerides (TGs, 51:20) and the
ketogenic AA threonine [31]. The serum concentrationsof LPCs, O-LPCs, several sphingomyelins (SMs, (40:2)/(18:1/22:1), d40:1), BCAAs and their breakdown products decreased in patients with severe TBI, whereas thelevels of the medium chain fatty acids decanoic acid andoctanoic acid increased with severity (Table 2) [31]. Thisfinding aligns with prior research in which the levels of
decanoic acid, octanoic acid, and 2- and 3-hydroxybutyric acids were increased in the sera and cerebral
dialysate of patients with sTBI [34]. Reductions in thelevels of serum BCAAs and their catabolic derivatives,
including several acylcarnitines, were also associatedwith increasing TBI severity and predicted elevated ICP
in a targeted analysis of these AAs [47]. Interestingly,
severe TBI was also associated with lower BCAA levels
than was orthopedic injury [47]. The detection of thesesignatures 24 h after TBI was associated with poorer clinical outcomes at 6 months [31].
Thomas et al. generated lipid metabolite clusters corresponding to CT pathological findings (i.e., mass lesions,intraventricular hemorrhage, etc.), which revealed consistent downregulation of threonine, LPC (18:2 and 20:5),
O-LPC (34:2, 34:3 and 36:3) and SM (40:1 and 40:2) inthe presence of positive imaging findings. Dickens et al.
identified six serum metabolites that could specifically
predict the need for imaging and reported that reductions in 2-aminobutyric acid (generated in the biosynthesis of the BCAA isoleucine) and increases in the
ketone body acetoacetic acid corresponded to positive
CT findings [41]. Additionally, higher levels of the fatty
acids 2-hydroxybutyric acid and decanoic acid, isovaleryl
glucuronide (related to glycogen synthesis) and a phenolic compound (originating from gut metabolism orexogenous propofol) were associated with CT masslesions rather than diffuse injury [41] (Table 2). Additional studies examining the utility of these metabolites as biomarkers for clinical decision making should
assess whether metabolite analysis can further enhance
diagnosis as well as prognosis and the risk for complication management. Banoei et al. conducted similar
analyses: they detected 188 total metabolites in serum
collected 1 and 4 days after severe TBI using 1H-NMR
and mass spectrometry and identified metabolite signatures that predicted favorable/unfavorable outcomes at
3 and 12 months after injury [30]. Increased LPCs (16:0,
17:0, 18:0), fatty acids (propionic, stearic, octadecanoic,

Oft et al. Journal of Neuroinflammation(2024) 21:184

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Table 2 Lipid metabolism marker findings from select TBI metabolomics sets
Biomarker

Finding

Model

References

SMs- Decreased SM 20:2 in a biosignature at 24 h and 4 days post injury predicting
poorer GOSE outcomes at 3 months

sTBI (Serum)

Banoei et al. [30]

- Increased SM 16:1 in a biosignature at 24 h post injury predicting poorer GOSE
outcomes at 12 months- Decreasing levels of SMs (d38:2, (40:2)/(18:1/22:1), d40:1) within 24 h after injury
predict increasing TBI severity

TBI (m/mod/s) (Serum) Thomas et al. [31]- Decreased SM(40:1) & SM(40:2), associated with positive CT findings- Decreased SM (40:2)/(18:1/22:1), d40:1) predicts unfavorable GOSE outcomesat 6 months
LPCs- Increased LPCs (16:0, 17:0, 18:0) in a biosignature at 24 h post injury predicting
poorer GOSE outcomes at 3 months

sTBI (Serum)

Banoei et al. [30]

- Increased LPCs (14:0, 20:3 & 28:1) in a biosignature at 4 days post injury predicting
poorer GOSE outcomes at 12 months- Increased LPCs (28:1, 14:0) in a biosignature at 4 days post injury predicting
poorer GOSE outcomes at 12 months- Decreasing levels of LPCs (16:0, 18:0, 18:2, 20:5) within 24 h after injury predict
increasing TBI severity

TBI (m/mod/s) (Serum) Thomas et al. [31]- Decreased LPC(18:2) & LPC(20:5) associated with positive CT findings (Serum)- Decreased LPC (18:0, 18:2, 20:5) predicts unfavorable GOSE outcomes at 6 months
PCs- Increased PC36:0 aa in a biosignature at 4 days post injury predicting poorer
GOSE outcomes at 3 months

sTBI (Serum)

Banoei et al. [30]

- Increased PCs (38:0 aa, 40:6 ae) and O-phosphocholine at 24 h post injury predict
3-month mortality- Increased PCs (38:0 aa, 36:00 aa) at 4 days post injury predict 3-month mortality- Decreasing levels of O-PCs (34:3, 36:3) within 24 h after injury predict increasing
TBI severity

TBI (m/mod/s) (Serum) Thomas et al. [31]- Decreased O-PC(34:2), O-PC(34:3), O-PC(36:3) associated with positive CT findings- Decreased O-PC 3:3 predicts unfavorable GOSE outcomes at 6 months
Ketogenic AAs/BCAAs - Increased leucine, tyrosine, threonine, phenylalanine, valine, 4-methyl-2-oxovaleric acid & propionylcarnitine associated with “healthier” metabolic statesTBI (CMD)

