El Baassiri et al. Journal of Neuroinflammation
https://doi.org/10.1186/s12974-024-03118-3(2024) 21:124

Journal of Neuroinflammation

Open Access

REVIEW

Dysregulated brain‑gut axis in the settingof traumatic brain injury: review of mechanisms
and anti‑inflammatory pharmacotherapies
Mahmoud G. El Baassiri1, Zachariah Raouf1, Sarah Badin1, Alejandro Escobosa1, Chhinder P. Sodhi1 andIsam W. Nasr1*   

Abstract
Traumatic brain injury (TBI) is a chronic and debilitating disease, associated with a high risk of psychiatric and neurodegenerative diseases. Despite significant advancements in improving outcomes, the lack of effective treatments
underscore the urgent need for innovative therapeutic strategies. The brain-gut axis has emerged as a crucial bidirectional pathway connecting the brain and the gastrointestinal (GI) system through an intricate network of neuronal,
hormonal, and immunological pathways. Four main pathways are primarily implicated in this crosstalk, including the systemic immune system, autonomic and enteric nervous systems, neuroendocrine system, and microbiome. TBI induces profound changes in the gut, initiating an unrestrained vicious cycle that exacerbates brain injury
through the brain-gut axis. Alterations in the gut include mucosal damage associated with the malabsorptionof nutrients/electrolytes, disintegration of the intestinal barrier, increased infiltration of systemic immune cells, dysmotility, dysbiosis, enteroendocrine cell (EEC) dysfunction and disruption in the enteric nervous system (ENS) and autonomic nervous system (ANS). Collectively, these changes further contribute to brain neuroinflammation and neurodegeneration via the gut-brain axis. In this review article, we elucidate the roles of various anti-inflammatory
pharmacotherapies capable of attenuating the dysregulated inflammatory response along the brain-gut axis in TBI.
These agents include hormones such as serotonin, ghrelin, and progesterone, ANS regulators such as beta-blockers,
lipid-lowering drugs like statins, and intestinal flora modulators such as probiotics and antibiotics. They attenuate neuroinflammation by targeting distinct inflammatory pathways in both the brain and the gut post-TBI. These therapeutic
agents exhibit promising potential in mitigating inflammation along the brain-gut axis and enhancing neurocognitive
outcomes for TBI patients.
Keywords TBI, Brain-gut axis, Intestinal inflammation, Microbiome, Enteroendocrine cell
Background
TBI is a public health concern in the United States, withapproximately 190 Americans dying each day from TBIrelated injuries [1]. Despite its well established clinical*Correspondence:
Isam W. Nasr
inasr1@jhmi.edu
1
Pediatric Surgery, Department of Surgery, Johns Hopkins University
School of Medicine, Baltimore, MD 21287, USA

course, the underlying mechanisms are yet to be fully
elucidated [2]. TBI significantly increases the risk of morbidity and mortality, contributing to various neurodegenerative and psychiatric disorders, including Alzheimer’s,
Parkinson’s, chronic traumatic encephalopathy, depression and epilepsy [3]. Recently, the gut has emerged as a
crucial player in the pathogenesis of TBI, where TBI has
been shown to induce detrimental changes along the GI
tract. These changes ultimately worsen brain inflammation and cognitive outcomes via the gut-brain axis [4]. In© 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://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

this review, we will explore the mechanisms of brain-gut
axis dysfunction post-TBI, with a specific focus on therole of various anti-inflammatory pharmacotherapies
capable of breaking this dysregulated cycle between thebrain and the gut.

Impact of TBI on brain neuroinflammation
TBI is a form of acquired brain injury resulting fromany external mechanical insult disrupting its structural
integrity. TBI is primarily categorized into primaryand secondary injuries. The irreversible primary injury
results from blunt or penetrating trauma such as falls,
motor vehicle accidents and gunshot wounds, followed
by a secondary dysregulated inflammatory response thatexacerbates tissue damage and neuronal injury [5]. TBI
leads to a wide spectrum of consequences, ranging fromimmediate clinical deterioration to more severe cognitive outcomes. Clinical manifestations involve focal anddiffuse brain swelling, vasospasm [6], hemodynamic
perturbations (hypotension [7], hypoxia [8, 9]), metabolic derangements (hypoglycemia/hyperglycemia) [10],increased intracranial pressures (ICP) and coagulopathy
disorders [11]. Moreover, TBI induces acute and chronic
cognitive disorders, characterized by attention-deficits,
memory problems and executive dysfunction [12]. At
the cellular level, the rapid release of damage-associatedmolecular patterns (DAMPs) shortly after TBI initiates adysregulated neuroinflammatory response. This involves
the activation of resident brain cells (microglia, astrocytes, oligodendrocytes, neurons) and the recruitmentof various immune cells into the injury site (monocytes,
neutrophils, B and T-cells). DAMPs bind to “patternrecognition receptors”, such as nucleotide-binding oligomerization domain-like receptors and toll-like receptors, leading to an increase in inflammatory chemokines,
cytokines and reactive oxygen species (ROS). This triggers a positive feedback loop that intensifies the inflammatory response by recruiting additional immune cells
to the injury site [13, 14]. The hallmark features of TBI
include neuronal injury, axonal damage, mitochondrial
dysfunction, excitotoxicity, oxidative stress, and blood–
brain-barrier (BBB) disruption [15, 16]. BBB breakdown
occurs due to endothelial cell death, degradation of tightjunction proteins, basement membrane damage, redistribution of aquaporin 4 (AQP4) channels, and swelling ofastrocytic endfeet, leading to brain edema and increased
ICP [17]. Excitotoxicity involves the heightened releaseof glutamate into the extracellular space, followed by theentry of calcium ­(Ca2+) into the cells, initiating a programmed cell death [18]. Additionally, the imbalance
between increased metabolic demands and decreased
mitochondrial adenosine triphosphate (ATP) production further aggravates the inflammatory response.

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Mitochondrial dysfunction results from a combination ofincreased ROS, ­Ca2+ overload and excitotoxicity, in addition to alterations in the expression of caspases, B-cell
lymphoma 2 (Bcl-2) family proteins and apoptosis inducing factors [19]. TBI has also been shown to increaselevels of polyunsaturated fatty acids within the brain, cerebrospinal fluid and serum in both preclinical and clinicalmodels [20, 21]. These fatty acids activate the arachidonic
acid metabolic pathways, leading to the release of prostaglandins and leukotrienes, further contributing to brain
injury [22].
Astrocytes and microglia are key cells in the CNS that
can initiate the inflammatory response post-TBI [13].
These cells have the ability to acquire proinflammatory
or anti-inflammatory phenotypes and can secrete various
chemokines, cytokines and growth factors [23, 24]. Thesechanges influence the local tissue microenvironment
and modulate secondary cellular damage or tissue repair[25]. Astrocytes undergo a process called reactive astrogliosis, which involves molecular, structural and functional changes [26]. They regulate the neuroinflammatory
responses, scar formation, blood–brain barrier permeability and synapse remodeling [27]. At the same time,
activated microglia can migrate toward the lesion site
to phagocytose debris and modulate the inflammatory
profile by secreting various cytokines and chemokines[28]. Microglia can have distinct roles in neurodegeneration and tissue repair depending on their activation state(pro/anti-inflammatory) [29]. Proinflammatory microglia
favor the production of cytokines that exacerbate neural
injury, while the anti-inflammatory microglia acquire aphagocytic role and promote repair by releasing neurotrophic factors [30, 31]. Recently, their role has expanded
to show that changes in the gut microbiome after TBI
can also alter microglial phenotypes in the brain and ultimately influence TBI outcomes [32]. The chronic activation of both astrocytes and microglia leads to increased
peripheral immune cell infiltration through the permeable BBB, further exacerbating cognitive outcomes andincreasing risk of morbidity and mortality [33].

Brain‑gut axis disruption following TBI
TBI is a systemic disease that impacts various peripheral organs, including the lungs, GI tract, liver and kidneys [34–37]. TBI survivors have an increased risk ofdeath from septicemia [38], pneumonia [39] and digestive diseases [40] compared to their healthy counterparts.
Furthermore, TBI induces gastroparesis and intestinal
dysmotility, resulting in feeding intolerance, where 50%of patients with severe TBI experience feeding intolerance within the first week after injury [41]. A singlecenter observational study conducted by McConnochie
et al. demonstrated that around 52% of TBI patients

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

often experience delayed bowel defecation, which was
associated with longer intensive care unit (ICU) stays
and higher gastric residual volumes [42]. A retrospective
study also revealed that patients with TBI are 2.5 times
more likely to die from digestive disease-related conditions and 12 times more likely to die from septicemia
compared to the general population [43]. Another retrospective study demonstrated rates of fecal incontinence
up to 70% in patients with acquired brain injury admitted to rehabilitation centers [44]. Fecal incontinence
also significantly correlated with the presence of frontal
lobe lesions and hemodynamic instability [45]. Furthermore, abdominal pain, distention and constipation werealso common symptoms in patients even two years after
their initial brain injury [46]. Therefore, current guidelines recommend initiating enteral nutrition within
24–48 h to attenuate TBI-induced intestinal dysfunction
and improve patient prognosis [47]. Various distinct andoverlapping pathways are also involved in TBI-induced
intestinal dysfunction, including systemic immune dysregulation, ANS dysfunction, intestinal flora dysbiosis
and neuroendocrine system disruption (Fig. 1).
Systemic immune dysregulation

TBI detrimentally affects the GI tract through systemic
pathways by modulating the peripheral immune system[48]. TBI triggers the activation of the hypothalamic–
pituitary–adrenal (HPA) axis and sympathetic nervous
system, resulting in elevated levels of glucocorticoids/
cortisol and catecholamines, respectively [49]. This
surge in cortisol can ultimately lead to a leaky gut by
increasing the intestinal barrier permeability [50, 51].
Subsequently, the translocation of luminal pathogenic
bacteria across the disintegrated barrier can induce asystemic inflammatory response syndrome (SIRS) andfurther aggravate systemic inflammation by releasing numerous cytokines and chemokines into the systemic circulation [52]. TBI leads to an acute increase inproinflammatory mediators such as TNF-α, IL-1β and
IL-6, which have been associated with worse cognitive
outcomes [53]. Elevated levels of IL-1β were linked to
impaired working memory in the acute phase, while
increased levels of chemokine ligand 2 (CCL2) correlated with greater severity of post-concussive symptoms [54]. Further studies demonstrate that an increasein cytokine score load shortly after injury correlateswith unfavorable Glasgow Coma Scale (GCS) scoresat six and twelve months post-TBI [55]. Moreover, elevated blood cortisol levels can elevate the risk of infections by inducing peripheral immunosuppression [56].
TBI results in increased levels of circulating neutrophils
and a decrease in circulating monocytes, T-cell lymphocytes and natural killer (NK) cells, accompanied byPage 3 of 31

