Role of the Gut-Brain Axis in Severe Traumatic Brain Injury: Insights from Experimental Models and Clinical Studies

Keywords

traumatic brain injury - gut microbiome - dysbiosis - neuroinflammation - gut-brain axis - microbiome-based interventions

Introduction

Traumatic brain injury (TBI) represents a major global health challenge, contributing significantly to mortality and long-term disability across all age groups. The complications that arise from TBI are not limited to the brain but also cause widespread inflammation that affects various bodily systems including the gastrointestinal (GI) tract. To properly manage TBI, it is important to address both the initial injury and prevent further complications, which could be targets for treatment.

Recent investigations have highlighted the significance of the gut-brain axis, a bidirectional communication network linking the central and enteric nervous systems (ENSs), in mediating systemic immune responses following neurological diseases.[1] [2] [3] [4] The gut microbiome is a complex community of microorganisms residing in the GI tract that plays a crucial role in maintaining host health through various mechanisms, including immune system modulation and the production of essential metabolites.[5]

Gut dysbiosis, characterized by an imbalance in the composition and function of the gut microbiota, has been implicated in a growing list of neuropathologies, including Parkinson's disease, autism, Guillain–Barre syndrome, anxiety, and depression. This highlights the far-reaching consequences of this microbial imbalance.[6] [7]

Mild TBI has been linked with changes in gut metabolism soon after the injury. These changes directly affect the intestinal mucosa, including the loss of tight junctions, contributing to increased intestinal permeability.[7] Although noticeable changes in gut metabolism and a weakening of the intestinal barrier, leading to increased permeability, have been reported following severe TBI (sTBI),[8] [9] there is a noticeable knowledge gap pertaining to the effect of gut microbiome dysbiosis on patient outcome following sTBI. Understanding the profound impact of gut dysbiosis on the pathophysiology of sTBI necessitates a comprehensive exploration of the intricate relationship between the gut microbiome and the central nervous system (CNS).

Scope of the review: This review provides a comprehensive analysis of gut microbiome dysbiosis in sTBI, focusing on microbial composition changes, their impact on patient outcomes, and potential therapeutic interventions. Given the scarcity of human clinical studies and the near absence of microbiome-targeted interventions for sTBI, this review highlights key knowledge gaps. It explores future directions for integrating gut microbiota modulation into TBI care.

Materials and Methods

This review presents findings from both human and experimental studies investigating gut microbiota alterations in sTBI, covering literature published between 2019 and 2025 (February). A systematic search was conducted across scientific databases, focusing on studies that characterized the gut microbiome in the context of sTBI. The search strategy employed the following terms: “brain injury and faecal microbiome AND association,” “brain injury and gut microbiome AND association,” “TBI and gut microbiome AND alteration,” and “probiotics OR prebiotics AND brain injury OR TBI AND microbiome AND microbiota AND alteration.” To ensure focus on severe cases, only studies explicitly detailing sTBI in either experimental or clinical settings were included.

The selection process involved initial screening of titles and abstracts, followed by a thorough review of full-text articles to determine eligibility. Peer-reviewed studies that documented gut microbiome profiles in sTBI patients or animal models were prioritized. Data extraction included study characteristics, microbiome assessment techniques, and key findings related to gut microbiota changes and their association with sTBI outcomes. Reference lists of selected articles were also examined to identify additional relevant publications. Exclusion criteria included studies that lacked specific data on sTBI, were review articles, focused on other brain injuries, were not in English, or had incomplete data.

Mechanisms Linking Gut Dysbiosis to TBI Pathophysiology

Following TBI, the delicate balance of forces within the GI tract is significantly disrupted, leading to potential damage. This imbalance stems from TBI-induced disruptions in protective mechanisms, such as mucosal blood flow and epithelial turnover, coupled with increased destructive forces like acid secretion and bile acid overproduction. Consequently, bacterial translocation and systemic inflammation ensue, potentially exacerbating brain injury.[10] [11] TBI triggers a stress response, elevating cortisol and catecholamine levels, which compromise gut barrier integrity and facilitate bacterial translocation. This process induces systemic inflammation, marked by increased proinflammatory cytokines.[9] Chronic stress post-TBI suppresses immune function, increasing infection susceptibility and complicating recovery. Prolonged stress responses contribute to immune aging and neurodegeneration by altering microglial phenotypes, perpetuating neuroinflammation[12] ([Fig. 1]).

Fig. 1 Traumatic brain injury (TBI)-induced alterations in brain-gut communication. Schematic representation of how TBI disrupts bidirectional signaling between the brain and gut, leading to neuroinflammation, dysbiosis, and systemic immune activation.