Eiden et al. [46]sTBI (Serum)

Banoei et al. [30]- Isoleucine among the top 10 most relevant metabolites for Therapy Intensity
Level (TIL) prediction- Decreased isoleucine, leucine, threonine phenylalanine & tyrosine in a biosignature at 24 h post injury predicting poorer GOSE outcomes at 3 months- Increased valine, lysine, tyrosine, isoleucine & leucine in a biosignature at 4 days
post injury predicting poorer GOSE outcomes at 3 months- Increased tyrosine, leucine & valine at 24 h and 4 days post injury predicting
poorer GOSE outcomes at 12 months- Decreased BCAAs at 24 h post injury predict 3-month mortality- Increased BCAAs, tyrosine, ornithine tryptophan & threonine at 4 days post injury
predict 3 month mortality- Threonine and BCAA breakdown products decrease with increasing TBI severity
and their downregulation within 24 h after injury predicts positive CT findings- AAs including threonine, tryptophan & phenylalanine are decreased in sTBI
patient sera (but not in mTBI patients) within 12 h after injury

TBI (m/mod/s) (Serum) Orešič et al. [34]- Decreased tryptophan and an unknown amino acid predict unfavorable GOSE
outcomes at 6–12 (Serum) month- Decreased serum 2-aminobutyric acid and an unknown amino acid within 12 hof admission for TBI predicted positive CT findings

TBI (m/mod/s) (Serum) Dickens et al. [41]Oft et al. Journal of Neuroinflammation(2024) 21:184

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Table 2 (continued)
Biomarker

Finding

Model

References

Fatty acids- Increased butyrylcarnitine associated with “healthier” metabolic statesTBI (CMD)

Eiden et al. [46]- Increased propionic, stearic, octadecanoic, myristic, oleic and linoleic acidsTBI (Serum)in a biosignature at 24 h post injury predicting poorer GOSE outcomes at 3 months

Banoei et al. [30]- Decreased medium straight chain fatty acids (decanoic acid and octanoic acid)associated with “healthier” metabolic state- Butryrylcarnitine, 10-hydroxydecanoic acid (10-OH-C10), suberic acid,8-hydroxyoctanoic acid (8- OHC8), 2-hydroxyoctanoic acid, dodecanoic acid areamong the top 10 most relevant metabolites for TIL prediction- Increased propionic acid, linoleic acid, valeric acid (C5) & medium-chain acylcarnitines in a biosignature at 24 h and 4 days post injury predicting poorer GOSE
outcomes at 12 months- Increased caproic acid (C6) & oleic acid in a biosignature at 4 days post injury
predicting poorer GOSE outcomes at 12 months- Increased acylcarnitines at 24 h post injury predict 3-month mortality- Octanoic and decanoic acid levels within 24 h after injury increase with increasing TBI (m/mod/s) (Serum) Thomas et al. [31]TBI severity

Ketone bodies- Octanoic and decanoic acid are increased in sTBI patient sera (and to a lesser
degree in mTBI patients) within 12 h after injury and predict unfavorable GOSE
outcomes at 6–12 months

TBI (m/mod/s) (Serum) Orešič et al. [34]- Increased decanoic acid is associated with mass lesion rather than diffuse lesionon CT

TBI (m/mod/s) (Serum) Dickens et al. [41]- Increased 3-hydroxybutyrate & 2-hydroxybutyrate associated with “healthier”
metabolic statesTBI (CMD)

Eiden et al. [46]- 3-hydroxybutyrate & acetoacetate among the top 10 most relevant metabolites
for TIL prediction- 3-hydroxybutyric acid & 2-hydroxybutyric acid are upregulated in sTBI patients(and to a lesser degree in mTBI patients) within 12 h after injury

TBI (m/mod/s) (Serum) Orešič et al. [34]- Increased Acetoacetic acid (3-oxobutanoic acid) predicts poorer GOSE outcomesat 6–12 months- Increased acetoacetic acid within 12 h of admission for TBI predicted positive CT
findings

TBI (m/mod/s) (Serum) Dickens et al. [41]- Increased 2-hydroxybutyric acid is associated with mass lesion rather than diffuse
injury on CT
NAA- Increased NAA in a biosignature at 4 days post injury predicting poorer GOSE
outcomes at 3 months

sTBI (Serum)

Banoei et al. [30]

CMD: Cerebral microdialysate; CT: Computed Tomography Scan; GOS(E): Glasgow Outcome Scale (Extended); LPCs = Lysophosphatidylcholine; NAA:
N-Acetylaspartate; O-PCs: Ether-linked phosphatidylcholine; PC: Phosphatidylcholine; TBI: sTBI = severeTBI; modTBI: moderate TBI; mTBI: mild TBI); TIL: Therapy
Intensity Level

myristic, oleic and linoleic acid), and decreased ketogenic
AAs (isoleucine, leucine, threonine phenylalanine, tyrosine), and SM (20:2) at 24 h after admission predictedunfavorable outcomes at 3 months (Table 2) [30]. Thisfinding aligns with the association of unfavorable outcomes with increased fatty acid metabolites and reduced
ketogenic/BCAA levels reported in Banoei et al. [31] but
contradicts Thomas et al.’s finding that increased LPCs
and SM corresponded to more favorable outcomes at
6 months [31]. At four days postinjury, patients predicted
to die had increased BCAA, ketogenic amino acid, fatty
acid, and phosphatidylcholine (PC, 38:0 aa and 36:0 aa)