defective phagocytosis [57, 58]. This is characterized by
impairments in respiratory burst and phagocytosis inneutrophils and monocytes, as well as decrease in percentage of perforin-positive NK cells [59, 60]. Additionally, TBI induces thymic involution, leading to chronic
T-cell lymphopenia [59]. These alterations result in ashift in systemic immunity towards an anti-inflammatory state, which could explain the increased risk of
nosocomial infections in hospitalized patients following TBI [61]. While these changes may be necessary tocombat TBI effects acutely, the chronic stress response
leads to a prolonged hyperinflammatory state that
can trigger multi-organ dysfunction and, ultimately,lead to death [62, 63]. Interestingly, TBI has also beenshown to increase age-related microglial phenotypes,
as depicted by lipid accumulation in microglia for up to
one year after injury [64]. All these acute, subacute andchronic changes in the neuroimmune responses exacerbate inflammation and accelerate immune aging andneurodegeneration [65].
To assess the impact of the systemic immune system on
gut inflammation following TBI, our group have demonstrated that knocking out peripheral inflammatory C–C
chemokine receptor type 2 (Ccr2)-dependent monocytes
reduce levels of intestinal tumor necrosis factor alpha(TNF-α), interleukin-1β (IL-1β) and lipocalin-2. Additionally, TBI induces a significant increase in the expression of intestinal toll-like receptor 4 (TLR4) shortly after
injury, which could explain aggravated intestinal inflammation. Notably, ­Ccr2ko mice showed decreased levels ofintestinal TLR4 on days 1 and 3 post-injury [66]. Thesefindings suggest a critical role for the systemic innate
immune system in modulating the bidirectional communication between the brain and the gut post-TBI. In addition to the innate immune system, adaptive immunity,
especially T-cells, has been shown to modulate the neuroinflammatory response along the brain-gut axis [67].
T-cells infiltrate the brain as early as 5 days post-TBI [68],and ­granzyme+ ­CD8+ T-cells have also been detected
8 months after TBI [69]. Daglas et al. demonstrated thatpharmacologic and genetic depletion of C
­ D8+ T-cells
improves neurologic outcomes and produces a neuroprotective Th2/Th17 immunologic shift [69]. Recent
studies have also shown that the gut microbiota modulate the trafficking of effector T-cells from the gut to the
leptomeninges, impacting injury outcomes in both stroke
and TBI models [70]. T-cell trafficking is thought to bemodulated by changes in the microbiome following CNS
injury, which ultimately regulates microglial functions in
the brain [71]. Further research is warranted to understand the role of intestinal innate and adaptive immunity, particularly macrophages/monocytes and T-cells, inmodulating neurocognitive outcomes post-TBI.

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

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Fig. 1 Bidirectional cross-talk between the brain and gut in TBI. TBI induces tissue and cellular disruption, leading to the release of various
inflammatory cytokines, chemokines, complement factors and damage-associated patterns (DAMPs), which promote diverse cellular responses:
a Microglia, the resident immune cells of the brain, become activated and migrate towards the injury site to phagocytose debris and releaseproinflammatory cytokines. b Astrocytes contribute to the inflammatory response and undergo reactive gliosis, leading to the formationof a protective glial scar to limit injury spread. c Increased production of reactive oxygen species (ROS), excessive release of excitatory
glutamate, and reduced blood flow to the brain promotes neuronal apoptosis and neurodegeneration. d Blood–brain barrier breakdown leads
to the infiltration of various immune cells, such as neutrophils, monocytes and T-cells, into the brain parenchyma to aid in debris clearance.
However, excessive infiltration can exacerbate tissue damage and worsen neurologic outcomes. I TBI affects the gut through several pathways,
including the activation of the hypothalamic–pituitary–adrenal (HPA) axis, which releases cortisol, and sympathetic arm of the autonomic nervous
system (ANS), which releases catecholamines, leading to gut intestinal barrier disintegration. e This allows the translocation of pathogenic bacteria
from the gut lumen into the intestinal parenchyma, exacerbating microbial dysbiosis. f The enteric nervous system (ENS) becomes dysfunctional,
with reactive gliosis in enteric glial cells, leading to dysmotility. g These changes also result in decreased expression of enteroendocrine cells(EECs), reducing their secretion of anti-inflammatory hormones such as serotonin. h Inflammatory immune cells, including T-cells and monocytes,
infiltrate the intestinal epithelium and further increase gut inflammation. The gut sends signal back to the brain through various pathways: (II)Decreased release of microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids, as well as reduced anti-inflammatory hormone
secretion from EECs, worsen this detrimental cycle. Furthermore, the impairment of afferent and efferent vagus nerve pathways disrupts brain-gut
homeostasis and exacerbate the neuroinflammatory response in the injured brain. These overlapping and interrelated pathways offer potential
therapeutic targets for mitigating TBI-induced neuroinflammation and improving neurologic outcomes. Created with www.​Biore​nder

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

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Autonomic and enteric nervous system dysfunction

following TBI when compared to placebo [85]. Therefore, dysautonomia plays a crucial role in mediating TBI
outcomes post injury, and therapies should be targeted at
attenuating the sympathetic storm with the potential useof beta-blockers. Additionally, there should be a greater
focus on stimulating the parasympathetic vagus arm andstudying its impact on immune cellular responses in thebrain and gut, in addition to functional outcomes including intestinal permeability, gut motility and neurobehavioral outcomes.

In addition to the HPA-axis, the CNS exerts its effects
on the gut through branches of the ANS. All divisions of
the ANS innervate the GI tract, including the parasympathetic nervous system, sympathetic nervous system aswell as the intrinsic ENS [72]. The bidirectional brain-gut
axis serves as a conduit through which ANS exerts its
influence on the ENS. TBI is associated with sympathetic
hyperactivity, resulting in a surge of circulating catecholamine levels that significantly impact various peripheralorgans, particularly the GI tract [73]. Increased catecholamine levels persist for weeks after injury and play a
critical role in inducing systemic immunosuppression,
exacerbating clinical outcomes, and increasing morbidity and mortality rates [74]. TBI induces a sympathetic
storm of systemic epinephrine, which redirects bloodaway from the GI tract, resulting in gut dysmotility andgastroparesis [75]. Elevated catecholamine levels in thegut also disrupt ENS homeostasis, which is primarilycholinergic in nature [76]. A study by Ma et al. demonstrated ENS dysregulation four weeks post-TBI, depictedby an increased activation of enteric glial cells (EGCs) inthe colon. This process, known as reactive gliosis, may
further contribute to intestinal dysmotility [77]. As forthe parasympathetic nervous system, the vagus nerve isthe major regulator of bidirectional neuroimmune interactions between the brain and the gut [78]. The vagus
nerve sends signals from the brain to the gut throughpostganglionic efferent neurons that regulate the secretomotor function of the gut by secreting Acetylcholine(Ach), thereby promoting gut motility [79]. Furthermore,
Ach also binds to the α7 subtype of the nicotinic acetylcholine receptor (α7nAChR) located on intestinal macrophages and decreases the production of inflammatory
cytokines [80]. Recent findings have also highlighted thatextracellular choline acetyltransferase (ChAT), the rate
limiting enzyme in Ach biosynthesis, reduces systemic
inflammation and inhibits the release of proinflammatory
cytokines. This effect was observed following vagus nerve
stimulation or administration of a bioactive recombinant
form of ChAT, as evidenced by reduced levels of serum
proinflammatory markers TNF-α and IL-6 in a DSS colitis model in mice, two weeks post-injury [81]. In turn,the vagus nerve carries information from the gut to thebrain through its afferent neurons which regulate brainneuroinflammatory outcomes. Visceral afferents respondto various mechanical and chemical stimuli [82], including changes in microbiome diversity [83], neuropeptides
and hormones secreted by enteroendocrine cells (EECs)[84], as well as sensitization to inflammatory mediators.
The importance of vagus nerve function is highlighted invagus nerve stimulation (VNS) preclinical trials, which
demonstrated improvements in cognitive outcomes

Intestinal flora dysbiosis

The impact of the gut microbiota on behavioral outcomes
and cognition is a rapidly expanding field of research,suggesting that alterations in the gut play a crucial rolein the pathophysiology of TBI [86]. The impact of TBI on
microbiome diversity and richness has been extensively
studied in the preclinical [87, 88] and clinical settings [89,90]. TBI leads to an increase in pathogenic bacteria anda decrease in protective populations [91]. These changes
have been shown to manifest as early as 2 h post-TBI[92] and can persist for years [89] after the initial injury.
Various factors could contribute to microbial dysbiosis,
including changes in intestinal motility and alterations
in paneth cells expression. Reduced gut peristalsis shifts
microbial composition into a pathogenic state, and thisin turn can worsen gut motility, triggering a detrimental
cycle between dysmotility and dysbiosis [93]. Additionally, Paneth cells are another type of epithelial cells foundthe in the intestinal crypts that secrete various antimicrobial peptides, including lysozyme and α-defensins [94].
They have been also shown to regulate the compositionof bacterial microbiome in various intestinal diseases
such as inflammatory bowel disease (IBD) and irritablebowel syndrome (IBS) [95]. In the setting of TBI, Yanget al. demonstrated a significant correlation between
decreased expression of lysozyme antimicrobial peptides
and increased translocation of pathogenic microbiome
across the disintegrated epithelial barrier [96]. Thesechanges suggest a critical role for paneth cells in modulating the microbiota-gut-brain axis following TBI.
The influence of gut microbiota on the brain is mediated mainly through vascular, neural and immune pathways. TBI results in mucosal damage and increased
epithelial barrier permeability which facilitates the translocation of luminal pathogenic bacteria into the intestinal parenchyma [96]. The intestinal microbiota alsotransforms dietary components into various metabolites
including short-chain fatty acids (SCFAs), tryptophan
metabolites, and bile acid metabolites [97]. These microbial metabolites can either influence the brain directly
by binding to receptors on vagal afferents, or indirectly
by entering the systemic circulation and modulating

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

cell–cell interactions between gut microbes and cells
in the central nervous system (CNS), primarily astrocytes, microglia and neurons [98, 99]. In a study Xiong
et al., it was demonstrated that administrating SCFAs
such as butyrate and acetate for six months following
TBI reduced microglial activation and promoted an antiinflammatory microglial phenotype, while also attenuating T-cell activation and cytotoxic-related pathways[100]. Similarly, the administration of antibiotics, specifically amoxicillin-clavulanic acid, was linked to decreased
infiltration of T-cells into the brain two days after TBI[70]. The interactions of various microbiome metabolites
and brain immune cells such as microglia and T-cells,
may ultimately impact cognition and neurobehavioral
outcomes. Therefore, therapies targeted towards promoting a healthy microbiome are essential in ameliorating
the hyperinflammatory response along the brain-gut axis
and improving cognitive outcomes following TBI.
Neuroendocrine system disruption

Previous research focused on investigating brain-gut
bidirectional communication following TBI, emphasizing the role of the HPA-axis, ANS, cellular immune
responses and the microbiome axis. However, a thorough examination of the neuroendocrine axis is warranted, given the gut’s capacity to release a diverse arrayof hormones that can ultimately influence cognitive outcomes [101]. EECs are specialized cells lining the intestinal epithelium which form the largest endocrine systemin the body. They play a pivotal role orchestrating thecrosstalk between the brain and the gut by releasing various hormones and peptides including 90% of the body’s
serotonin, ghrelin and glucagon-like peptide 1 (GLP-1),
neuropeptide Y and cholecystokinin [101, 102]. EECs
can also influence the brain directly through excitatory
synaptic connections with the vagus nerve [103] and/or
indirectly by releasing various hormones into the systemic circulation [104], thereby forming an interface
between the brain and the gut. Our group was the firstto show substantial reductions in the expression of EECs
three days following TBI as demonstrated by a significant
downregulation in the expression of chromogranin A(ChgA), which is the main marker of EECs (Fig. 2A–C).
We have also shown reduction in the transcription factors implicated in the differentiation of Leucine-richrepeat-containing G-protein coupled receptor 5 ­(Lgr5+)
intestinal stem cells into mature C­ hgA+ cells, including
notch receptor 1 (Notch1), atonal bHLH transcription
factor 1 (Atoh1), and neurogenin 3 (Neurog3) (Fig. 2D,E). The involvement of EECs in brain-gut communication
has been also studied in various neurologic and psychiatric disorders such as Parkinson’s disease and schizophrenia [105, 106]. In Parkinson’s, EECs have been shown toPage 6 of 31

express the α-synuclein misfolded proteins which directly
connect to α-synuclein–containing nerves, forming aneural circuit between the gut and the nervous system[106]. More research is expected down the line to study
the impact of EEC changes during acute and chronic
timepoints post-TBI, alongside the various hormones
they produce especially serotonin, ghrelin and GLP-1
which are primarily characterized as anti-inflammatory
agents.
In summary, the bidirectional communication between
the brain and gut occurs through systemic immune pathways, neural networks, endocrine hormones, and themicrobiota axis, thereby inducing detrimental changes
along the GI tract post-TBI. These changes further exacerbate brain injury, as illustrated in Fig. 3. Strong evidence supports the role of diverse therapeutic agentsin breaking this deleterious cycle and reducing inflammation through distinct mechanisms in the brain andthe gut. In this comprehensive review, we highlight theanti-inflammatory role of various therapeutic modalities,
including hormones such as (1) serotonin; (2) ghrelin; (3)progesterone; ANS modulators such as (4) beta-blockers;
lipid-lowering agents such as (5) statins; and intestinal
flora modulators such as (6) probiotics/antibiotics. We
describe how these therapeutic interventions attenuate
the hyperinflammatory response along the brain-gut axis
following TBI.