Beyond the hypothalamic-pituitary-adrenal axis, the autonomic nervous system significantly influences gut function post-TBI. Sympathetic hyperactivity leads to excessive catecholamine release, impairing gut motility and disrupting ENS homeostasis.[13] Conversely, the parasympathetic vagus nerve regulates gut-brain communication, promoting anti-inflammatory responses. Vagus nerve stimulation may improve TBI outcomes by restoring autonomic balance. Therapies targeting autonomic dysfunction, like β-blockers and vagus nerve stimulation, show promise in TBI management.[14] TBI significantly alters gut microbiota composition, increasing pathogenic bacteria and reducing beneficial microbes. Reduced gut motility and altered Paneth cell function exacerbate dysbiosis. Paneth cells, crucial for gut barrier function, show reduced lysozyme expression post-TBI, correlating with increased bacterial translocation. This reinforces the role of gut microbiota in TBI pathophysiology. Enteroendocrine cells (EECs) play a critical role in gut-brain communication post-TBI. EECs secrete hormones influencing cognition and inflammation. TBI reduces EEC expression, impairing differentiation. Given their role in neurological conditions, further research is needed to explore EEC alterations post-TBI and their therapeutic potential.[15]

Antibiotic Treatment Induces Microbiome Dysbiosis in Traumatic Brain Injury

Antibiotic treatment following TBI presents a paradoxical challenge, as it is essential for infection control but simultaneously disrupts the gut microbiome, leading to dysbiosis. Broad-spectrum antibiotics, commonly used in TBI management, can significantly alter microbial diversity, impair gut barrier function, and exacerbate systemic inflammation.[16] This disruption may, in turn, negatively influence neuroinflammation and brain recovery. However, research suggests that antibiotics can also have neuroprotective effects, as their role in reducing inflammation and preventing secondary infections may outweigh the risks of microbiome disruption in some cases.[17] [18] Given the pivotal role of the gut-brain axis in neurological health, preserving a balanced microbiome in TBI patients is increasingly recognized as a critical aspect of care.[19]

Microbial Metabolites for Gut-Brain Axis Signaling

Short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, are pivotal metabolites the gut microbiota produces through dietary fiber fermentation. Firmicutes (e.g., Faecalibacterium prausnitzii, Roseburia) produce butyrate, Bacteroidetes produce propionate, and both phyla contribute to acetate production. A fraction of SCFAs enters systemic circulation, affecting peripheral organs and reaching the brain. These SCFAs influence energy metabolism, immune function, and neuroinflammation. Alterations in SCFA levels have been implicated in neurological disorders such as Parkinson's disease and autism spectrum disorder, underscoring their significance in maintaining neurological health.[20] SCFAs serve as vital metabolic fuels for the host. Butyrate is a primary energy source for colonocytes, meeting up to 70% of their energy demands,[21] while acetate and propionate contribute to gluconeogenesis and lipid metabolism. They also modulate metabolic pathways, which play a role in cellular growth and neuronal function.[22]

Beyond their metabolic roles, SCFAs are critical mediators of gut-brain axis communication. They interact with the ENS and activate G protein-coupled receptors like FFAR2 and FFAR3, thereby influencing neuronal activity.[23] SCFAs can traverse the blood–brain barrier (BBB) and are detectable in the cerebrospinal fluid, suggesting a direct impact on the CNS. They also play a crucial role in maintaining BBB integrity by modulating tight junction proteins. Furthermore, SCFAs influence appetite regulation by affecting hormones like ghrelin, peptide YY, and glucagon-like peptide-1.[24] Notably, SCFAs interact with glial cells, including microglia, and modulate neuroimmune function, impacting neuroinflammation. They exhibit both pro- and anti-inflammatory responses depending on cell type and other factors like lipopolysaccharide (LPS), and they interact with the vagus nerve[25] ([Fig. 2]).

Fig. 2 Role of short-chain fatty acids (SCFAs) in brain-gut communication. Overview of SCFA production by gut microbiota and their impact on neuroinflammation, blood–brain barrier integrity, and neuronal function following traumatic brain injury (TBI).

SCFAs exert a profound influence on brain health, acting through multiple pathways to modulate neurological function and potentially mitigate the effects of neurodegenerative disorders and TBI.[22] [26]

SCFA dysregulation in TBI reflects the disrupted communication within the gut-brain axis, impacting both gut microbiota composition and metabolic profiles. Studies in rats and mice have demonstrated that TBI induces significant alterations in gut microbiota, with changes in the abundance of various bacterial genera, notably Agathobacter.[27] These shifts in microbial populations are accompanied by changes in metabolite concentrations, including critical amino acids like citrulline and tryptophan, which play roles in neurological function and recovery. Furthermore, research indicates that TBI leads to a decrease in gut microbial diversity and alters the types and abundance of metabolites, with some of these metabolites showing significant correlations with the altered gut microbes.[28] This disruption highlights the complex interplay between the injured brain and the distant gut, where changes in microbiota and metabolites serve as intermediary mediators. The observed associations between altered gut metabolites and microbes suggest that TBI-induced dysregulation of SCFAs and other metabolites may contribute to the severity of TBI and influence neurological recovery.