levels and decreased acylcarnitine and LPC 26:0 levels[30]. Most predictive of poor clinical outcomes at 3 and12 months were increases in LPCs (14:0, 16:0, 16:1, 17:0,
18:0, 18:2, 20:3 and 28:1), ketogenic AA, acylcarnitines,
as well as BCAAs, NAA (n-acetylaspartate upregulates
lipid degradation and fatty acid mobilization [48]), andtyrosine over the first four days after injury. Several studies chose to validate their defined signatures in a secondary dataset and noted improved prediction of outcomeswhen metabolic biomarkers were used with protein biomarkers (S100b, UCH-L1, GFAP, etc.) [30, 31]. Again, themetabolites identified above do not necessarily reflect theOft et al. Journal of Neuroinflammation(2024) 21:184

brain’s cellular processes in isolation, though BBB disruption, limited glymphatic [49] and passive transport to theperiphery all increase after TBI [45]. A small trial compared the serum/blood levels of metabolites in arterial
and jugular venous blood to indirectly assess metabolite
uptake into the brain [50]. In addition to a net cerebral
uptake of glucose-6-phosphate and depletion of systemic
AAs, they noted a release of xanthine and choline. Their
analysis also emphasized that some medications administered in ICU care may distort systemic metabolites or
cerebral uptake and that these effects should be considered in the interpretation of clinical data [50].
Taken together, lipid pathways have not been as consistently described in clinical studies, as reflected in thelimited pool of CMD/serum studies assessing lipid-associated metabolites in TBI. A recent review encompassing
clinical metabolomic data emphasized the recurrence of
key lipid biomarkers in sTBI: increased medium chain
fatty acids (octanoic and decanoic acid) and choline aswell as decreased BCAAs (valine, leucine) and NAA[51]. These signatures correspond to fatty acid metabolism, ketone and ketogenic/BCAA metabolism pathways.
The clinical sites, sample sources (CENTER TBI [31, 41]
and the CanTBI bank [30]), severity of TBI, health statusof controls, time points and methods for characterizing
lipid metabolism varied between trials and contributed
to the observed differences. Even when the same experimental approach was used, findings in metabolomic
studies were not always as consistent in the validation
cohorts [41]. Expanding the amount and diversity of lipidomic data for patients with TBI will be necessary beforechanges in lipid metabolism can be considered reliable
clinical biomarkers.

New insight into glucose metabolism
dysregulation in TBI
Current consensus suggests that primary TBI immediately resulting from mechanical stress and displacementof brain tissues is compounded by progressive secondary injury (damage to the BBB, protein aggregation,etc.) that is partially mediated by metabolic dysfunction[27]. Whether alterations in metabolism drive secondary injury processes or simply result from the subsequent depletion of cellular energy stores and oxidative
stress is less clear. Studies suggest that these processes
feed each other, leading to a cycle of damage in which
initial metabolic disturbances are exacerbated by tissue
destruction and vice versa [33, 52]. Characterizationsof this state of “metabolic crisis” have distinguished low“fuel” (ischemic) states from conditions in which metabolic substrates are available but not effectively utilized(mitochondrial dysfunction). Critically, these states may
require different approaches for clinical management andPage 8 of 17

prognostication [38, 53, 54]. Consequently, distinguishing the mechanisms/processes underlying these distinct
states may be highly informative for patient care.
Under normal conditions, the adult brain consumes
more than 20% of metabolized glucose. The majority of this glucose is aerobically metabolized by astrocytes and, to a lesser extent, by oligodendrocytes, which
ultimately release the metabolites (chiefly lactate) that
fuel neurons though monocarboxylate transporters inglial-neuronal gap junctions [55]. This astrocyte–neuron lactate shuttle (ANLS), initially hypothesized byPellerin and Magistretti, holds that BBB cells take up
blood glucose via astrocytic/endothelial GLUT1 transport, allowing cerebral lactate buffering by astrocytic
glycogen stores [56]. Lactate metabolism is critical forhomeostatic axonal maintenance [55], but neurons also
participate in the direct uptake of glucose (via GLUT3),
which they metabolize primarily through oxidative
phosphorylation. Downstream metabolites of glucose/lactate are ultimately used to generate ATP (the principal energy source for CNS cells) or engage in metabolite
signaling [57]. Through these mechanisms, as well as
systemic glucose targeting to the brain, cerebral metabolism relies on alternative substrates (ketone metabolism)
only when glucose availability is severely disrupted [58].
TBI-induced ischemia, due to reduced CBF or microvascular damage that impedes blood glucose delivery
despite preserved CBF, causes increased utilization of allthese energy sources, which subsequently stresses cellular glucose/glycogen/lactate stores within the first few
hours after injury [39, 59, 60]. Simultaneously, insulin
resistance, up- and downregulation of vessel GLUT and
increased BBB permeability drive systemic hyperglycemia and reduced utilization of glucose at the cellularlevel [38, 58, 61]. Ischemic cells compensate for reduced
oxygen delivery by increasing anaerobic glycolysis, leading to acidosis as well as glucose derivatives that promote
signaling related to oxidative stress and inflammation[38, 57, 62]. This is reflected in the increases in the LPR
and the ratio of lactate to bicarbonate observed via magnetic resonance spectroscopic imaging in rats subjected
to TBI [63]. This state of “relative hyperglycolysis” isfacilitated by a hypoxia-induced increase in neuronal
GLUT3 [62] and glycolytic enzymes, including pyruvatekinase and hexokinase, the rate-limiting enzymes of glycolysis. Notably, lactate dehydrogenase expression andactivity are also increased days after TBI, providing additional ATP through lactate fermentation [64]. Inhibiting
glycolysis through hexokinase knockdown in preclinicalmodels acutely attenuated microglial activation and proinflammatory cytokine release after ischemic injury [65].
Pharmacological inhibition of glycolysis with 2-deoxyglucose reduced inflammatory signaling, posttraumaticOft et al. Journal of Neuroinflammation(2024) 21:184