Therapies attenuating brain‑gut axis disruption
following TBI
Serotonin

In the brain, serotonin is produced by neurons originating in the raphe nucleus located in the brainstem. Serotonin works as a neurotransmitter known for its role inregulating mood; however, it has also been shown to be
involved in other processes such as neurogenesis andplasticity [107–109], cognition [110, 111], memory [112],
inflammation [113], and gut motility [114, 115]. Serotonin and kynurenine, which are upregulated in inflammatory states, are both synthesized from tryptophan andcompete for its availability. Most of the tryptophan in the
body is used for the synthesis of kynurenine, and only
a minority is used for serotonin. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme of 5-HT (serotonin) synthesis and is present both in the CNS and the
peripheral organs. Serotonin cannot cross the BBB, andas such, it is synthesized via TPH1 in the EEC of the gut,
which are responsible for the synthesis of 90% of the serotonin in the body and via TPH2 in the CNS [107, 112,
113, 115]. There are a total of 14 known serotonin receptors that are divided into 7 classes, 5-HT1 to 5-HT7. The
receptor that 5-HT activates, its location in the body, andEl Baassiri et al. Journal of Neuroinflammation(2024) 21:124

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Fig. 2 TBI induces enteroendocrine cell loss and decreases EEC differentiation. male C57BL/6 mice were used at the age of 4–6 weeks to induce
moderate-severe TBI as previously described [66]. Mice were sacrificed three days later, and the ileum was harvested to investigate the expressionof EECs. Intestinal tissues were fixed overnight with 4% paraformaldehyde and processed for paraffin embedding. Subsequently, 5-μm tissue
sections were cut from paraffin blocks using a CUT 6062 microtome (SLEE Medical GmbH, D-55129 Mainz, Germany) and stained for DAPI
(blue) and chromogranin A (ChgA) (green). ­ChgA+ cells were counted using ImageJ2 software. Scale bars, 50-μm. A–C Representative confocal
images showing decreased intestinal ChgA expression in TBI mice when compared to sham on post-injury day (PID) 3. D An illustration of EEC
differentiation pathway in the intestine. TBI reduces the expression of key transcription factors implicated in the differentiation of ­Lgr5+ intestinal
stem cells into ­ChgA+ mature EECs, including E Notch1, F Atoh1, and G Nuerog3, as measured by quantitative reverse transcription polymerase
chain reaction (qRT-PCR). The mRNA levels are expressed as relative to housekeeping gene Rplp0 expression. Statistical significance was determinedby student’s t-test using GraphPad Prism 10 software. Each dot on the graph represents a different mouse. Error bars indicate the mean ± SEM.
*p < 0.05, **p < 0.01, ***p < 0.001

the concentration it activates it with, determine the effectit exerts [107, 112, 113, 115].
Altered serotonin levels have been observed in TBI
patients, which could be explained by alterations intryptophan metabolism [109]. Zhang et al. showed thata rabbit subjected to controlled cortical impact had
increased inflammation and upregulation of the enzyme

responsible for kynurenine synthesis, shifting tryptophan away from serotonin synthesis. Although serotonin levels were not significantly decreased, there was asignificant decrease in the serotonin/tryptophan ratio,with a decrease in the mean and total length of serotonin fibers compared to sham [109]. These alterations in
5-HT levels could contribute to brain dysfunction, as

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Fig. 3 TBI induces gut dysfunction via the brain-gut axis. This illustration depicts the intricate pathways through which TBI disrupts gut function
via the brain-gut axis. Four main pathways contribute to the cross-talk between the brain and gut, including the systemic immune system,
autonomic and enteric nervous systems, neuroendocrine system, and microbiota axis. In a healthy gut (left), (i) a balanced microbial flora transforms
dietary components into various metabolites, including short-chain fatty acids (SCFAs), tryptophan metabolites, and bile acids. SCFAs, particularly
acetate, propionate and butyrate exert various beneficial effects on brain function by acting as energy substrates for neurons and microglia. They
have the ability to directly influence the brain by entering the systemic circulation and crossing the blood–brain-barrier or indirectly by binding
to receptors on vagus nerve endings; (ii) Additionally, enteroendocrine cells (EECs), the largest endocrine system in the body, regulate digestive
processes by secreting various hormones, such as like serotonin, ghrelin and glucagon-like peptide 1 (GLP-1), in response to luminal stimuli.
These cells communicate bidirectionally with the CNS by sending hormonal signals to the brain via the blood stream or and neural signals
through vagal afferent pathways; (iii) An intact vagus nerve also releases acetylcholine (Ach), which binds to the α7-subtype of the nicotinic
acetylcholine receptor (α7nAChR) located on intestinal macrophages and decreases the production of inflammatory cytokines. Ach also binds
to muscarinic receptors located on smooth muscle cells in the GI tract facilitating peristalsis and Ach also stimulate excitatory motor neurons
in the ENS which further enhances gut motility; (iv) In normal homeostasis, immune cell activation is balanced, cortisol secretion follows diurnal
rhythms and catecholamine levels remain within physiologic ranges, collectively maintaining a stable circulation and tissue perfusion. However,
TBI-induced intestinal dysfunction triggers a cascade of changes (right). (I) The microbiome shifts towards a pathogenic state, with bacteriatranslocating into the intestinal parenchyma through the compromised intestinal barrier; (II) EECs become dysfunctional, reducing their expression,differentiation and secretion of anti-inflammatory hormones; (III) Concurrently, vagus nerve dysfunction occurs, resulting in decreased Ach, which
can polarize macrophages into a proinflammatory state and heighten inflammation; and (IV) The activation of hypothalamic–pituitary–adrenal(HPA) axis during TBI increased circulating catecholamines and cortisol, leading to a leaky gut and mucosal damage. Furthermore, systemic
monocytes and T-cells infiltrate the gut and exacerbate inflammation by upregulating proinflammatory cytokines. In addition, reactive gliosis
in enteric glial cells (EGCs) results in intestinal dysmotility. Finally, Paneth cells reduce their secretion of antimicrobial peptides, further exacerbating
microbiome dysbiosis. These intricate changes collectively aggravate brain inflammation and neurodegeneration through the gut-brain axis.
Created with www.​Biore​nder

cognitive impairment was demonstrated to be mediatedby 5-HT in the hippocampus in a tryptophan depletion
clinical trial [112]. Considering such evidence, the roleof serotonin in treating or altering the outcomes of TBI
is under study [66, 116, 117]. Data about the efficacy of
selective serotonin reuptake inhibitors (SSRIs) in treating

TBI patients comes from preclinical models. Weaver
et al. showed that mice subjected to severe controlled
cortical impact, followed directly by a single injection of
intraperitoneal (IP) fluoxetine (5 mg/kg), had decreasedcolonic permeability and improved motor coordination
starting day 4 post-TBI compared to those treated with

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

placebo [117]. Craine et al. studied the role of chronic IP
milnacipran treatment (30 mg/kg/day), a serotonin-norepinephrine reuptake inhibitor (SNRI), in improving cognition in male rats subjected to frontal lobe injury. After
TBI, rats treated with milnacipran performed significantly better in attentional set-shifting tasks comparedto those treated with placebo, and their performance wascomparable to that seen in sham rats [111]. In humans,a systematic review conducted by Yue et al. demonstrated that the administration of SSRIs was associatedwith improvements in depressive symptoms following
TBI [118, 119]. In addition to TBI, many CNS disorders
have been associated with altered levels of 5-HT. For
example, patients with Alzheimer’s disease (AD) were
found to have decreased total levels of 5-HT and 5-HT
receptors [120–122], and a decrease in 5-HT along withan increase in kynurenine was associated with increased
cognitive dysfunction and inflammation [123]. Similarly,
in Parkinson’s patients, 5-HT depletion was associatedwith worse cognitive functioning [124–126]. In healthy
individuals, acute serotonin depletion achieved throughtryptophan depletion has been associated with impaired
verbal memory and emotional processing [127, 128]. Thisevidence is further supported by the impact of SSRIs in
alleviating some of these conditions. Preclinical studies
showed that treatment with SSRIs decreased amyloidbeta plaques in female mice with AD, which was associated with improved cognitive function, learning andmemory [129]. There is also evidence that longer treatment duration with SSRIs is protective against dementia[130, 131]. The mechanism of how serotonin can improvethese conditions is not fully understood, as preclinical models show that agonism of different 5-HT receptors can result in either a positive or negative impact on
memory and cognition [132, 133].
Since the gut is the main source of 5-HT in the body,
it is not surprising the serotonin levels are altered in TBI
patients. Mercado et al. show that male mouse models
subjected to moderate TBI have a significant decrease in
TPH1 in the duodenum and colon by 0.9-fold and 0.5fold, respectively. Additionally, there was a reduction inserotonin expression in the colon on immunofluorescent
staining accompanied by a significant increase in colonicserotonin reuptake transporters (Sert) compared tosham. This was reflected as an overall significant decreasein 5-HT level in the peripheral circulation [116]. Furthermore, our group was the first to demonstrate a significant
downregulation in the expression of EECs along the intestinal epithelium, particularly the ileum, following severe
unilateral TBI in male mice. This results in decreased
levels of serotonin synthesis genes, especially dopa decarboxylase, another essential enzyme responsible for serotonin synthesis [66]. The long-term gut dysbiosis that