Primarily, SCFAs play a critical role in neuroprotection by regulating oxidative stress, enhancing synaptic plasticity, and promoting neurogenesis.[22] They can reduce inflammatory cytokine production, a key factor in neurodegenerative diseases like Alzheimer's disease, thereby protecting neural tissues from damage.[29] [30] Furthermore, SCFAs influence neurotransmitter levels, including serotonin, dopamine, and gamma-aminobutyric acid, which are essential for mood regulation, cognitive function, and behavioral responses.[22] Dysregulation of SCFAs has been observed in TBI, where they may contribute to the persistent cognitive deficits and structural brain abnormalities observed postinjury.[31] [32] [33] Specifically, studies have indicated that TBI can trigger chronic inflammatory responses mediated by microglia, which SCFAs can modulate, highlighting their potential therapeutic role in managing long-term neurological outcomes following TBI. Further research is warranted to fully elucidate the mechanisms by which SCFAs impact brain health and to explore their therapeutic potential in neurological disorders.

Preclinical Investigations of the Gut-Brain Axis in Traumatic Brain Injury: Animal Model Insights

Disruption of Gut Barrier Function Post-TBI

TBI disrupts the delicate balance of the brain-gut axis, leading to increased intestinal permeability and subsequent bacterial translocation. Studies consistently demonstrate that TBI induces a “leaky gut” phenomenon characterized by compromised intestinal barrier integrity.[9] [10] This increased permeability is associated with a decrease in tight junction proteins, such as ZO-1 and occludin, crucial for maintaining intestinal architectural and functional integrity.[10] Consequently, pathogenic bacteria and their products can translocate from the gut lumen into the systemic circulation, triggering systemic inflammatory response syndrome and contributing to multiorgan dysfunction.[34] Furthermore, TBI-induced intestinal dysfunction can lead to changes in the gut microbiota composition, including an acute bloom of Akkermansia muciniphila, which may be a compensatory response to systemic stress.[8] Moreover, intestinal inflammation during chronic TBI exacerbates neurological deficits, induces dysautonomia, and leads to persistent systemic and CNS inflammation.[35] These findings underscore the critical role of gut permeability and bacterial translocation in the secondary sequelae of TBI, highlighting the brain-gut axis as a potential therapeutic target.

A comprehensive bibliometric analysis of research on intestinal barrier damage after TBI further highlights the importance of this area, identifying “intestinal permeability” and “tight junctions” as key hotspots, and suggesting that “gut microbiota” and “ecological imbalance” are at the forefront of future research.[36] These findings collectively underscore the critical role of gut permeability and bacterial translocation in the secondary sequelae of TBI, highlighting the brain-gut axis as a potential therapeutic target ([Fig. 3] and [Table 1]).[34] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50]

Fig. 3 Sequence of traumatic brain injury (TBI)-induced gut barrier dysfunction. Illustration of the progressive changes in gut permeability, microbiome composition, and immune responses post-TBI, contributing to systemic inflammation and secondary brain injury.

Table 1 Summary of studies on the gut microbiome in experimental models of traumatic brain injury (TBI)

