Keywords
traumatic brain injury - brain–gut axis - microbiome - dysbiosis - therapeutic interventions
Introduction
Traumatic brain injury (TBI) impacts more than 50 million people annually worldwide,
with higher rates in developing countries due to factors such as increased road traffic
accidents and limited health care access.[1] In India, the burden of TBI is exceptionally high, with estimates suggesting more
than 1 million cases annually.[2] The socioeconomic impact of TBI in India is considerable, it accounts for substantial
health care costs and loss of productivity, making it a public health priority.[2] Despite significant advances in TBI care, limited access to quality trauma care
continues to drive higher mortality and disability rates. TBI systemic inflammation
influences the cardiovascular, respiratory, and gastrointestinal (GI) systems. Effective
TBI management, therefore, requires both immediate treatment of the initial injury
and the prevention and treatment of secondary effects, presenting critical opportunities
for therapeutic interventions.[3]
TBI significantly impacts intestinal function, leading to local inflammation, ischemia,
and intestinal stasis.[4] These effects can disrupt gut microbiota balance, potentially facilitating bacterial
translocation. The primary brain injury causes direct damage and triggers cellular
and inflammatory cascades that affect the entire body.[2] Biochemical mediators from the brain translocate through the disrupted blood–brain
barrier (BBB), inducing inflammation in the GI, cardiovascular, and neuroendocrine
systems. This response, driven by interleukins (ILs), cytokines, and adhesion molecules,
heightens intestinal permeability and toxin release.[3]
[4]
[5]
The impact of brain–gut interaction in regulating GI balance could be a potential
therapeutic target in TBI. We examine the link between brain injury and GI dysfunction,
focusing on the brain–gut axis (BGA) as an emerging target. This review highlights
how TBI-induced GI disruptions, such as dysbiosis, mucosal permeability, and gut inflammation
contribute to increased patient morbidity. Also, it outlines the need for advanced
diagnostic strategies and early interventions to enhance patient outcomes and reduce
health care costs. The findings underscore the urgent need for research investment
to mitigate long-term complications and improve the quality of life for TBI survivors.
Methodology
This review compiles data from human and animal studies on gut microbiome dysbiosis
in brain injury patients following trauma, spanning up till 2024. A comprehensive
search was performed in scientific databases, focusing on literature that characterizes
the gut microbiome concerning TBI. Search terms included “microbiome” OR “microbiota” AND “gut” OR “gastrointestinal” OR “intestinal” AND “head injury” OR “brain injury” OR “traumatic brain injury,” AND “gut-brain axis” AND “animal,” OR “human.” Results were filtered based on title and abstract relevance,
focusing on peer-reviewed studies that documented gut microbiome profiles in TBI patients
and/or animal models. References of selected studies were also reviewed for additional
relevant research. Studies with incomplete data, review articles, those on other central
nervous system (CNS) injuries, and non-English articles were excluded. This review
aims to consolidate data on gut microbiota dysbiosis following TBI, its impact on
patient outcomes, and identify any potential therapeutic targets.
Brain–Gut Axis Disturbance in TBI: Exploring the Bidirectional Communication Pathways
Brain–Gut Axis Disturbance in TBI: Exploring the Bidirectional Communication Pathways
The BGA is a complex interface connecting CNS and the enteric nervous system (ENS).