Page 9 of 31

occurs because of inflammation and impaired motility in
TBI is another factor that explains the changes in 5-HTlevels [4, 134]. Studies involving alterations in gut microbiota whether in induced or in disease states such as IBS
have been correlated with changes in 5-HT levels and inbehavior [135–137]. Similarly, people who suffer fromschizophrenia [138] or depression [139] harbor pathogenic microbiota and reduced 5-HT levels [140, 141]
than controls highlighting the bidirectional interaction.
In the GI system, serotonin has been shown to play arole in regulating motility through 5-HT3 and 5-HT4,
and peristalsis through its action on 5-HT2B on the interstitial cells of Cajal (ICC), which are the cells responsiblefor initiating rhythmic contraction [112–115]. In addition to TBI and other neurological diseases, alterationsin 5-HT levels have been extensively described in intestinal diseases such as IBDs [142, 143], celiac disease [144,145], colitis [146], and diverticulitis [147]. Serotonin has
been shown to improve esophageal motility in cases ofdysfunction [148], increase stool frequency and improveits consistency in patients with inflammatory bowel syndrome associated with constipation [149]. Interestingly,
chronic treatment with SSRIs has been associated withdecreased gut motility and delayed transit both in mouseand human studies [150, 151], highlighting the complexity of serotonin signaling. 5-HT has been also shown toregulate inflammation in the gut by exerting both proinflammatory and anti-inflammatory effects throughvarious receptors found on immune cells [152]. Given
that intestinal epithelial cells express the serotonin reuptake transporter (Sert) on their apical membranes [153]and considering that TBI increases the expression ofthese receptors in the intestinal epithelium of colonic villi[116], administering SSRIs such as fluoxetine presents apromising avenue to explore the impact of intestinal serotonin on gut-brain axis interactions and neurobehavioral outcomes following TBI.
GhrelinFirst characterized in 1999, ghrelin is an orexigenic
peptide hormone mainly produced by P/D1 cells in thestomach with small amounts also released by the small
intestine, pancreas and brain. Ghrelin is well known for
its effects on pituitary regulation, hunger, and satiety[154–156]. More recently, its anti-inflammatory properties have become better understood [157, 158]. Investigation into the role of exogenous ghrelin in models ofbrain injury has uncovered several mechanisms throughwhich ghrelin can simultaneously ameliorate GI dysfunction and exert various neuroprotective effects. The neuroprotective effects of ghrelin have been linked to BBB
preservation, reduction in oxidative damage, as well asother neuroprotective mechanisms. In a weight drop

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124(WD) model of TBI, IP administration of ghrelin (20 μg
total) in male mice was found to reduce neuronal degeneration and decrease vascular permeability and perivascular expression of AQP-4 [159]. Increased AQP-4 has
been shown to be linked to cellular edema following TBI[160] which contributes to TBI-induced neuronal damage. In this study, S100B -a neurobiochemical marker ofbrain damage- was also found to be reduced in the serumof mice that receive ghrelin alongside TBI [159, 161],
adding evidence that ghrelin prevents neuronal damage
and apoptosis following trauma through preservation of
the BBB. The protective role of ghrelin in TBI was linked
to fibroblast growth factor (FGF) where a study by Shaoet al. found that both FGF-binding protein (FGF-BP) andbasic FGF (bFGF) were downregulated in the ipsilateralhemisphere following treatment with IV ghrelin (20 μg/kg) in a TBI rat model. The group proposed that ghrelin attenuates brain injury by competitively inhibitingbFGF/FGF-BP-induced neovascularization. However, itremains to be investigated whether this discovered relationship between ghrelin and both bFGF and FGF-BP iscausative or competitive [162]. An alternative mechanism
has been identified in relation to ghrelin’s protective role
against brain injury during sepsis. Sun et al. found that
PI3K/Akt signaling activation mediates ghrelin’s ability toattenuate brain edema, neuronal apoptosis and enhanced
BBB integrity [163]. Phosphoinositide 3-kinases (PI3K)
activation results in the production of phosphatidylinositol 3,4,5 trisphosphate (PIP3) and phosphatidylinositol 3,4 bisphosphate (PIP2), leading to the activation ofProtein kinase B (Pkb/Akt). Akt promotes cell survival
by phosphorylating both glycogen synthase kinase 3beta(GSK-3beta) and the Bcl-2 family [164, 165]. These twomolecules are tied closely to neuronal survival, highlighting a potential mechanism through which ghrelin exerts
its neuroprotective effects during sepsis. Lastly, ghrelinhas been shown to be exhibit neuroprotective properties in cerebral models of ischemia–reperfusion injury(IRI) [166]. When compared to IRI controls, treatment
with un-acylated ghrelin in rat and mice models of cerebral IRI resulted in decreased injury, apoptosis, inflammation and BBB disruption through the reduction ofoxidative damage [167, 168]. Ghrelin has also been found
to reduce neutrophil infiltration following spinal cord
injury (SCI), resulting in less lipid peroxidation and DNA
damage following the insult [169, 170]. However, despite
these potential protective roles, investigation into ghrelin
has not yielded universally positive findings. For example,
Ersahin et al. found that IP ghrelin (10 μg/kg/day) did not
reduce neurological deterioration following SCI in rats[169]. This divergence in available data emphasizes theneed for further investigation into the potential role ofPage 10 of 31

ghrelin as a protective agent that acts on and through thebrain-gut axis.
Ghrelin’s ability to reduce GI dysfunction following
CNS injury has been attributed to several mechanisms,
including a link with the vagus nerve, preservation of theintestinal barrier, and activation of the mammalian target of rapamycin (mTOR) pathway following ischemic
injury. Evidence supports the role of ghrelin in mediating protective responses of the gut-brain axis following
TBI. Bansal et al. showed that the administration of 2
doses of IP ghrelin (20 μg/kg total) right before and after
severe WD TBI preserved intestinal barrier integrity,
restored villous architecture and reduced ileal levels of
TNF-α [171].They also demonstrated that the beneficial
effects of vagus nerve stimulation (VNS) following TBI
may be mediated through ghrelin [172, 173]. VNS wasshown to both increase serum ghrelin levels and decrease
serum inflammatory cytokines following TBI. Exogenous ghrelin was found to mimic the response seen to
VNS by decreasing circulating TNF-α. Importantly, theprotective effects of VNS were abolished when a ghrelin
receptor antagonist was administered alongside VNS,
highlighting a potential ghrelin-dependent mechanism
through which VNS works during TBI. The localization of ghrelin receptors to the dorsal motor nucleus of
the vagus in the brain supports this link [174]. Furthermore, the administration of 1 dose of intravenous ghrelin (20 μg/kg) 30 min following severe TBI in male rats
improved intestinal motility and preserved ileal mucosalarchitecture [175]. Aside from its important and wellestablished anti-inflammatory role, ghrelin has beenshown to attenuate intestinal barrier dysfunction following intracerebral hemorrhage (ICH) in mice [176]. In amale mouse model of ICH, 2 doses of IP ghrelin (20 μg
total) markedly reduced ileal mucosal injury at both histological and ultrastructural levels. Ghrelin also reduced
the increase in intestinal permeability commonly seen
following ICH by upregulating intestinal tight junctionrelated proteins Zonula occludens-1 (ZO-1) and claudin-5 [176]. The activation of the mTOR has also been
implicated in the gastro-protective mechanisms of ghrelin. Zhang et al. found that ghrelin increased the phosphorylation of mTOR following superior mesentericartery (SMA) occlusion [177]. This finding did not occur
when the specific ghrelin antagonist, growth hormonereleasing peptide 6, was co-administered. Ghrelin’s ability
to activate mTOR was ultimately correlated with findingsof attenuated organ injury and increased survival in micethat received ghrelin treatment alongside SMA occlusion[177]. There are several mechanisms through which ghrelin can ameliorate both brain and gut injury following an
insult. The lack of a consistent mechanism throughout

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

the highlighted papers supports the hypothesis that ghrelin’s pleiotropy contributes to its beneficial impact.
Progesterone

Progesterone is a steroid hormone primarily producedby the gonads and the adrenal cortex that regulates uterine function and female reproduction [178]. However,research suggests that progesterone plays a role beyond
the female reproductive tract, including the CNS, where
it is secreted by neurons and glial cells. Its effects include
promoting neurogenesis and myelination and improving learning and memory [179]. The role of progesterone
has been extensively described in multiple CNS diseases
including TBI, Parkinson’s disease and AD, where it has
been labeled as neuroprotective due to its anti-inflammatory properties [180]. The therapeutic benefits of progesterone were explored in TBI [181], stroke [182] andneurodegenerative diseases’ animal models [183], whereprogesterone receptors are expressed in various CNS
cells such as neurons, astrocytes and oligodendrocytes,
in addition to Schwann cells in the peripheral nervous
system [184]. Studies have shown that early administration of progesterone post-TBI reduces the expression ofproinflammatory cytokines [185], repairs BBB [186], promotes myelin and axonal regeneration [187], attenuates
oxidative damage of mitochondria [188], and improvescognitive and motor outcomes [189]. Progesterone also
stimulates synaptogenesis and neurogenesis by increasing the expression of nerve growth factor and brainderived neurotrophic factor (BDNF) [190].
Guo et al. demonstrated that subcutaneous (SQ)
administration of progesterone (16 mg/kg) decreased
brain edema 3 days following TBI in male rats by increasing the expression of AQP4 water channels near thelesion site [186]. Other studies also revealed that progesterone attenuates the neuroinflammatory response following TBI by lowering the activation of the transcription
factor NF-κB and the expression of the proinflammatory
cytokines TNF-α and IL-1β [185, 191]. Ultimately, thisleads to a reduction in the activation of cFos, a transcription factor known to promote apoptosis and inflammation [192, 193]. Consistent with these results, Yao et al.
demonstrated that progesterone administration following moderate lateral fluid percussion injury (FPI) in malerats decreased the proapoptotic genes Bad and Bax’s
expression and increased the anti-apoptotic gene Bcl-2[194]. Furthermore, progesterone increases circulating
endothelial progenitor cells (CD31 and CD34) whichfacilitates neural regeneration and vascular remodeling, leading to improved cognitive outcomes [187]. Analternative mechanism by which progesterone exerts its
therapeutic effects involves the activation of complement

Page 11 of 31

decay-accelerating factor (CD55), a potent inhibitor of
the neuroinflammatory cascade [195].
One systematic review found that progesterone administration immediately after experimental brain injury
reduced the lesion volume [196], but a more recent systematic review showed that it did not reduce mortality
or adverse outcomes after TBI [197]. Due to the promising results of numerous preclinical studies, researchers
conducted phase II clinical trials to study the efficacy ofprogesterone in human subjects following acute TBI. In
the first phase II trial in Atlanta, GA named ProTECT,
progesterone was shown to decrease mortality on postinjury day 30 [198]. Afterward, a more extended clinical
trial was conducted in Hangzhou, China, which demonstrated improved functional outcomes and recovery
at 3 months post-injury [199]. Ultimately, two phase III
clinical trials (ProTECT III and SyNAPSe) failed to confirm the previous promising pro-regenerative results.
Nonetheless, research critics attributed its failure to thereliance on subjective measures and the lack of objective measures to accurately evaluate the outcomes. Issues
with medication dosage and the tendency to overvalue
false positive results in preclinical trials were also identified [200]. However, a notable oversight in launching
the trials was the failure to understand how progesterone affects gut motility [201] and the subsequent temporal changes in the gut’s immune profile [66, 202], which
could potentially influence neurological outcomes. Even
though Phase III clinical trials were disappointing, progesterone may still be regarded as a crucial targetedpharmacological therapy, especially in the absence of any
FDA-approved drug for treating TBIs.
Progesterone’s neuroprotective quality has led
researchers to study its role in TBI-related intestinal
dysfunction. Chen et al. showed that SQ progesterone(16 mg/kg) administration for 5 days helped preserve
ileal mucosal integrity and decrease inflammation following TBI by lowering the proinflammatory cytokines
IL-1β and TNF-α, as well as reducing cellular apoptosis [203]. Then, they also discovered that progesterone
decreased the activation of transcription factor NF-κB,
which was thought to be responsible for its therapeutic
effects [204]. Subsequent investigations revealed that the
antioxidant transcription factor nuclear factor erythroid
2-related factor 2 (Nrf2) also alleviates intestinal inflammation following TBI by decreasing the activation of
NF-κB [205], leading to the possibility that progesterone
decreases NF-κB activation by modulating the Nrf2 pathway. In addition, Jin et al. observed an elevation in intestinal permeability following TBI in Nrf2-deficient mice,
which consequently led to increased levels of plasma
endotoxins. This, in turn, resulted in decreased levels ofantioxidant and detoxifying enzymes [206]. Furthermore,El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

it is worth mentioning that Nrf2-deficient mice exhibited increased levels of intercellular adhesion molecule-1(ICAM-1) expression, while progesterone therapy successfully decreased ICAM-1 expression following TBI[204, 205]. These studies demonstrate the restorative synergistic effects of progesterone and the Nrf2 pathway inpreserving mucosal integrity. More studies are necessary
to fully elucidate the precise mechanisms underlying theeffects of progesterone on the Nrf2 pathway via progesterone receptors. Later, Zhou et al. conducted in vitro
experiments which demonstrated that progesterone
effectively reduced gut permeability by upregulating theexpression of the tight junction occludin [207]. In addition, gut dysfunction is observed in brain disorders like
subarachnoid hemorrhage (SAH) and Parkinson’s disease, and the use of progesterone has been shown to alleviate intestinal inflammation, suggesting its protectiverole in brain-gut axis dysfunction. In a male rat modelof SAH, IP administration of progesterone (16 mg/kg)
for 5 days reduced the expression of proinflammatory
cytokines IL-1β, TNF-α and IL-6 and restored mucosal
integrity in the ileum [208]. In a mouse model of Parkinson’s disease, the use of progesterone also demonstrated
anti-inflammatory effects in the ileal tissues [209]. In
conclusion, these studies demonstrate the synergistic roleof progesterone in mitigating brain and intestinal inflammation following TBI.
ANS modulators
Beta‑blockers