hyperexcitability and epileptiform activity [66, 67]. As
edema in the brain resolves (~ 48–120 h to days after
injury), glycolytic enzymes and GLUTs are downregulated [60, 64]. Mild TBI models either recovered quickly
or upregulated glycolysis more gradually compared tomore severe injuries, suggesting that metabolic regulation depends on the degree of brain damage [64]. The
differences in the mechanism of injury and outcomes inmild TBI models still limit our understanding of metabolic changes in these states [62, 64].
Since increased glycolysis, particularly in the context of
impaired electron transport, increases the ratio of NADH
to NAD +, excess NADH is thought to directly promote
postischemic inflammation. Findings from other models of CNS degeneration, suggesting that normalizationof the NADH/NAD + ratio promotes viability, support
that this ratio (which is also a proxy for LPR) represents the connection between metabolic and inflammatory processes after injury [68, 69]. Protective treatment
approaches aimed at restoring the NADH/NAD ratio also
include increasing flux to parallel pathways such as the
pentose phosphate pathway [57, 70], Krebs cycle (TCA)
and oxidative phosphorylation (Fig. 1) [71, 72]. Studies
with these approaches have revealed improved inflammation resolution and recovery through glutathione
reactive oxygen species (ROS) and glycating agent scavenging [57], which are downregulated after severe injury[64]. Moreover, in lipopolysaccharide (LPS)-treated miceor primary microglial cultures, increasing NADH levels
reversed the protective effects of glycolytic inhibition,
driving NF-κB-mediated proinflammatory gene expression (IL1β, IL6, and iNOS) through dimerization of theNAD(H)-sensitive transcriptional corepressor CtBP [66].
It is well established that metabolic changes drive microglial polarization, and a number of pathways, including
hypoxia-inducible factor-1alpha (HIF-1α), forkhead box
P3 (FOXP3), and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, have been implicated in facilitatingthese effects [73].

Impact of mitochondrial injury on metabolism
dysregulation after TBI
Corresponding to an elevated LPR despite normal/
elevated substrate levels, mitochondrial dysfunction is
also common after TBI [28]. Impairments in the ability
to generate ATP from canonical mitochondrial pathways, such as the TCA or electron transport chain,drive additional neurophysiological impairments evenafter primary injury and initial ischemia resolve. Clinical trials in patients with TBI have revealed reductions
in cerebral glucose utilization years after injury, accompanied by persistent cognitive impairments [74]. This
also prolongs the reliance on anaerobic sources of ATP:

Page 9 of 17

relative hyperglycolysis after TBI has been observedin the absence of hypoxia, when P­ btO2 is normal [70].
Downstream of glycolysis, ATP generation throughthe mitochondrial TCA and electron transport is significantly reduced, even when substrate is in abundance[64, 72]. Ex vivo analysis of mitochondria derived fromrats subjected to ballistic injury revealed decreases inthe enzymatic activity of pyruvate dehydrogenase andglutamate dehydrogenase, which reduce input fromglucose and glucogenic AAs into the citric acid cycle(reduced CoA-SH and acetyl-CoA concentrations), at
24 h after injury [72, 75]. Expression of these enzymes isalso reduced but they are further inhibited by pyruvate
dehydrogenase kinase isoforms, which are overexpressedin severe experimental TBI models [75]. Gene and protein expression of key TCA enzymes is also reduced inthese models, while milder impact models actually demonstrate a gradual increase in these enzymes as micerecover from impact [75]. The reduced flux throughthe oxidative phosphorylation pathway also carries forward to the electron transport chain at the inner mitochondrial membrane. The activity of complex I and IV
was reduced in isolated mitochondria after TBI [72].
The overall mitochondrial availability of NAD(H) andFAD(H) was reduced, reflecting a diminished capacity
for electron and proton transport at the inner membrane.
Posttraumatic leakage of electrons across the inner mitochondrial membrane drives free radical formation shortly
after injury, which further damages cell membranes andnucleic acids.
After TBI, mitochondrial membrane disruption not
only critically impairs oxidative phosphorylation at thesite of electron transport but also activates downstream
signaling pathways (ROS, caspases, calpains, etc.) thatlead to cell death [76]. Uncoupling agents allow ions tomove down their electrophysiological gradient, reversing the posttraumatic accumulation of protons (and C­ a2+ions) in the mitochondrial matrix that is thought to promote these signals [77]. For example, treatment with the
2,4-dinitrophenol prodrug MP201 restored maximal
mitochondrial oxygen consumption as well as complex
I respiration at 25 h in a mouse TBI model. Critically,
MP201-treated mice exhibited improved novel object recognition, reduced cortical lesion volume and increased
hippocampal neuron density two weeks after TBI [77].
Mitochondrial ion accumulation also contributes to theimpact of antioxidant therapies [78, 79] that reduce therelease/impact of mitochondrial ROS after TBI. The Nrf2
pathway is a key player in the antioxidant response to
ROS accumulation that regulates glutathione peroxidase(GSH), heme oxygenase-1, NADPH oxidase (NOX) andseveral other critical pathways [80]. Nrf2 is also directly
involved in maintaining mitochondrial membraneOft et al. Journal of Neuroinflammation(2024) 21:184