First author et al, Year	Experimental model	Severity of TBI	Time-point sampled postinjury	Intervention	Techniques for microbiome assessment	Other investigations	Study outcome	Microbiome changes observed	Conclusion	Clinical implications
Treangen et al, 2018[37]	Mouse (CCI)	Severe	24 h	None (observational)	16S rRNA sequencing	None	Rapid dysbiosis post-TBI	Increased Marvinbryantia, Clostridiales; reduced Lactobacillus	TBI disrupts microbiome early postinjury Some bacteria may drive post-TBI inflammation	Microbiome-targeted early interventions may aid recovery
Ma et al, 2019[38]	Mouse (weight-drop model)	Moderate/severe	1 d, 3 d, 7 d	L. acidophilus administration	16S rRNA sequencing	Neuroinflammation markers, rotarod test, serum endotoxin	Restored gut microbiota, improved sensorimotor function	Increased Lactobacillus acidophilus, reduced TNF-α, IL1-β	LA mitigates neuroinflammation and improves recovery Inflammation modulation via gut microbiota	Potential therapeutic for TBI-induced neuroinflammation
Simon et al, 2020[39]	Mouse (CCI)	Severe	1 wk, 1 mo	Antibiotic-induced microbiome depletion	16S rRNA sequencing	Neurological function tests	Microbiome depletion improved neurological recovery	Decreased microbial diversity but enhanced cognitive function	Gut microbiome depletion may benefit recovery Possible tradeoff between gut depletion and inflammation	Gut microbiome as a modifiable target for TBI therapy
Davis et al, 2022[40]	Mouse (CCI)	Severe	1 h post-TBI, weekly	FMT	16S rRNA sequencing	MRI, behavior tests, histology	Improved cognitive function, reduced gut dysbiosis	Restoration of microbial diversity post-FMT	FMT rescues post-TBI neurocognitive deficits Gut microbiome restoration is key for neuroprotection	FMT could be a therapeutic option for TBI recovery
Opeyemi et al, 2021[33]	Mouse (CCI)	Moderate/severe	24 h, 7 d, 28 d	SCFA supplementation	16S rRNA sequencing, HPLC-MS	Behavioral tests, SCFA analysis	TBI led to gut dysbiosis and SCFA depletion, supplementation improved cognitive recovery	Reduced Lachnospiraceae, Ruminococcaceae, Bacteroidaceae; increased Verrucomicrobiaceae	SCFA supplementation can mitigate cognitive deficits SCFA therapy may restore gut-brain axis function	Potential therapeutic target for cognitive recovery post-TBI
Wang et al, 2021[28]	Mouse (CCI)	Moderate/severe	Not specified	None (observational)	16S rRNA sequencing, LC-MS	Pearson correlation analysis	TBI alters gut microbiota and metabolic profiles	Microbial diversity reduced; metabolite shifts noted	Gut microbiota-metabolite interactions in TBI recovery Metabolite-targeted interventions may be useful	Potential for gut metabolome as a therapeutic target
Frankot et al, 2023[41]	Rat (bilateral frontal TBI)	Severe	3 d, 30 d, 60 d	High-fat diet versus low-fat diet	16S rRNA sequencing	Rodent Gambling Task, metagenomics	Increased impulsivity and decision-making deficits	Dysbiosis correlated with psychiatric-like symptoms	Gut microbiome composition at 3 d postinjury predicts chronic deficits Microbiome-targeted interventions could modify TBI-induced behavior	Gut as an acute treatment target for psychiatric symptoms
Medel-Matus et al, 2022[42]	Rat (lateral fluid percussion injury)	Moderate/severe	1 wk, 1 mo, 7 mo	None (observational study)	16S rRNA sequencing	EEG, SCFA analysis	Pre-TBI microbiome profile predicts post-TBI epilepsy	Changes in Lachnospiraceae family abundance	Gut microbiota composition influences epilepsy susceptibility Preinjury gut health as a biomarker	Gut microbiota as a predictor of post-TBI epilepsy
Pechacek et al, 2022[43]	Rat (bilateral frontal TBI)	Severe	1 h, 9 wk	Minocycline treatment	Microbiome analysis (not detailed)	5CSRT, IHC for IBA-1	No improvement in impulsivity or attention deficits	Minocycline altered gut microbiome but not behavior	Minocycline ineffective for TBI-related psychiatric symptoms Minocycline impacts gut microbiota but not neuroinflammation	Microbiome-targeted therapies needed for psychiatric outcomes
Yang et al, 2022[34]	Mouse (sTBI)	Severe	3 h, 7 d, 14 d	None (observational)	16S rRNA sequencing	MPO, LBP, sCD14, zonulin, histology	Gut bacteria detected in lungs after TBI	Increased Acinetobacter, Bacteroides, Streptococcus	Paneth cell dysfunction contributes to gut barrier breakdown Gut-targeted therapies could prevent post-TBI lung infections	Gut-lung axis is a key factor in secondary TBI infections
Zheng et al, 2022[44]	Mouse (CCI)	Severe	7 d, 28 d	None (observational)	16S rRNA sequencing, RNA-seq	Microglial activation (Lyz2 expression)	Dysbiosis linked to persistent neuroinflammation	Altered tryptophan metabolism, increased Lyz2 expression	Targeting microbiota could reduce prolonged inflammation Potential role of gut microbiome in chronic TBI recovery
Fagan et al, 2023[45]	Piglet (pediatric model)	Moderate/severe (CCI)	1 d, 7 d	Fecal microbiota transplantation (FMT)	16S rRNA sequencing	MRI, histology, behavior, gait analysis	Reduced lesion volume, improved motor function	FMT reduced dysbiosis and increased Lactobacillus spp.	FMT promotes functional recovery post-TBI FMT reduced neuroinflammation and ileum tissue damage	Potential therapeutic strategy for pediatric TBI
Bao et al, 2023[46]	Mouse (CCI)	Moderate/severe	7 d	None (observational study)	16S rRNA sequencing, RNA-seq	Behavioral tests, histology	Increased Bifidobacterium post-TBI, immune gene upregulation	TBI alters gut microbiota and brain gene expression	Gut microbiome drives neuroinflammation post-TBI Interaction between gut flora and brain transcriptome	Microbiota-targeted interventions could reduce neurodegeneration
Ritter et al, 2023[47]	Mouse (CCI)	Severe	72 h	Pre-TBI antibiotic depletion	16S rRNA sequencing	IL-1β, C3, TSPO, MHC2, BBB assessment	Reduced neuroinflammation markers post-TBI	Altered gut microbiome but no impact on brain pathology	Gut microbiota contribute to early neuroinflammatory responses Antibiotics could modulate acute post-TBI inflammation	Targeted microbiome modulation may aid acute TBI treatment
Gu et al, 2024[48]	Mouse (CCI)	Severe	7 d	P. copri transplantation	16S rDNA sequencing	qPCR, metabolite analysis, ELISA, Western blot	Improved motor/cognitive function, reduced oxidative stress	Increased P. copri abundance, altered gut flora	P. copri modulates oxidative stress via PI3K/Akt pathway Reshaping gut flora reduces neuronal apoptosis	Potential neuroprotective strategy for TBI
DeSana et al, 2024[8]	Mouse (CCI)	Severe	4 h, 8 h, 1 d, 3 d, 4 wk	None (observational study)	16S rRNA sequencing, qPCR	FITC-dextran permeability, hypoxia markers	Increased intestinal permeability at 4 h post-TBI	Akkermansia muciniphila bloom observed at 1–3 d	Gut environment changes facilitate beneficial bacterial shifts Potential protective role of Akkermansia in TBI	Microbiome shifts could serve as early diagnostic markers
Pasam et al, 2024[49]	Mouse (CCI)	Severe	1 d, 3 d, 7 d	L. helveticus treatment	16S rRNA sequencing	GFAP, Iba-1, TNF-α, IL-1β, CRH, BDNF	L. helveticus improved neurological deficits and SCFA levels	Gut dysbiosis reversed with increased Lactobacillus spp.	Probiotics modulate gut-brain axis and inflammation Sex-specific differences in microbiota response observed	Probiotics could aid TBI recovery and reduce inflammation
Rewell et al, 2025[50]	Mouse (CCI + LPS)	Severe	6 h, 24 h, 7 d, 6 mo	LPS immune challenge	16S rRNA sequencing, cytokine assays	IL-1β, IL-6, TNF-α, CCL2, spleen weight	Acute increase in inflammation and gut dysbiosis	24 h: Reduced bacterial diversity, altered key genera	Gut dysbiosis in early TBI is transient Systemic immune responses alter gut microbiota post-TBI	Hospital-acquired infections could exacerbate acute TBI responses