Catecholamines, namely norepinephrine (NE), exert theireffects through the activation of beta-receptors: beta1-3
and alpha-receptors: alpha1-2 [210, 211]. Beta1-3 receptors are found in various organs in the body, where theylead to increased cardiac contractility, increased heartrate, vasodilation, and bronchodilation. They also play arole in regulating lipolysis in white adipose tissue, thermogenesis in brown adipose tissue and mobilization ofhematopoietic progenitor cells [212]. It has been shownthat TBI patients experience sympathetic hyperactivity, causing a catecholamine surge [213–218]. This surge
causes secondary insults, which manifest as posttraumatic hyperthermia [216, 218], increased inflammationand leukocyte migration [219, 220], impaired cerebral
homeostasis and perfusion [217], and cardiovascular dysfunction [216], and has been associated with increased
mortality [221]. In light of such evidence, the use ofbeta-blockers to alleviate secondary damage caused by
TBI gained interest. Beta-blockers can be selective to
one type of receptor, such as metoprolol (beta-1 receptor blocker), or act non-selectively on all beta-receptors,
such as propranolol. Some, like labetalol (beta-1 andPage 12 of 31

2 receptor blocker), can also act on alpha-1 receptors,
thereby altering the expected outcome [212].
A study by Lopez et al. subjected male mice to severe
TBI via controlled cortical impact and tested the effectsof treating them with the non-selective beta-blocker
propranolol for two [219] and fourteen days [220]. Propranolol treatment led to decreased penumbral leukocyte
migration in a dose-dependent manner and improved
weight recovery at both timelines and decreased cerebral
edema and albumin leakage at two days. Other preclinical trials revealed decreased p-tau accumulation [222],
improved cerebral oxygenation and perfusion [212], restoration of cerebral autoregulation [217], decreased hippocampal necrosis [217], higher neurologic scores [212,219] and improved behavioral [222], cognitive and memory [223] performances with beta-blocker treatment.
Beta-blockers are hypothesized to act by (a) providing aneuroprotective environment by increasing protective
proteins, such as heat shock protein 70 (HSP-70) anddownregulating ubiquitin carboxyl-terminal hydrolase
L1 (UCHL-1), which is involved in oxidative damage[223]; (b) decreasing calcium entry into the cell, which
decreases apoptosis [223]; (c) modulating microglial
function and synaptic plasticity [224]; and (d) inhibiting
pro-inflammatory IL-6 signaling [217].
The success seen with beta-blocker treatment inpreclinical trials translated well into clinical studies.
Observational studies showed a significant decrease inmortality in TBI patients treated with beta-blockers, particularly propranolol, compared to those administeredplacebo [225] and better long-term neurologic functioning [215]. Results were associated with increased lengthof hospital stay with inconsistent results on length of ICU
stay [214, 216, 225]. The adverse effects of using betablockers included a longer time on the ventilator andincreased infection rates [214, 216]; however, both betablocker and placebo groups experienced similar rates ofcardiopulmonary adverse events such as hypotension,bradycardia, heart blocks, arrest, and bronchospasms[215]. Asmar et al. demonstrated that beta-blockers,
particularly propranolol, play a role in alleviating thedysregulation in body temperature after TBI by significantly decreasing the number of hyperthermic episodes, lowering the median temperature, and spacingout the episodes. The results were more pronounced inpatients with severe head injury, and these patients further showed decreased lengths of ICU stay and higher
Glasgow Coma Scale scores at discharge [218]. In a prospective randomized controlled trial, Khalili et al. showedthat treating patients with severe isolated TBI with propranolol resulted in decreased mortality and improved
functional outcomes at 6 months compared to placebo(Level II evidence) [226]. The Eastern Association for theEl Baassiri et al. Journal of Neuroinflammation(2024) 21:124

Surgery of Trauma (EAST) recommends the use of betablockers in adult TBI patients with no contraindications
and only in an ICU setting where cardiovascular side
effects, primarily hypotension, and bradycardia, can bemonitored and treated promptly [213].
Evidence shows that TBI is associated with increased
intestinal permeability, which correlates with increased
mortality, that is significantly reduced with beta-blocker
treatment [221, 227]. Lang et al. also showed that malerats subjected to TBI had increased epinephrine levels,
higher intestinal TNF-a levels, decreased ZO-1 protein
expression, which forms tight junction in the intestine,
and worse mucosal damage on ileum histopathology
compared to sham rats. All these changes were reversed
significantly when the rats were treated with 1 dose of
IP labetalol (beta-1 and 2 receptor blocker) right after
TBI [227]. Gut dysfunction seen in TBI can also inducechanges in the brain via NE signaling that can further
exacerbate gut dysfunction as NE plays a bidirectionalrole in the brain-gut axis. For instance, rat models showthat gastric distension induces a signification increasein NE in the ventral bed nucleus of the stria terminalis(vBNST), which is known to be involved in response tostress. In turn agonism of beta-receptors in the vBNST
leads to a significant decrease in gastric emptying andsmall intestinal transit, which is reversed with the administration of beta-blockers [228].
Alpha‑agonists/antagonists

In the setting of the brain-gut axis, alpha-adrenergic
receptor modulation remains relatively unstudied.
Despite the lack of bi-directional data on the therapeutic action of alpha receptor modulators, their action on
the brain following TBI is of significant interest in bothtranslational and clinical research settings [229, 230]. In
male rats, the alpha-2 adrenergic agonist mafedine promotes the restoration of interhemispheric connectivity
in remote brain regions and intrahemispheric connection within the unaffected hemisphere post-TBI day 7[231]. The authors also found that mafedine improved
cortical response to photic and somatosensory stimulation [231]. Alongside alpha-2 agonists, the role of alpha-1
antagonists is also being actively explored in the settingof TBI. Kobori et al. have shown that IP administration of the alpha-1 antagonist (2-[b-(4-Hydroxyphenyl)
ethyl]aminomethyl-1-tetralone hydrochloride (HEAT))(0.1 mg/kg) improved working memory in male Sprague
Dawley rats post-TBI day 14 [232]. Such studies suggestthat modulation of alpha adrenoceptors and, by extension, norepinephrine signaling may benefit TBI patients.
These findings add to existing clinical data from the
COMA-TBI study showing that elevated catecholamines
are associated with unfavorable outcomes following

Page 13 of 31

isolated moderate to severe TBI [73, 233]. Importantly
the COMA-TBI study highlights the differences in thepredictive use of both epinephrine (Epi) and norepinephrine (NE), with admission levels Epi associated withhigher rates of unfavorable outcomes and mortality andchanges in NE associated with higher mortality risks.
The differences in the predictive value of each of thesecatecholamines may well be due to their affinities foradrenoceptor sub-types.
In the clinical setting, the role of alpha-2 agonists has
been investigated extensively in the setting of severe TBI
with the hopes that these agents may attenuate sympathetic hyperactivity following brain injury [234]. Clonidine (alpha-2 agonist), in combination with propranolol,
has been studied in patients with severe TBI as it reduceslevels of circulating catecholamines and decreases levels of cerebral vasoconstriction without altering cerebral
blood flow [235]. To date, several studies, including the“DASH After TBI Study” [236] and the Nordness et al.
[237] pilot study have found that while adrenergic blockade with propranolol and clonidine is safe and feasible,
the drugs do not alter ventilator-free day numbers inpatients with severe TBI.
Statins

Since their discovery in the early 1970s, statins havebecome the mainstay treatment for patients with highcholesterol levels [238]. As research advanced, the use ofstatins expanded due to their anti-inflammatory properties where they have been shown to be effective in the
management of coronary artery disease [239], arthritis[240], brain injuries [241] and intestinal inflammation[242]. The protective role of statins in the CNS following brain injuries has been widely described [243–245].
Statins have been shown to attenuate neurodegeneration
by decreasing neuronal death, apoptosis, microglial activation and astrogliosis [246]. Statins also promote neurogenesis, synaptogenesis and angiogenesis in the brain,
particularly in the boundary zone of the lesion and the
hippocampus [247]. Studies have shown that statin use
after TBI is associated with decreased risk of death andimproved function and capacity at 12 months post-injury[248]. In a randomized double-blind clinical trial, statins
improved functional recovery at 3 months post injury,
although they had no effect on brain contusion volume[249]. Rat animal models also showed enhanced spatial
memory function with atorvastatin treatment following
TBI [250, 251]. A systematic review by Sultan et al. suggested that statins display a neuroprotective role, particularly in improving cognitive outcomes and reducing
the risk of dementia [243]. Statins were also shown to
reduce beta-amyloid peptide levels post TBI, which may

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

play a role in the improvement in cognitive outcomes anddecreasing the risk of AD in TBI patients [252].
The anti-inflammatory effects of statins are numerous,
such as reduction in the expression of proinflammatory
markers TNFα and IL-1β, as well as a decrease in theactivation of microglia and astrocytes, as evidenced by adecrease in the expression of cluster of differentiation 68(CD68) and glial fibrillary acidic protein (GFAP), respectively [253, 254]. Statins reduce astrogliosis by modulating caveolin-1 expression and epidermal growth factor
receptor in astrocyte lipid rafts [255]. Statins also upregulate the expression of vascular endothelial growth factor(VEGF) and BDNF in the dentate gyrus of the hippocampus through Akt-dependent signaling pathways, upregulating the expression of GSK-3beta and cAMP response
element-binding proteins, ultimately increasing cellular
proliferation and enhancing neurogenesis [256]. In addition, daily oral simvastatin administration (1 mg/kg/day)
reduces neuronal apoptosis following TBI in male rats
through increased Akt phosphorylation and activation ofits downstream targets, such as Forkhead transcription
factor 1, inhibitory-kappaB, and endothelial nitric oxide
synthase, while attenuating the activation of caspase-3.
All these effects lead to improved neuronal survival
and function [257]. Furthermore, statins decrease brain
edema following injury by reducing BBB permeability
due to a decrease in ICAM-1 and neutrophil infiltration[258]. Taken together, these findings suggest that statins
play a beneficial role in attenuating the neuroinflammatory response post-TBI and improving outcomes.
The protective role of statins along the brain-gut axis
is emerging. First, it is significant to note that cluster ofdifferentiation 40 (CD40), a transmembrane receptorof the tumor necrosis factor receptor family, is strongly
implicated in intestinal inflammation in various diseases
such as TBI, IRI and IBD [259]. In a rat model of TBI, Hu
et al. demonstrated that the expression of CD40 increases
in the jejunum which is positively correlated with anincrease in the activity of NF-κB and levels of TNF-α, vascular cell adhesion molecule-1 (VCAM-1) and ICAM-1[260]. Ultimately, studies revealed that one dose of IP(30 mg/kg) rosuvastatin right after TBI attenuated jejunal injury by reducing the expression of TNF-α and IL-1β
and blocking the CD40/NF-κB pathway. Statins also alleviated TBI-induced intestinal morphometric alterations
by preserving normal mucosal architecture and maintaining villous integrity [261]. Furthermore, in vivo (experimental murine colitis model) and in vitro (intestinal
epithelial cells) studies both reconfirmed the anti-inflammatory properties of statins by blocking the activity of
NF-κB, inhibiting the phosphorylation of IκB and eventually lowering the expression of TNF-α [262]. Statins havealso been shown to decrease CD40 expression in humanPage 14 of 31