Page 10 of 17

Fig. 1 Cellular metabolism dysregulation in TBI. TBI-induced changes of canonical glucose metabolism including increased reliance on lactate
and glycolytic metabolism, lipid derived metabolites, increased oxidative stress, inflammation and altered mitochondrial function are schematicallydisplayed. ATP: Adenosine triphosphate; BBB: Blood Brain Barrier leakage; BCAA: Branched Chain Amino Acid; GLUTs: Glucose transporters; Cyt C:
Cytochrome C; FAD: Flavin adenine dinucleotide; NAD: Nicotinamide adenine dinucleotide; Nrf2: Nuclear factor erythroid 2-related factor 2; PLA2:
Phospholipase A2; ROS: Reactive Oxygen Species; Sirt1: Sirtuin 1

potential. After TBI, the NAD-dependent deacetylase
sirtuin-1 (Sirt1) that promotes Nrf2 is downregulated,
reducing Nrf2 signaling and Nrf2-induced transcriptionof antioxidant, antiapoptotic and metabolic genes [80].
Preventing this decrease, with the administration of a
SIRT-1 activator, reversed ROS bursts, increased downstream nuclear PGC-1a and Nrf2 expression, and attenuated increases in mitochondrial membrane potential andneuronal apoptosis induced by ischemia/reperfusion
injury [78]. Sirt1 activator treatment of neurons in vitro
resulted in a dose-dependent increase in ATP, basal
aerobic respiration, and pyruvate transport even in thepresence of ETC inhibitors [78]. Pretreatment (but nottreatment) also reduced infarct size and partially restoredcomplex II, IV and V activity and complex I, II, and III
expression [78]. Overall, dysfunctional mitochondrialOft et al. Journal of Neuroinflammation(2024) 21:184

respiration is linked to tissue damage and cognitive
impairments observed after TBI, for which targeted therapies such as uncouplers and antioxidant therapies may bepromising. Mitochondrial functions outside of canonicalglucose metabolism are also critically disrupted by TBI,
and key changes in lipid metabolism that result from TBI
are further discussed in the following sections.

Significance of lipid signals from clinical TBI data
Among the lipids implicated in clinical studies, several lipids and lipid metabolites are not directly utilized
as fuel but nevertheless play an important role in TBI
pathology [45]. Cell membrane phospholipids (ex. PC)
may be released following mechanical damage to plasma
membranes and BBB disruption after brain injury [45].
After the impact, the influx of C
­ a2+ ions into the cell
cytoplasm leads to the phosphorylation/activation ofphospholipases that cleave phospholipids into fatty acids,
diaglycerols and lysophospholipids like LPC, which initiates signaling cascades that drive inflammation, BBB
destruction, demyelination, and protein aggregation inseveral neurodegenerative contexts [81]. The principle
lipase implicated in TBI is cytoplasmic phospholipase A2(cPLA2), which is upregulated after in vivo and in vitro
experimental TBI and preferentially cleaves arachidonic
acid as an essential part of enzymatic lipid peroxidationand inflammatory signal transduction [82]. The activated cPLA2 complex also binds to the lysosomal membrane and facilitates the release of enzymes that damageorganelle membranes, leading to mitochondrial damage,organelle degradation and cell death associated with secondary injury [82]. Other enzymes involved in peroxidation include cytochrome c/P450, lipoxygenases, andcyclooxygenases. Polyunsaturated fatty acids undergo
nonenzymatic peroxidation when oxygen radicals generated by mitochondrial ROS production remove a hydrogen atom from the lipid, resulting in a lipid radical thatcan propagate to generate more peroxyl/alkoxyl radicals
and hydroperoxide [83]. In spinal cord injury, this peroxidation has been shown to precede mitochondrial dysfunction [83], while inhibition of lipid peroxidation with
21-aminosteroid in rats attenuated controlled cortical
impact (CCI)-induced decreases in mitochondrial respiration [84]. Administration of 21-aminosteroid attenuated post-CCI lipid peroxide accumulation and increased
basal and maximal ETC activity as well as ETC/ATP synthase uncoupling [84]. Blocking lipid peroxidation also
increased complex I and II activity and the overall efficiency of ETC coupling to ATP synthesis (as measured
by the ratio of State III/IV ­O2 consumption: RCR). Thisfinding suggested that lipid peroxidation contributes tothe disruption of aerobic mitochondrial metabolism thatdefines secondary injury in TBI.