Abbreviations: 5CSRT, five-choice serial-reaction time; BBB, blood–brain barrier; BDNF, brain-derived neurotrophic factor; CCI, controlled cortical impact; CRH, corticotrophin-releasing hormone; EEG, electroencephalogram; ELISA, enzyme-linked immunosorbent assay; FITC, fluorescein isothiocyanate; FMT, fecal microbiota transplantation; GFAP, glial fibrillary acidic protein; HPLC-MS, high-performance liquid chromatography-mass spectrometry; IHC, immunohistochemistry; IL1-β, interleukin-1-β; LA, Lactobacillus acidophilus; LBP, lipopolysaccharide-binding protein; LC-MS, chromatography-mass spectrometry; LPS, lipopolysaccharide; MPO, myeloperoxidase; MRI, magnetic resonance imaging; qPCR, quantitative polymerase chain reaction; rDNA, recombinant deoxyribonucleic acid; rRNA, ribosomal ribonucleic acid; SCFA, short-chain fatty acid; sTBI, severe TBI; TNF-α, tumor necrosis factor-α∙

Gut Microbiome Dysbiosis in Animal Models of Traumatic Brain Injury

Animal models have provided critical insights into the temporal dynamics of gut dysbiosis following TBI and its implications on neuroinflammation, recovery, and systemic complications. Preclinical studies indicate that TBI induces acute and chronic shifts in gut microbiota composition. Treangen et al[37] first identified significant shifts in microbial communities within 24 hours post-TBI, noting an increase in Marvinbryantia and Clostridiales with a concurrent decrease in Lactobacillus. Similarly, Nicholson et al[51] found that moderate TBI to sTBI resulted in decreased α diversity of gut microbiota, with a notable loss of Bacteroides and Firmicutes, which are known for their role in maintaining gut homeostasis. Wang et al[28] further elaborated on these shifts, identifying alterations in gut microbiota metabolic pathways associated with energy production and inflammatory regulation. These studies highlight that TBI-induced gut dysbiosis occurs rapidly and may persist over time, contributing to sustained neuroinflammatory responses and potentially exacerbating secondary brain injury and delayed recovery.

Recent findings by Pasam et al[49] suggest that the extent of dysbiosis correlates with injury severity. In mild TBI models, microbial diversity showed partial recovery over time, whereas in sTBI, dysbiosis persisted beyond 4 weeks, indicating long-term gut-brain axis disruption.