vascular cells [263]. In addition, Ozacmac et al. revealed
that daily PO atorvastatin (10 mg/kg) 3 days before IRI
promoted gut motility and ileal contractility possibly due
to a decrease in oxidative stress, neutrophil accumulation and tissue malondialdehyde expression, as well as anincrease in reduced glutathione levels [264]. An alternative mechanism in which statins exert their protective
effects in the gut is by modulating the gut microbiome.
A growing body of evidence suggests that TBI alters thecomposition of the gut microbiome and promotes pathogenic bacteria over commensal bacteria mainly due tointestinal dysmotility and increased paracellular permeability, therefore, aggravating disease progression [4]. In
turn, the vagus nerve can reciprocally affect the CNS bysensing the microbial products through its afferent fibers[99]. This leads to a deleterious cycle between the injured
brain and the dysbiotic gut. One possible way to halt thisinflammatory cycle is through the use of statin therapy.
Statins have been shown to promote healthy gut flora andameliorate gut dysbiosis [265]. Studies have also shownthat statins demonstrate anti-inflammatory effects in IBD
and are linked to a decreased requirement of steroids[242, 266]. The potential use of these drugs is promisingand interesting. More studies are encouraged to better
elucidate how statin therapy regulates the brain-gut axis
in the context of TBI.
Microbiome modulators
Antibiotics

Recent investigations indicate that gut microbial dysbiosis impacts intestinal function not only in diseases
like IBS and IBD but also in neurologic conditions suchas TBI and strokes [267, 268]. TBI promotes the presence of pathogenic bacteria over commensal bacteria,leading to heightened intestinal inflammation, increased
barrier permeability and dysmotility [93, 268]. To gaina better understanding of alterations in the microbiome
and their implications on brain inflammation after TBI,
studies have utilized various antibiotic combinations todeplete the microbiome, in addition to the administration of beneficial probiotic strains to promote a healthy
intestinal flora. Many animal studies initially utilized
germ-free (GF) mice to elucidate relation between microbial dysbiosis and the host’s physiologic response [71,269]. A study by Simon et al. demonstrated that administering a combination of antibiotics (1 g/L of ampicillin,
metronidazole, neomycin and vancomycin) two weeks
before TBI in male mice improved intestinal barrier
permeability, as evidenced by increased ZO-1 staining
along the cecum epithelium. This resulted in decreased
microglial activation, increased hippocampal neuronaldensity, reduced lesion volume, and improved learning
outcomes [269]. Conversely, another study by Celorrio

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

et al., using the same antibiotic regimen for two weeks
before injury, showed worsened neuronal loss in the hippocampus, triggering a more pronounced fear response
in adult male mice [202]. The opposing outcomes may
be attributed to various factors, including differencesin mice intestinal flora in distinct animal facilities, variations in diet impacting the host microbiome, and differences in injury severity and time points of behavioral
analysis [270, 271]. Celorrio et al.’s study also revealed
the intricate interplay between the gut microbiome andthe immune system. Antibiotic administration for 1 week
after TBI reduced the infiltration of peripheral monocytes and T-lymphocytes into the brain while increasing
microglial inflammatory markers 3 days after injury. The
heightened expression of proinflammatory surface markers (TLR4 and MHCII) by microglia, along with alterations in their morphology toward an amoeboid shape,correlated with decreased neurogenesis in the dentate
gyrus and increased neuronal degeneration in the CA3
region of the hippocampus [71, 202]. Benakis et al. also
demonstrated that alterations in the intestinal flora ofmale mice induced by a two-week course of amoxicillinclavulanic acid (1 g/L) resulted in reduced ischemic brain
injury. This reduction was attributed to an increase inintestinal regulatory T-cells and a decrease in the infiltration of IL-17 + γδ T cells into the brain, observed 16
h post-injury [70]. Targeting the gut-microbiota-immune
axis offers a promising approach to improve recovery following TBI.
Probiotics

In an effort to better understand microbiome changes,
the administration of probiotics has been widely experimented in TBI models. Probiotics regulate microbial
populations in the gut lumen by favoring the colonizationof beneficial bacteria and reducing pathogenic populations [272]. They enhance epithelial cell differentiationand proliferation and maintains epithelial barrier integrity, thereby limiting the translocation of harmful bacteria into the intestinal parenchyma [273]. A study by Ma
et al. showed that the supplementation of probiotics,
specifically LA for 7 days after weight-drop TBI, has protective effects on the ileum after TBI. This was revealed
by improvements in intestinal barrier function and the
gut’s absorptive capacity for nutrients and electrolytes[274, 275]. The effects of LA also included improvements
in ileal villous architecture and enhanced ileal motility through the restoration of the gut’s pacemaker cells,
known as the interstitial cells of Cajal (ICC), by increasinglevels of myosin light chain kinase protein and promoting
smooth muscle contraction [276]. Lactobacillus reuteri
was also utilized in clinical trials involving military veterans with mild TBI. Results demonstrated significant

Page 15 of 31

reductions in serum inflammatory C-reactive protein
levels in patients taking Lactobacillus reuteri daily for
8 weeks compared to the placebo group [277]. Furthermore, a systemic review and meta-analysis conducted by
Du et al. showed that early enteral nutrition with probiotics after TBI reduced mortality and decreased GI complications such as constipation, abdominal distention, reflux
and stress ulcers [278].
Probiotics also stimulate the release of SCFAs, suchas acetate, butyrate, and propionate, into the peripheral
circulation which can ultimately cross the BBB and ameliorate brain inflammation by decreasing the expressionof proinflammatory cytokines and promoting neurogenesis [279–281]. A study by Li et al. demonstrated theneuroprotective effects of Clostridium butyricum (Cb), a
butyrate-producing probiotic, after TBI via the brain-gut
axis by increasing the levels of GLP-1 and glucagon-like
peptide 1 receptor in the colon. Intragastric Cb supplementation ­(109 CFU/ml), once daily for 2 weeks pre andpost-TBI, improved neurological outcomes in male miceby attenuating neurodegeneration, decreasing apoptosis and enhancing BBB integrity [282]. In parallel, theadministration of the probiotic Lactobacillus acidophilus (LA) (1 × ­1010 CFU) for 7 days after weight-drop TBI
shifts the microbiome towards a healthier profile in malemice. LA improved neurological outcomes by decreasing
the activation of astrocytes and microglia, and reduced
brain edema by preserving the BBB integrity. LA supplementation also decreased the expression of gram negative bacteria receptors in the brain, mainly TLR4 [275].
Last, a randomized clinical trial showed that the dailyadministration of a combination of probiotics (Bifidobacterium longum, Lactobacillus bulgaricus, Streptococcus thermophilus) for 21 days after severe TBI attenuatedsystemic inflammation by lowering the levels of IL-4 andIL-10 and reducing the risk of nosocomial infections[283].These studies emphasize the link between the hostgut microbiome and immune responses in the brain following TBI. The utilization of antibiotics/probiotics holds
substantial therapeutic potential in TBI management,with further studies warranted to better elucidate theireffects on brain inflammation and behavioral outcomes.
Microbial metabolites

Studies have also revealed that TBI induces alterations
in gut microbial metabolites, including SCFAs and bile
acids. Among these metabolites, SCFAs such as butyrate,
propionate and acetate play a crucial role [284]. They
serve as alternative energy sources for the injured brain
and help regulate mitochondrial homeostasis [285].
A study by Opeyemi et al. demonstrated a significant
decrease in fecal SCFAs concentrations 24 h and 28 days
post-TBI in adult male mice. This decrease correlated

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

with worse learning outcomes, while the administrationof SCFAs improved spatial learning in these mice [286].
Furthermore, the role of bile acids has been studied invarious neurological diseases, such as intracranial hemorrhage and ischemic stroke [287, 288]. The administration of tauroursodeoxycholic acid has been shown to
improve neurologic function and decrease infarct size
two and seven days after reperfusion [289]. In the context of TBI, You et al. demonstrated decreased levels ofbile acids in serum and fecal samples one day after TBI
in adult male mice [268]. Moreover, Zhu et al. conducteda prospective study which showed decreased levels ofplasma bile acids in TBI patients [290]. Therefore, supplementation of microbial metabolites byproducts suchas bile acids and SCFAs present promising therapies for
mitigating neuroinflammation post-TBI.
Mycobiome

In addition to the dominant bacterial microbiome, thegut mycobiome (fungal microbiome) emerges as anothercrucial therapeutic target, regulating brain-gut homeostasis. Imbalances in the mycobiome have been observedin various intestinal diseases including IBS [291], IBD[292] and colorectal cancers [293]. Visceral hypersensitivity in IBS has been associated with increased fungal dysbiosis [294]. While their role is still understudied
in traumatic brain injury, a recent prospective observational cohort study conducted by Park et al. revealed
dysregulated mycobiome balance in critically ill trauma
and sepsis for up to two to three weeks after intensive
care unit hospitalizations. Dominance in Candida spp
population and reduction in commensal fungal species
correlated with heightened vulnerability to infections[295]. Interestingly, another study by Hunag et al. demonstrated that changes in gut mycobial abundance inmice three days post-TBI were linked to dysfunctional
regulation of ­N6-methyadensoine ­(m6A), which is crucial
in posttranscriptional modification of eukaryotic mRNA[296]. Given the intricate relationship between bacterial
and fungal microbiomes, more studies are warranted
to better understand the role of fungemia, particularly,
candidemia, in TBI patients, and how modulating the
mycobiome can modulate neurologic outcomes.
Current limitations

Human and animal studies are pivotal in investigating
microbiome alterations and their impact on neurological outcomes following TBI [297, 298]. Various methodologies are utilized to detect these changes, including
the administration of antibiotics [299], probiotics [283],
SCFAs [300], and the use of fecal microbiome transplant[301]. Studies on the impact of antibiotics are particularly
crucial, given that some patients with open head injuries

Page 16 of 31

and polytrauma necessitate antibiotic administration[302, 303], yet the neurological consequences of suchinterventions remain poorly understood. Very few clinical studies have examined the impact of antibiotics on
TBI outcomes and there are currently no general guidelines on the administration of antibiotics [299]. In thecontext of TBI-induced gut microbial dysbiosis, there isa need to develop well-controlled clinical trials to explore
the effects of antibiotic administration on changes in
infection rates and neurological outcomes over the
long-term.
A primary challenge in microbiota research in TBI
originates from the widespread variability in sample
collection and processing methods, including targeted
sequencing and metagenomic sequencing [304]. Moreover, the heterogeneity in individual’s dietary patterns
and pre-existing microbiome diversity present additional challenges in detecting microbiome variations[305]. Although preclinical animal models offer controlled experimental conditions such as standardized
environments, their findings pose challenges in translational efforts [306]. Another significant aspect is the timerequired for probiotics to exert their effects on neurocognitive outcomes, potentially spanning years [307]. Thus,
well-designed long-term clinical trials are necessary
to fully comprehend the impact of microbiome in TBI.
Addressing these limitations is essential for developing
effective therapeutic interventions.
Tables 1 and 2 present a summary of various antiinflammatory agents that attenuate brain and gut inflammation following TBI.