Page 11 of 17

The relevance of lipid markers (SM, PC, cholesterol)
to neuroinflammation-mediated reinjury of TBI brains
is supported by the timeline of their release into the CSF
both acutely and again at 4 days postinjury in patients[45]. Serial CSF collection from 10 patients with TBI
revealed that patients who died exhibited a peak in CSF
phospholipid levels, particularly PCs, on day 4 after
injury [85]. Phospholipid release has been observedin experimental TBI models, which have shown anacute increase in serum SM and PC species as well as adecrease in serum TGs after mTBI in rats [86]. At subacute timepoints, these PCs and PEs (particularly thosecontaining polyunsaturated fatty acids) as well as SMs
and LPC 20:2 are downregulated, while diaglycerols andfree fatty acids/polyunsaturated fatty acids are increased
in serum of rats with TBI [87]. This suggests that an initial increase in phospholipid release is proportional to
injury severity and is gradually reduced as these lipids
are utilized (i.e., undergo peroxidation, oxidation, etc.
[88]) (Fig. 1). Lower levels of phospholipids compared tothe control group were maintained across all phospholipid species at 3 months and as late as 24 months after
mild CCI, while lipid peroxide production increased [88].
Lipid oxidation into bioactive lipids, including oxidized
cardiolipin, eicosanoids (prostaglandins, thromboxanes,
leukotrienes, etc.), octadecanoids and docosanoids, also
contributes to acute signaling changes after TBI [45,89]. Although fatty acid oxidation produces pro- andanti-inflammatory signals immediately after injury, antiinflammatory and vasodilatory signals persist in serum
after proinflammatory octadecanoids and eicosanoids arecleared [89]. Despite promising preclinical data, targeting lipid peroxidation in clinical trials has not been successful [90], indicating that additional research exploring
BBB penetrance of potential therapeutics and a better
understanding of how lipid peroxides work in the temporal/biological context of TBI will be necessary before
these metabolites can be harnessed for clinical benefit.

Lipids as an energy source in TBI metabolism
In addition to the effects of lipid peroxides on mitochondrial membrane integrity and ETC activity, lipids may be
used as alternative fuel sources in low glucose or aerobic
metabolic states generated by TBI. Metabolic dysfunction induced by TBI impairs the availability/utilizationof cerebral glucose for aerobic ATP generation and promotes release of alternative substrates (i.e. ketone bodies, KBs) to fuel the increased metabolism demanded
for brain recovery. The brains’ ability to maintain a stable/optimal glucose level is associated with successful
recovery in other CMD studies [28]. To accomplish this,glucose transport to the brain is increased [62] while
increased cerebral reliance on KB metabolism reduces

Oft et al. Journal of Neuroinflammation(2024) 21:184

the need for glucose consumption. Bernini et al. [91]observe that brain KBs and blood glucose are inversely
correlated such that a systemic drop in blood sugar (inpart due to increased uptake into the brain), is associatedwith increased systemic production and cerebral uptake
of KBs. Shifting this metabolic balance toward ketometabolism is thought to reduce the reliance on anaerobic metabolic processes that drive oxidative stress [92].
After TBI, increased expression of monocarboxylatetransporters, which import ketone bodies generated byastrocytes or from fatty acids in the liver into neurons,
facilitates increased ketometabolism [93]. Ketone bodies
are converted by ketolytic enzymes to acetyl-CoA, which
can enter the TCA for energy generation [93]. Fatty acidoxidation in cell peroxisomes also generates succinate,
which can also enter this cycle and offers another pathfor lipids in cell metabolism [94] (Fig. 1). While the activity of ETC components decreases following TBI, evidence regarding the activity of complex II, which accepts
electrons from ketones, varies and may not show as significant inhibition as other complexes [72, 84]. Several
studies have demonstrated the therapeutic benefit of a
ketogenic diet for recovery in adult rodent TBI models aswell as in pediatric mice, which rely on ketone metabolism at baseline [95]. A high-fat, low-carbohydrate dietincreases the serum ketone body concentration in mTBI
mice and restores visual and spatial memory performanceand reverses neuronal loss in the cortex and hippocampus [92]. Increasing fatty acid and ketone metabolism
after a ketogenic diet also attenuated reductions in ATP,
NAD, mitochondrial fragmentation, and myelination in amurine diffuse axonal injury model, while treatment withketone bodies reduced neuronal/myelin damage induced
by glucose deprivation in vitro [96]. A high-fat diet also
increased Sirt1 expression up to one month after injury,
suggesting that the Sirtuin pathway also contributes toimprovements in mitochondrial metabolism and oxidative stress associated with following ketone supplementation [92]. Downstream changes may include ketogenic
diet-induced increases in mitochondrial uncoupling
protein expression and activity [97], which improve cognitive, pathological and mitochondrial recovery after
experimental TBI [77]. Uncoupling may also contributeto the ETC activity changes observed in lipid peroxidation inhibition (since blocking this process frees up additional fatty acids for metabolism).
It should be noted that most preclinical works explore
TBI ketometabolism through nutritional supplementation and do not directly assess endogenous ketones
in TBI pathology. Perhaps due to these unknowns or
the concerns about the effects of prolonged ketosis,
ketogenic diets have not yet passed beyond phase I clinical trials for TBI [98]. While short term implementation