Preclinical Findings: The Gut-Brain Axis and Neuroinflammation after TBI

Studies have indicated that TBI leads to significant gut dysbiosis, characterized by a reduction in beneficial bacteria and decreased levels of SCFAs, which are crucial for maintaining gut barrier integrity and modulating inflammation.[33] Additionally, several studies have explored the long-term effects of gut dysbiosis on microglial activation, a key component of neuroinflammation. Zheng et al[44] observed that gut dysbiosis contributes to persistent microglial activation up to 28 days post-TBI, suggesting a prolonged impact of gut health on brain inflammation. Additionally, gut microbiota has been found to influence the expression of tight junction proteins in the BBB, affecting its permeability.[47] These findings suggest that the gut microbiome is a potential therapeutic target for neurological conditions. Moreover, research has also examined how additional immune challenges post-TBI, such as hospital-acquired infections, affect neuroinflammation and gut dysbiosis. Rewell et al used LPS to mimic a bacterial infection and observed an acute increase in both inflammation and gut dysbiosis, indicating that systemic immune responses can significantly alter the gut microbiota and exacerbate acute neuroinflammation post-TBI.[50]

A comparative analysis of the included studies ([Table 1]) reveals significant variability in experimental design, TBI severity, and intervention strategies, which impact the interpretation and generalization of findings. Studies utilized diverse animal models, primarily mouse models of controlled cortical impact and sTBI, introducing heterogeneity in TBI induction and subsequent physiological responses. The severity of induced TBI also varied, ranging from moderate to severe, influencing the extent of gut dysbiosis and neuroinflammatory outcomes. Interventions spanned a broad spectrum, including SCFA supplementation, probiotic administration (Lactobacillus helveticus), antibiotic-induced microbiome depletion, and LPS immune challenges, each targeting different aspects of the gut-brain axis.

Furthermore, while 16S ribosomal ribonucleic acid (rRNA) sequencing was consistently employed for microbiome assessment, variations in supplementary techniques, such as high-performance liquid chromatography-mass spectrometry and liquid chromatography-mass spectrometry, contributed to methodological diversity. The inclusion of various investigations, including behavioral tests, SCFA analysis, and cytokine assays, provided a multifaceted view of TBI effects as well as added complexity to cross-study comparisons.

Gut Microbiome Dysbiosis in sTBI: Insights from Human Studies

Following sTBI, the gut microbiome undergoes significant compositional shifts characterized by a decrease in beneficial bacteria and an increase in pathogenic bacteria. Studies have consistently reported a reduction in Bacteroidales, Fusobacteriales, and Verrucomicrobiales, while observing an increase in Clostridiales and Enterococcus members within 72 hours postinjury, indicating rapid changes in the gut microbiome following TBI.[52] These compositional changes highlight the dynamic nature of the gut microbiome in response to TBI and its potential impact on patient outcomes. Similarly, Urban et al found a persistent decrease in Prevotella spp. postinjury, suggesting long-term alterations in the gut microbiome.[7] These changes indicate a shift toward a less diverse and potentially harmful microbial community.

Beyond compositional changes, TBI also induces significant alterations in the functional capacity of the gut microbiome. Pyles et al reported that the TBI fecal microbiome remains stable over time with distinct functional profiles, including altered amino acid metabolism, lipid metabolism, and SCFA production.[53] These functional changes may contribute to chronic TBI sequelae and highlight the potential of targeting the microbiome for therapeutic interventions.

The integrity of the BBB is crucial for maintaining the homeostasis of the CNS. Gut microbiota dysbiosis has been shown to compromise the BBB integrity, potentially exacerbating neurological damage.[54] Gut microbiota dysbiosis was associated with increased levels of inflammatory cytokines in premature infants with brain injuries, which are known to disrupt the BBB[55] ([Table 2]).[52] [53] [54] [55] [56] [57]

Table 2 Summary of clinical studies on the gut microbiome in traumatic brain injury (TBI) patients