Brain‑gut axis dysfunction in military veterans
Military veterans provide a unique human model forstudying the impact of traumatic brain injuries on the gut
in a realistic environment [308]. Following military occupational training involving blast exposure, a significant
increase in intestinal permeability and evidence of gut
bacterial translocation into the circulation were observed
1 to 16 h later, accompanied by a stepwise increase inalpha microbial diversity and elevated levels of intestinal permeability protein biomarkers such as zonulin andoccludin-3 [309]. Additionally, another study involving
26 male Operation Enduring Freedom/Operation Iraqi
Freedom/Operation New Dawn (OEF/OEI/OND) veterans revealed that differences in gut microbial composition, specifically Verrucomicrobiota, correlated withpsychiatric and cognitive symptoms, including fatigue,
depressive symptoms, and PTSD severity, as well as difficulties with attention, executive function, learning andmemory [310]. These findings emphasize the intricate
relationship between gut microbiota and mental healthin veterans. Furthermore, research on Gulf War veteransProgesterone

GhrelinMale

SNRIs (Milnacipran) 30 mg/kg/
day via IP osmotic minipumps
until sacrifice

Male

Male

IP Progesterone (8 mg/kg) and Allopregnanolone (4 mg/kg) for 5 days
post-TBISQ Progesterone (16 mg/kg) dailyfor 14 days post-TBI

Male

3 doses of IP des-acylated ghrelin (1mg/kg) on same day after stroke

Male

N/A

1 dose of IV ghrelin (20 μg/kg) 30
min after injury

3 doses of SQ Progesterone (16 mg/kg) 6, 24 and 48 h post-TBI

Male

2 doses of IP ghrelin (20 μg total),
one hour before and right after TBI

PO SSRIs (sertraline) 50 mg dailyMalefor 24 weeks to patients with history
of TBI

N/A

IP SSRIs (fluoxetine) 5 mg/kg, single
dose immediately after injury

Serotonin

Sex

Intervention

Therapy

Rats

Rats

Rats

Mice

Rats

Mice

7 days post-TBI

Timepoints

Single unilateral moderate TBI (FPI)

Bilateral, severe TBI (CCI)

Bilateral TBI (CCI)

Transient middle cerebral artery
occlusion (tMCAo)Single unilateral TBI (CCI)

Single unilateral TBI (WD)

2 weeks post-TBI

6 days post-TBI

72 h post-TBI

24 h post-stroke

24, 48 and 72 h post-TBI

6 h post-TBI

24 weeks post-treatment

Single unilateral, moderate TBI (CCI) 5 weeks post-TBI

Single unilateral, severe TBI (CCI)

Humans Moderate-Severe TBI

Rats

Mice

Species Model

Table 1 Summarized findings of the impact of various pharmacotherapies on TBI-induced neuroinflammation

Improves neurological outcomeson MWM test and induces vascularremodeling in the injured parietal lobe by increasing circulating
endothelial progenitor cells [187]Reduces expression of proinflammatory cytokines IL-1B and TNF-ain the frontal lobe [185]Reduces brain edema by decreasing the expression of peri-contusion
AQP-4 channels in the injured cortex[186]

Reduces infarct size, decreases
apoptosis and maintain BBB integrityby upregulating tight junction
proteins occludin and claudin-5
in the ischemic cerebral hemisphere[167]

Reduces brain inflammationand improves neurological severity
score by decreasing basic fibroblast
growth factor (bFGF) in the injured
cortex [162]Prevents BBB disruption by decreasing vascular permeability and AQP-4
expression in the injured areaof the cortex [159]Significant improvement in moodand depressive symptoms [119]Enhancement of serotonergic tonein the medial prefrontal cortex
and improvement of attentional setshifting task performance [111]Improved motor recovery and coordination on rota-rod [117]Impact on Brain Inflammation

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124
Page 17 of 31

Male

IP propranolol (4 mg/kg) daily for 7
days post-TBI

Rats

Mice

Male

2 doses of PO simvastatin (37.5 mg/kg) 1 and 6 h post-TBI

Male
Antibiotics/probiotics PO ampicillin, metronidazole, vancomycin, neomycin (1g/L) daily for 2
weeks pre-TBI

Mice

Male

PO gavage lactobacillus acidophilus(1 × ­1010 CFU) one daily until sacrificed

2 and 14 days post-TBI

4 h post-TBI

Timepoints

Single unilateral TBI (WD)Single TBI (WD)Single unilateral TBI (CCI)

Single unilateral moderate TBI (FPI)

Single unilateral TBI (CCI)

Single TBI (CCI)

Improves memory, learningand cognition by reducing cell deathin the hippocampal-CA1 area [223]

Reduces edema and preserves
cerebral BBB permeability in a dosedependent manner [219, 220]

Decreases hippocampal neuronal
death by downregulating IL-6 expression [217]Impact on Brain Inflammation

1,3 and 7 days post-TBI

2 weeks post-TBI

3 days post-TBI

24 h post-TBI

Decreases the activation of astrocytes
and microglia in the injured cortex
and reduces brain edema by preserving the BBB integrity [275]

Improves neurological dysfunction, decreases brain edema
and reduces neuronal degeneration
around the lesion site [282]Increases hippocampal neuronal density and reduces lesion volume [269]

Reduced brain edema by preserving
BBB integrity through upregulating
claudin-5 [258]

1, 3, 7, 14, and 35 days post-TBI Improves spatial learning and promotes neurogenesis by increasing
VEGF and BDNF expression in the ipsilateral hippocampus through Aktdependent signaling [256, 257]

1, 3, 7, 14, and 35 days post-TBI Downregulates the expression of inflammatory cytokinesand decreases the activation of astrocytes and microglia around the lesion
boundary zone [253]Single unilateral moderate TBI (CCI) 7 days post-TBI

Single severe TBI (CCI)

Single moderate TBI (FPI)

CCI, controlled cortical impact; WD, weight drop; FPI, fluid percussion injury; TBI, traumatic brain injury

Mice

Male

Intragastric gavage of Clostridium
butyricum ­(109 CFU/ml) once dailyfor 2 weeks pre and post-TBI

Rats

Male

PO Simvastatin (1 mg/kg/day) daily
until sacrifice

Rats

Male

Mice

PO Simvastatin (1 mg/kg/day) daily
until sacrifice

StatinsMale

IP propranolol (1–4 mg/kg) dailyfor 2 and 14 days post-TBI

Mice

Male and Female Pigs

1 dose of IV propranolol (1 mg/kg)
1 h post-TBI

Species Model

Beta-blockers

Sex

Intervention

Therapy

Table 1 (continued)

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124
Page 18 of 31

Rats
Mice

Male

1 dose of IV ghrelin (20 μg/kg) 30 min
after TBI

2 doses of IP ghrelin (20 μg total) right Maleafter ICH

Statins

Beta-blockers

ProgesteroneMice

2 doses of IP ghrelin (20 μg total), one Malehour before and right after TBI

Single unilateral TBI (WD)

Subarachnoid hemorrhage (SAH)

Single unilateral TBI (WD)Single unilateral TBI (WD)Intracerebral hemorrhage (ICH)

Single unilateral severe TBI (CCI)

Single unilateral, severe TBI (WD)Single unilateral, severe TBI (CCI)

Model

Male

Male

PO atorvastatin (10 mg/kg) daily 3days before inducing ischemia

Rats

Rats

Intestinal ischemia reperfusion injury(IRI)

Single unilateral TBI (WD)Male and Female Drosophila Closed head TBI using high-impact
trauma device

One dose of IP rosuvastatin (30 mg/kg) right after TBI

PO labetalol (62.5 μM in 1 M sucrose)
after TBI

Rats

Rats

IP progesterone (16 mg/kg) daily for 5 Male
days post-SAH

1 dose of IP labetalol (30 mg/kg) right Maleafter TBI

Rats

Male

SQ progesterone (16 mg/kg) daily
for 5 days post-TBI

Rats

Male

SQ progesterone (16 mg/kg) daily
for 5 days post-TBI

Mice

Ghrelin

N/A

SSRIs (IP fluoxetine) 5 mg/kg, single
dose immediately after injury

Species

Serotonin

Sex

Intervention

Therapy

Table 2 Summarized findings of the impact of various pharmacotherapies on TBI-induced gut inflammation

3 h post-reperfusion

24 h post-TBI

24 h post-TBI

3, 6, and 12 h post-TBI

5 days post-SAH

5 days post-TBI

5 days post-TBI

1 day post ICH

1–3 days post-TBI

6 h post-TBI

4 days post-TBI

Timepoints

Promotes ileum motility possibly
through reducing oxidative stressand increasing glutathione levels [264]

Downregulates jejunal TNF-α and IL-1β
levels and enhances villous histology
by blocking the CD40/NF-κB pathway[261]

Reduces intestinal permeability
and early mortality [221]Decreases hyperactivity of adrenergic
tone, reduces intestinal TNF-α levels,and prevents an increase in ileum
permeability [227]

Restores ileum mucosal integrity
and reduces proinflammatory
cytokines IL-1β, TNF-α and IL-6 [208]Reduces ileum NF-κB activationand proinflammatory cytokines expression [204]

Downregulates the expressionsof ileum TNF-α, IL-1β, and ICAM1
and reduces mucosal apoptosis [203]

Reduces ileal permeability by upregulating tight junctions ZO-1 and claudin-5 [176]

Improves intestinal motility and protects ileum mucosal epithelium [175]

Maintains ileal barrier integrity
and architecture and decreases TNF-αlevels [171]Preserves colonic barrier integrityby reducing FITC-dextran permeability[117]

Impact on gut inflammation

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124
Page 19 of 31

Male

Male

Male

Antibiotics/probiotics PO ampicillin, metronidazole, vancomycin, neomycin (1g/L) daily for 2
weeks pre-TBI

PO gavage lactobacillus acidophilus(1 × ­1010 CFU) one daily until sacrificed

PO gavage lactobacillus acidophilus(1 × ­1010 CFU) one daily until sacrificed
Mice

Mice

Mice

SpeciesSingle unilateral TBI (WD)Single unilateral TBI (WD)Single unilateral TBI (CCI)

Model

CCI, controlled cortical impact; WD, weight drop; FPI, fluid percussion injury; TBI, traumatic brain injury; N/A, not available

Sex

Intervention

Therapy

Table 2 (continued)

Improves intestinal permeability
by increasing epithelial ZO1 expression
in the cecum [269]Impact on gut inflammation

1,3 and 7 days post-TBI Improves ileum barrier function
and gut’s absorptive capacity for nutrients and electrolytes [275]

1,3 and 7 days post-TBI Reduces ileum inflammation, maintains
barrier integrity, and promotes gut
motility through PKC/MLCK/MLC signaling pathway [276]

3 days post-TBI

Timepoints

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124
Page 20 of 31

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

indicated that a higher abundance of phyla Bacteroidetes,
Actinobacteria, Euryarchaeota, and Proteobacteria, as
well as higher abundances of the families Bacteroidaceae,
Erysipelotrichaceae, and Bifidobacteriaceae, correlatedwith increased GI symptoms severity and higher levels of
the inflammatory cytokine TNF-α, alongside reports ofchronic pain, fatigue and sleep difficulties [311]. The Veterans in the US Veteran Microbiome Project (US-VMP)
demonstrated a significant association between microbiome composition, episodes of gastroenteritis and symptoms of severe depression [312]. Additionally, an RCT
conducted on OEF/OEI/OND veterans revealed thatdaily administration of Lactobacilli Reuteri for 8 weeks
resulted in a decrease in plasma CRP levels compared
to untreated groups, indicating the potential of microbiome-targeted interventions in mitigating post-TBI
inflammation [277]. Conversely, some studies on US military veterans and US Marines did not find significant differences in gut microbial diversity and permeability after
moderate/severe TBI [313, 314]. These conflicting findings underscore the complexity of studying the microbiome in real-world settings. Numerous limitations exist insuch studies due to challenges in identifying true control
participants, variations in the timing of stool collection,and differences in diet regimens and medications, whichsignificantly impact the microbiome [313]. Efforts toaddress these limitations and refine study methodologies
are crucial for advancing our understanding of the braingut axis in the context of TBI in military populations.