Page 12 of 17

of ketogenic diets has shown potential in several neurodegenerative diseases for improving metabolic function
and producing neuroprotective and anti-inflammatoryintermediates [99], long-term implementation is limited
by decreased patient adherence and occasional adverse
cardiac, renal and cognitive events (particularly in pediatric patients) [100]. Accordingly, there are very few studies examining the impact of long-term ketosis exceeding
24 or even 12 months. Ketogenic diets that induce greater
ketosis also suffer pooper compliance due to side effects,
diet restrictiveness and psychosocial factors compared
to milder ketogenic diets [101]. Common early adverse
effects after beginning ketogenic diet include mild headaches, digestive system complaints or wooziness [102].
Although far less common, long-term increases in freefatty acids and reduced short-chain fatty acid production can precipitate myocardial insulin-resistance [102]
while ketone bodies can promote cardiac scarring andcell senescence [103]. Severe restriction has rarely been
associated with cognitive/systemic changes induced byketoacidosis [104, 105]. Physicians considering this intervention for patients with cardiac risk factors must consider the long term impact of increased nutritional fat
content and low fiber diet, such as cardiovascular damage and renal complications like kidney stones [103]. Dueto lack of research on prolonged ketosis in the context
of TBI, the extent to which adverse events of ketogenic
diets could impact the unique pathological state of thesepatients remains a concern for many physicians that recognize its clinical potential [106].

TBI‑induced changes of systemic and microbiome
metabolism
In addition to the cellular pathways discussed here, TBI
impacts systemic metabolism through systemic immune
activation and by altering brain signaling that maintains
homeostatic metabolic function [i.e. (para)sympathetic
nervous system function & neuroendocrine signaling[107]]. Concurrently, shifts in GI function/microbiota
feedback on the CNS through rapid neurotransmission
by the autonomic nervous system and vagus nerve or
more slowly through the release of cytokines, pathogenassociated molecular patterns, metabolites, hormonesand even neurotransmitters [108]. These fluctuations
directly contribute to the changes in serum metabolites and to cerebral metabolism that we have described
here. As a consequence, interpretation of “omics” data
must consider the bidirectional gut-brain connection which facilitates the delivery of metabolites to the
CNS and impacts GI function/microbiota after brain
injury [107]. Brain injury induces the release of inflammatory and stress signals which increase enteric glial
cell activation, immune cell infiltration and mucosal

Oft et al. Journal of Neuroinflammation(2024) 21:184

barrier permeability, decrease GI motility and alter the
populations of enteric microbiota [107]. Mechanical or
inflammatory injury to the hypothalamus alters neuroendocrine secretion and contributes to systemic insulin
resistance induced by inflammation/hyperglycemia, further impairing metabolic regulation and glucose uptake[60]. The external risk factors associated with TBI, suchas antibiotic administration, hospital stay, enteral nutrition, etc., can also increase this risk [109, 110]. These
clinical decisions correspond to exacerbation or attenuation of the TBI-induced reduction in GI microbiome
diversity over time [109]. The extent of microbiome distortion is also associated with severity of injury: reductions in microbiome diversity and overgrowth of somebacterial phyla/species upon admission predicted mortality in trauma patients [111]. Moreover, TBI was associated with reduced commensal bacterial species andincreased relative abundance of pathogenic bacteria in
oral, rectal and skin samples from pediatric study participants [109]. In a preclinical TBI model, ablation of thisprogression through antibiotic depletion of gut microbiota attenuated CA-1 (but not CA-3) neuronal loss,
microgliosis, and associative learning deficits induced
by CCI [112]. Microbiome depletion also reduced cortical lesion size and the loss of cecal tight junction staining [112]. As gut microbiota are highly responsive to diet,and nutritional support is already a protocolized partof TBI care (due to observational studies demonstrating an association between delayed enteral nutrition andworse neurologic outcome [113]) there has been muchinterest in identifying dietary interventions which can
improve recovery and reduce mortality [114]. In a 2013
review of smaller randomized control trials and nonrandomized prospective studies, Wang et al. observedthat better outcomes (mortality, infection/complication
rate, functional outcome score) were associated withearly refeeding, a combination of parenteral and enteralnutrition, and “immune enhancing” formulas supplemented with a combination of probiotics, glutamine,arginine, fats (saturated and poly unsaturated, omega-3
fatty acids), protein, vitamins and minerals [114–117].
However, these interventions have not been tested in arobust, large scale randomized trial and conclusions fromprior assessment are often contradictory [118]. These trials have not explored the impact of this supplementationon the gut microbiome but have demonstrated beneficial
effects of parenteral lactate [119–121] and oral [122, 123]
or parenteral BCAAs [124, 125]. Other supplements,
such as omega-3 fatty acids, short chain fatty acids, andketogenic diets, that have generated results in animalmodels, have yet to be tested in clinic [92, 126, 127]. The
benefits of ketogenic diets described above, for instance,
demonstrate the importance of GI microbiota, which isPage 13 of 17

a required intermediary for the effect of these diets inseizure protection (by modulating GABA production or
AMPA receptor binding, for instance [128, 129]). Probiotic therapies are also being applied with various degrees
of success in a broad spectrum of neurodegenerative diseases [130]. These approaches are subject to many of thesame limitations as nutritional/microbiota therapies for
TBI, including the lack of a suitable animal model of thehuman microbiome, heterogeneity in the methods/quality of microbiome data collection, the protracted timeline and inevitable presence of confounding variables inhuman diet trials [130].