First author, Year	Severity of TBI	Sample size	Time-point sampled postinjury	Techniques used for microbiome assessment	Other investigations	Study outcome	Microbiome changes observed?	Conclusion of study findings	Clinical implications	Future study recommendations
Urban et al, 2020[7]	Moderate to severe	22 TBI, 18 controls	Long-term postinjury	16S rRNA sequencing, metagenomics	Blood biomarkers (AAs, cytokines, hormones)	Significant differences in microbiome composition between TBI and controls	Yes, persistent dysbiosis in TBI patients. Decreased Prevotella spp., increased Ruminococcaceae	Correlation between reduced tryptophan levels and specific microbiota changes	Gut dysbiosis may contribute to cognitive and metabolic dysfunction in chronic TBI	Further mechanistic studies on gut-brain axis dysfunction in TBI patients
Pyles et al, 2024[53]	Moderate to severe	5 TBI (longitudinal)	5 years post-injury	Metagenomics, metatranscriptomics, qPCR	Bacterial RNA expression analysis	TBI microbiome remains stable over time with distinct functional profiles	Yes, long-term stability of dysbiotic patterns. Increased Corynebacterium, reduced Parabacteroides	Functional changes in metabolism and inflammation-related pathways. Altered amino acid metabolism, lipid metabolism, and SCFA production	Dysbiotic microbiota may contribute to chronic TBI sequelae	Targeting microbiome for therapeutic interventions
Mahajan et al, 2023[56]	Moderate to severe	101	Days 0, 3, 7 postinjury	Culture-based microbiome assessment	Identification of colistin-resistant and MDR organisms	Shift in microbiome composition post-TBI	Yes, increased Proteobacteria, Enterobacteriaceae. Dominance of Escherichia coli, Klebsiella pneumoniae	Early microbiome shifts may contribute to post-TBI complications. High prevalence of antibiotic-resistant strains	Potential role of microbiome in post-TBI infections and inflammation	Longitudinal sequencing studies to track microbiome evolution
Seki et al, 2024[54]	Neonatal brain injury	30 premature infants	Days 1–57 postbirth	Long-read nanopore sequencing	Metagenomics, inflammation markers	Gut microbiome composition associated with severe brain injury	Yes, altered microbial traits in infants with brain injury. High prevalence of Enterobacter hormaechei, Klebsiella pneumoniae	Loss of genomic functional redundancy in gut microbiota. Increased iron scavenging and nitrate respiration pathways	Gut microbiome composition may predict neurodevelopmental outcomes	Microbiome-targeted therapies for early intervention
Pristner et al, 2024[55]	Neonatal brain injury	51 premature infants	Days 3, 7, 28, term-equivalent age	16S rRNA sequencing, metabolomics (LC-MS/MS)	Cytokine, growth factor, T cell profiles	Early metabolic alterations linked to brain injury	Yes, changes in bile acids and neuroactive metabolites	Gut-immune-brain interactions contribute to neurodevelopmental impairment	Role of gut microbiota in shaping neonatal brain health	Exploring therapeutic microbiome modulation for neuroprotection
Burmeister et al, 2020[5]	Severe trauma	67 trauma patients	Admission to ED	16S rRNA sequencing (QIIME pipeline)	Clinical outcomes (LOS, ICU stay, infections, mortality)	Gut microbiome diversity on admission predicts clinical outcomes	Yes, significant differences in β-diversity in nonsurvivors. Klebsiella overgrowth associated with inflammation	Gut microbiome composition at admission correlates with mortality risk	Potential for microbiome-based diagnostics and interventions	Larger studies needed to confirm prognostic value of gut microbiome
Howard et al, 2017[52]	Severe trauma	12 trauma, 10 controls	0, 24, 72 hours postinjury	16S rRNA sequencing (Illumina MiSeq)	None	Rapid changes in gut microbiome within 72 hours postinjury	Yes, loss of Bacteroidales, Fusobacteriales, Verrucomicrobiales; enrichment of Clostridiales, Enterococcus	Initial microbiome composition does not differ from controls but changes rapidly		Exploring microbiome-targeted therapies for trauma recovery
Brenner et al, 2020[57]	Moderate to severe	34 TBI, 79 no TBI, 297 no/mild TBI	Years postinjury (median 29 years)	16S rRNA sequencing (PICRUSt2)	None	No significant differences in α or β diversity associated with TBI	No significant microbiome differences between TBI and control groups	Moderate/severe TBI does not result in long-term persistent gut microbiome changes. Other factors (e.g., diet, lifestyle) may influence gut microbiome more than TBI history	Limited role of microbiome in chronic TBI outcomes	Studies with multiomics approaches to explore host-microbiome interactions

Abbreviations: ED, emergency department; ICU, intensive care unit; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LOS, length of stay; MDR, multidrug resistant; qPCR, quantitative polymerase chain reaction; rRNA, ribosomal ribonucleic acid; SCFA, short-chain fatty acid.

Potential Role of Gut Microbiome Alteration in Complications and Outcomes in sTBI patients

The alterations in gut microbiome composition and function have profound implications for clinical outcomes in sTBI patients. Dysbiosis can lead to increased gut permeability, systemic inflammation, and impaired neurological recovery.[55] The reduction in Prevotella spp. has been correlated with decreased levels of L-tryptophan, an essential amino acid for neurological function.[7] Burmeister et al[5] found that gut microbiome diversity on admission to the emergency department predicts clinical outcomes, including mortality, in trauma patients. Similarly, Seki et al[54] reported that gut microbiome composition is associated with severe brain injury in premature infants, suggesting that the gut microbiome may predict neurodevelopmental outcomes. These studies highlight the potential of the gut microbiome as a prognostic marker and a therapeutic target in TBI.