Why do TBI treatments keep failing?
Despite extensive TBI research and significant investment in various therapies, there remains a lack of effective treatments to attenuate disease progression [315].
Many clinical trials have failed to replicate the antiinflammatory effects observed in preclinical animal models due to several challenges [316]. First, TBI is inherently
heterogenous and triggers complex pathogenic pathways,
rendering it a highly intricate disease to manage [317]. In
basic science, most of the research is focused on specificcellular processes in the brain, often missing the broader
picture of the disease [316]. Additionally, each model utilizes different injury paradigms and anatomical locations
to induce injury. It is essential to recognize that focal
contusion, concussion, and blast injuries elicit distinct
inflammatory pathways in response to injury [318]. The
tendency to extrapolate inflammatory models from focal
contusion to concussion and blasts presents a significant
issue due to each injury type’s unique inflammatory profiles [319, 320].
Another key challenge in TBI research is the overrepresentation of males in both clinical trials and preclinical models [321]. Sex differences in TBI responses are

Page 21 of 31

evident, with males showing better recovery in clinical
trials and females exhibiting superior outcomes in preclinical studies [322]. Emerging evidence suggests the
crucial role of sex in brain-gut homeostasis by modulating the gut microbiota and immune system activation[323, 324]. Animal studies reveal notable differencesin gut microbiome composition between males andfemales, with females demonstrating greater diversity[325, 326]. Although the impact of sex on the microbiome in TBI is underexplored, studies in other diseases
suggest that females are more susceptible to autoimmune
diseases due to microbial alterations [327, 328]. Similarly,
the higher prevalence of IBS in women may be linked
to microbiome changes driven by estrogen-mediatedresponses or compromised gut barrier function [329]. To
comprehensively understand the sex’s impact on braingut axis, clinical trials and animal models with more
female representation are warranted.
The complexity of immune response post-TBI presents
another challenge [330]. The evolution of immune cell
activation over time involves both beneficial and detrimental components, making attempts to target specificimmune pathways often unsuccessful [331]. Furthermore,
the existing classification of M1/M2 microglia basedon in vitro cell culturing excludes the diverse array ofcytokines and cellular signals encountered by these cells
in vivo, particularly in a complex disease like TBI [332].
A shift away from M1 and M2 classification towards
incorporating transcriptomic and proteomic profilingfor better analysis is needed [333]. Additionally, inflammation in TBI is not confined to the CNS; there is also
global systemic immune dysfunction that remains understudied [57]. The gut, which harbors the largest immune
reservoir, exhibits significant alterations in macrophageand T-cell immune profile, necessitating a better understanding of interactions between intestinal immunity andbrain immune cells [4, 66].
Most drugs lose efficacy with increasing intervals
between injury time and initiation of treatment [334].
Moreover, certain treatments, such as probiotics,
require prolonged administration periods, potentiallyspanning years before cognitive improvements areobserved [307]. The therapeutic time window in treatment of TBI remains a significant focus of investigation to advance the development of TBI therapies andsuccessfully translate from preclinical to clinical settings [335]. While animal models often receive therapy
immediately after injury, clinical trials at specialized
trauma centers typically enroll patients 4–7 h after
moderate to severe TBI [336]. Additionally, individuals with mild injuries may delay treatment until they are
symptomatic, which may occur years after injury [337,338]. The significance of the therapeutic time window

El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

was underscored by the failure of progesterone treatment in phase III clinical trials PROTECT and SYNAPSE [339]. Both trials recruited patients within 4 and7 h after TBI, respectively, failing to replicate the benefits observed in preclinical animal models where progesterone was administered within an hour of injury[340]. These clinical trial failures highlight the importance of therapeutic window in initiating treatment.
Preclinical models are encouraged to investigate drug
efficacy with progressively delayed dosing post-injury
to simulate real-life settings.
In addition to treatment timing, understanding the
optimal duration of treatment is essential for elucidating long-term outcomes [341]. While some drugs,
such as beta-blockers, have demonstrated significant
improvements with short-term administration, evenas brief as two days or two weeks, others, like probiotics, may require prolonged treatment periods to exert
neuroprotective effects, especially for chronic conditions like TBI [219, 220, 277, 342]. A comprehensive
understanding of the temporal and spatial dynamics
of immune, hormonal and neural pathways within thebrain-gut axis is imperative for evaluating the effects
of chronic treatment regimens post-TBI [343]. Current
animal studies predominantly focus on acute changes,
missing potential chronic alterations that may influence drug efficacy and subsequent neurologic outcomes[15]. Persistent microbiome alterations observed foryears post-TBI emphasize the potential necessity forextended treatment durations to mitigate brain injury
consequences [89]. Studying the therapeutic window
for treatment, the duration of treatments, and theirimpact on brain-gut homeostasis is crucial for thedevelopment of successful TBI therapies [334].
In clinical trials, numerous challenges are encountered, including the nonuniform population of patientswith comorbid diseases and ethical considerations for
randomization [344]. Additionally, the classificationof mild-moderate-severe TBI is overly broad and fails
to account for radiological and clinical findings, making it subjective [345]. Improved classifications systems
are necessary to address this issue. The recent FDA
approval for Abbott’s i-STAT TBI cartridge, designed
to identify blood biomarkers such as GFAP and UCHL1 within just 15 min at the patient’s bedside, promises more objective results to stratify injury severity
and tailor management away from the conventional
mild-moderate-severe classification [346]. Last, thereliance on monotherapy to treat such a complicateddisease compound the challenges [347]. There should
be greater emphasis on targeting various pathways inthe brain and gut at the same time to effectively manage
this complex disease.

Page 22 of 31

Conclusion
In conclusion, we present the first comprehensive review
of various pharmacotherapies targeting inflammation
along the brain-gut axis in TBI, which include hormonessuch as serotonin, ghrelin, and progesterone, alongside
ANS modulators like beta-blockers and alpha-adrenergic
agonists, antilipidemic agents such as statins, and intestinal flora modulators such as probiotics and antibiotics (summarized in Tables 1 and 2). They enhance gut
function by mitigating inflammation, preserving intestinal barrier integrity, promoting motility and favoringa healthy microbiome. Importantly, these pharmacotherapies also impact neurological outcomes directly bycrossing the BBB or indirectly by modulating immune,
hormonal and neural pathways.
With the gut serving as the largest immune reservoir,
housing the body’s second “little brain”-the ENS [348],
and hosting a diverse microbiome, it emerges as a focal
point in understanding TBI pathogenesis. Deciphering
the complex interplay between microbial dysbiosis, ENS
disruption, EEC dysfunction, ANS dysregulation andintestinal immune cell activation is crucial to develop
successful TBI therapies, which have been elusive for decades. This entails understanding the temporal changes in
immune system activation across the brain and the gut,
as well as elucidating the effects of gut microbial metabolites and hormones, and the role of autonomic nervous
system and systemic inflammation in the pathophysiological process of acute and chronic TBI.
Abbreviations
TBI	Traumatic brain injury
GI	Gastrointestinal system
ENS	Enteric nervous system
ANS	Autonomic nervous system
ICP	Intracranial pressure
DAMP	Damage-associated molecular pattern
ROS	Reactive oxygen species
BBB	Blood–brain-barrier
AQP4	Aquaporin 4ATP	Adenosine triphosphate
Bcl-2	B-cell lymphoma 2
ICU	Intensive care unit
HPA	Hypothalamic–pituitary–adrenal
Ccr2	C–C chemokine receptor type 2
TNF-α	Tumor necrosis factor alphaIL-1β	Interleukin-1 beta
TLR4	Toll-like receptor 4
EGC	Enteric glial cellAch	Acetylcholine
α7nAChR	α7 Subtype of the nicotinic acetylcholine receptor
EEC	Enteroendocrine cell
VNS	Vagus/Vagal nerve stimulation
IBD	Inflammatory bowel disease
IBS	Irritable bowel syndrome
CNS	Central nervous system
GLP-1	Glucagon-like peptide 1
ChgA	Chromogranin A
Lgr5	Leucine-rich repeat-containing G-protein coupled receptor 5
Notch1	Notch receptor 1
Atoh1	Atonal bHLH transcription factor 1El Baassiri et al. Journal of Neuroinflammation(2024) 21:124

Neurog3	Neurogenin 3
TPH	Tryptophan hydroxylase
SSRI	Selective serotonin reuptake inhibitor
SNRI	Serotonin-norepinephrine reuptake inhibitor
ICC	Interstitial cells of Cajal
IP	Intraperitoneal
FGF	Fibroblast growth factor
FGF-BP	FGF-binding protein
bFGF	Basic FGF
PI3K	Phosphoinositide 3-kinase
PIP3	Phosphatidylinositol 3,4,5 trisphosphate
PIP2	Phosphatidylinositol 3,4 bisphosphate
Pkb/Akt	Protein kinase B
IRI	Ischemia–reperfusion injury
SCI	Spinal cord injury
mTOR	Mammalian target of rapamycin
WD	Weight drop
ICH	Intracerebral hemorrhage
SMA	Superior mesenteric artery
BDNF	Brain-derived neurotrophic factor
CD55	Complement decay-accelerating factor
Nrf2	Nuclear factor erythroid 2-related factor 2
ICAM-1	Intercellular adhesion molecule-1
SAH	Subarachnoid hemorrhageNE	Norepinephrine
HSP-70	Heat shock protein 70
UCHL-1	Ubiquitin carboxyl-terminal hydrolase L1
ZO-1	Zonula Occludens-1
vBNST	Ventral bed nucleus of the stria terminalis
AD	Alzheimer’s disease
CD68	Cluster of differentiation 68
GFAP	Glial fibrillary acidic protein
VEGF	Vascular endothelial growth factor
GSK-3beta	Glycogen synthase kinase-3beta
CD40	Cluster of differentiation 40
VCAM-1	Vascular cell adhesion molecule-1
SCFA	Short-chain fatty acidCb	
Clostridium butyricumLA	
Lactobacillus acidophilus
Acknowledgements
Not applicable.
Author contributions
M.G. El Baassiri and I.W. Nasr conceptualized the review and prepared themanuscript. Z. Raouf, S. Badin and A. Escobosa assisted in preparing themanuscript. M.G. El Baassiri, C.P. Sodhi and I.W. Nasr made critical suggestions,reviewed, and prepared the manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.

Declarations
Ethics approval and consent to participate
The Institutional Animal Care and Use Committee (IACUC) approved animal
protocol (Protocol # MO22M233), and experiments have been carried out instrict adherence to the National Institutes of Health Guidelines for the Use ofLaboratory Animals.
Consent for publication
Not applicable.
Competing interests
The authors declare they have no competing interests.

Page 23 of 31

Received: 29 February 2024 Accepted: 30 April 2024

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