Conclusion
TBI drives changes to cerebral and systemic metabolismthat reduce aerobic metabolism of glucose in the brain
and compensate by upregulating alternative pathways
such as anaerobic glycolysis, lactate fermentation, gluco/
ketogenic amino acid metabolism, and lipid metabolism.
Here, we discussed relevant changes to these pathways
and their clinical utility in predicting imaging findings,
mortality and functional outcomes. Preclinical study ofthe metabolic pathway disruptions that give rise to thesebiomarkers facilitates enhanced understanding of TBI
pathology and identification of new therapeutic targets.
However, clinical trials investigating these pathways, aresubject to limitations including the heterogeneity in TBI
severity/etiology, variations in experimental time points
and the methods applied to measure metabolites. Mass
spectrometry or 1H-NMR-based capture of metabolites
in cerebral microdialysate is limited by the invasivenessof CMD catheter placement and the regional specificity
of detected parenchymal changes [131]. In vivo PET, MRI
or CT scanning are more easily administered but do notreflect temporal changes to metabolism unless administered at greater frequency than clinically indicated [131].
Studies of serum metabolites allows for larger cohort
sizes and ease of implementation but is an indirect
marker of cerebral metabolism that is impacted by GI
function/microbial metabolism. Nevertheless, therapeutic interventions aimed at altering cerebral or systemic
metabolism have been promising. This review emphasizes the need for additional research into the metabolic
underpinnings of TBI pathology, particularly into emerging areas like lipid and microbiome driven processes.
Abbreviations
2,3-BPG	2,3-Bisphosphoglyceric acidAA	Amino acid
ANLS	Astrocyte-neuron lactate shuttleATP	Adenosine triphosphate
AUC​	Area under the curve
BBB	Blood–brain barrier
BCAA​	Branched chain amino acid
CCI	Controlled cortical impact

Oft et al. Journal of Neuroinflammation(2024) 21:184

CMD	Cerebral microdialysis
CNS	Central nervous system
coA	Coenzyme A
cPLA2	Cytosolic phospholipases A2
CSF	Cerebrospinal fluid
CT	Computed tomography
ETC	Electron transport chain
FOXP3	Forkhead box P3
GCS	Glasgow coma scale
GFAP	Glial fibrillary acidic protein
GLUT	Glucose transporters
GOS(E)	Glasgow outcome scale (extended)
GSH	Glutathione peroxidase
H-NMR	Proton nuclear magnetic resonanceHIF-1α	Hypoxia-inducible factor-1alpha
ICP	Intracranial pressure
ICU	Intensive care unit
IL	Interleukin
iNOS	Inducible nitric oxide synthase
LPC	Lysophosphatidylcholine
LPR	Lactate/Pyruvate ratio
LPS	Lipopolysaccharide
MS	Mass spectrometry
NAA	N-acetylaspartate
NAD(H)	Nicotinamide adenine dinucleotide
NADP(H)	Nicotinamide adenine dinucleotide phosphate
NF-κB	Nuclear factor kappa B
NOX	NADPH oxidase
NRF2	Nuclear factor erythroid 2-related factor 2
O-LPC	Ether lysophosphatidylcholine
PbtO2	Partial pressure of brain tissue oxygen
PEP	Phosphatidylethanolamines
PET	Positron emission tomography
PGC1a	Peroxisome proliferator–activated receptor gamma coactivator-1
alphaROS	Reactive oxygen species
S100B	S100 calcium-binding protein B
Sirt1	NAD-dependent deacetylase sirtuin-1
SM	Sphingomyelin
TBI	Traumatic brain injury
TCA​	Citric acid cycle, krebs cycle
TG	Triglyceride
TIL	Therapeutic intensity level
UCH-L1	Ubiquitin C-terminal hydrolase-L1
Acknowledgements
Not applicable.
Author contributions
H. C. Oft: conceptualization, investigation, and writing. D. W. Simon, D. Sun:review, editing, writing.
Funding
This study was funded by the Veterans Affairs Merit Awards I01 BX004625(Sun) and I01 BX006372-01 (Sun), and the Career Research Scientist award
IK6BX005647 (Sun) with additional support from the National Institute of
Neurological Disorders and Stroke of the National Institutes of Health underaward R01NS127372-02 (Simon).
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated oranalysed during the current study.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.

Page 14 of 17

Competing interests
The authors declare that they have no competing interests.
Received: 1 May 2024 Accepted: 16 July 2024

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