Therapeutic Implications: Targeting the Gut Microbiome in TBI

TBI disrupts the gut-brain axis, leading to intestinal dysbiosis and increased permeability, which exacerbates neuroinflammation.[38] Strategies such as selective antibiotic use, probiotic supplementation, and fecal microbiota transplantation (FMT) have been proposed to mitigate antibiotic-induced dysbiosis while ensuring effective infection management.[19]

Probiotics such as Lactobacillus acidophilus and Bifidobacterium spps. have demonstrated neuroprotective effects by restoring microbial balance, reducing systemic inflammation, and enhancing intestinal barrier integrity. Preclinical studies have reported improved neurological outcomes in TBI models treated with probiotics.[38] However, the optimal strains, dosages, and duration of probiotic therapy in TBI patients require further investigation. Pasam et al[49] found that L. helveticus treatment improved neurological deficits and reversed gut dysbiosis, with an increase in Lactobacillus spp. and a reduction in inflammatory markers. This suggests that probiotics could aid TBI recovery and reduce inflammation by modulating the gut-brain axis. Enterogermina, a widely used probiotic containing Bacillus clausii, has demonstrated anti-inflammatory and gut-protective effects in preclinical TBI models.[58] Animal studies suggest that B. clausii supplementation can improve neurological function by modulating gut microbiota and reducing systemic inflammation. While these findings are promising, clinical trials are needed to establish its efficacy and safety in TBI patients.

Nutritional support is critical in TBI due to increased metabolic demands and the need to mitigate secondary brain injury.[59] Omega-3 fatty acids, particularly docosahexaenoic acid, have shown promise in reducing neuroinflammation and promoting neuronal repair. Other supplements, such as branched-chain amino acids and antioxidants, may contribute to cognitive and functional recovery. Early enteral nutrition is preferred over parenteral nutrition to preserve gut integrity and reduce infection risk. However, the specific role of dietary supplements in improving TBI outcomes remains an active area of research. Opeyemi et al[33] found that TBI led to gut dysbiosis and SCFA depletion, which was associated with neuroinflammation and poor cognitive recovery. Supplementation with SCFAs improved cognitive recovery, suggesting that SCFA therapy may restore gut-brain axis function and could be a potential therapeutic target for cognitive recovery post-TBI.

Ritter et al[47] found that antibiotic treatment reduced neuroinflammation markers post-TBI, suggesting that gut microbiota contribute to early neuroinflammatory responses. This indicates that antibiotics could modulate acute post-TBI inflammation and that targeted microbiome modulation may aid acute TBI treatment. Simon et al[39] found that microbiome depletion improved neurological recovery and enhanced cognitive function, suggesting that gut microbiota may sustain inflammation post-TBI. This indicates that gut microbiome depletion may benefit recovery, although there may be a tradeoff between gut depletion and inflammation.

Knowledge Gaps and Future Directions

The landscape of gut microbiome research in TBI is marked by a growing understanding of its pivotal role, yet significant knowledge gaps persist. A critical challenge lies in the variability across studies (as summarized in the provided [Tables 1] and [2]). Urban et al[7] and Pyles et al[53] employed 16S rRNA sequencing and metagenomics, whereas Mahajan et al[56] used culture-based methods, leading to differences in microbial diversity detection. Furthermore, the wide range in sample sizes and the disparate time points at which samples are collected postinjury complicate direct comparisons. To facilitate robust, reproducible research, future studies must prioritize the standardization of methodologies, including sample collection time points, sequencing, and bioinformatic analysis.

Future research should integrate multiomics approaches, including transcriptomics, metabolomics, and proteomics, to uncover molecular pathways involved in gut-brain communication. Although Brenner et al[57] explored probiotics, they lacked robust clinical outcomes. There is also limited research on how dietary interventions and antibiotics influence microbiome recovery and neuroinflammation post-TBI hospital stay.

Another critical area requiring attention is the translational gap between preclinical and clinical studies. While animal models provide valuable mechanistic insights, differences in gut microbiome composition, immune responses, and injury severity limit their direct applicability to human TBI. Standardized protocols and collaborative multicenter human studies will be essential in bridging this gap. Additionally, the therapeutic potential of microbiome-targeted interventions, such as probiotics, prebiotics, and FMT, requires rigorous clinical trials with well-defined endpoints to determine their efficacy and safety in TBI populations. Future research should explore personalized microbiome-based interventions that consider individual differences in microbial composition and metabolic profiles.

Conclusion

The gut microbiome represents a promising frontier in TBI research, with growing evidence linking microbial dysbiosis to neuroinflammatory and metabolic dysfunctions. Future studies integrating microbiome profiling with clinical and neurological assessments will be crucial in developing microbiome-based interventions for TBI patients.

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