This bidirectional system allows for mutual influence between the brain and gut, primarily
through vagal pathways that regulate the GI tract function. The disruption of the
BGA in TBI illustrates a complex, bidirectional relationship between neurological
and GI health. The GI consequences of TBI include intestinal dysmotility mucosal injury
and disruption, impacting posttraumatic morbidity and mortality.[6] TBI-induced intestinal injury, inflammation, barrier dysfunction, and endotoxemia
have been reported to occur within 3 days of the injury.[4] Diarrhea in critical TBI patients ranges from 10.5 to 74%, with a higher length
of hospitalization.[7] Feeding intolerance was seen in 50% of severe TBI patients within 7 days of injury.[8] Additionally, symptoms such as abdominal pain, bloating, and constipation remain
common even 2 years postinjury.[7] Findings of a recent genome-wide association study data suggested that immunophenotypes
mediate the impact of gut microbiota on TBI risk, with different microbiome taxa having
varying effects on TBI. These insights underscore the importance of maintaining host–microbe
equilibrium for effective TBI prevention and management.[9]
Mechanisms of TBI-Induced Changes in Brain–Gut Axis Signaling
Mechanisms of TBI-Induced Changes in Brain–Gut Axis Signaling
Several theories aim to explain the pathophysiology of GI damage post-TBI, but the
mechanism remains unclear. One theory suggests an imbalance between defensive factors
such as mucosal blood circulation, the mucus–bicarbonate barrier, prostaglandins,
and epithelial turnover and esophageal mucosa-damaging factors, such as acid, pepsin,
and conjugated bile acids.[10] Another theory involves elevated levels of the Bacteroidales family, particularly
Prevotellaceae, and the Clostridiales family, specifically Peptococcaceae, which are
important components of the intestinal microbiota and have a positive correlation
with cytokine C-C motif chemokine ligand 5, which contributes to colitis.[11] This crosstalk involves four primary pathways; the dysregulation of the immune system,
dysfunction of the autonomic nervous system (ANS) and ENS, the neuroendocrine system
disruption, and the intestinal flora dysbiosis.[12]
Systemic Immune Dysregulation
TBI activates the hypothalamic–pituitary–adrenal axis and sympathetic ANS, causing
a rise in stress hormones, glucocorticoids and catecholamines levels leading to a
“leaky gut.”[13] Consequently, pathogenic organism translocation across the disrupted barrier causes
a surge of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-1β,
and IL-6, associated with impaired working memory and postconcussive symptoms in TBI
patients.[11] Additionally, elevated blood cortisol increases infection risk through peripheral
immunosuppression, elevating circulating neutrophil levels while reducing monocytes
and T-lymphocytes.[14] TBI also induces thymic involution, resulting in chronic T cell lymphopenia and
a shift toward an anti-inflammatory state, increasing the risk of nosocomial infections.[14] While necessary for acute recovery, the chronic stress response causes extended
hyperinflammation, organ dysfunction, and neurodegeration.[12]
Autonomic and Enteric Nervous System Dysfunction
TBI triggers sympathetic system activation, raising circulating catecholamine levels
that affect the GI tract, for weeks after injury, worsening clinical outcomes, and
increasing mortality.[15] Elevated catecholamine levels also disrupt the ENS homeostasis in the gut. Reactive
gliosis, marked by increased activation of enteric glial cells (EGCs), has been reported
to last up to 4 weeks after injury, leading to intestinal dysmotility.[16]
Neuroendocrine System Disruption
The intestinal epithelium plays a vital role in brain–gut communication by releasing
intestinal hormones and peptides such as serotonin, ghrelin, glucagon-like peptide
1 (GLP-1), cholecystokinin, and neuropeptide Y. Postinjury, enteroendocrine cells
expression significantly falls within 3 days, affecting cognitive outcomes.[12]
Gut Microbiome Dysbiosis
Gut organisms coexist within a sensitive ecosystem, essential for host development
and maintaining homeostasis. They contribute to metabolism, digestion and absorption,
immune system development, and response control. “Dysbiosis” is the alteration of
the normal gut flora to a dysfunctional array of organisms that can enhance disease
states. Disruptions to this microbiome occur due to reduced peristalsis, lower secretion
of antimicrobial peptides such as lysozyme and α-defensins, and partly due to altered
Paneth cell expression.[12] Acute physiological stress further impairs the gut motility and alters microbial
balance, with ischemia-reperfusion injuries also causing significant shifts in the
microbiota of the ileum and colon.[17]
Most gut organisms belong to the phyla Firmicutes, Bacteroidetes, Proteobacteria,
Actinobacteria, and Verrucomicrobia.[18] TBI significantly impacts gut microbiota composition and diversity ([Fig. 1]). TBI patients experience infections, primarily due to an impaired immune response
associated with malnutrition and weakened intestinal barriers.[14] Following TBI, the gut undergoes structural changes such as villus fusion and fragmentation,
epithelial cell shedding, localized ulcers, mucosal atrophy, reduced tight junction
protein expression, and edema in the lamina propria and villous interstitium.[19] These changes stem from dysregulation in the ENS, which leads to reduced smooth
muscle contractility and slower intestinal transit times, further complicating gut
function and immune response.
Fig. 1 Comparative overview of the gut-brain axis in healthy and TBI-induced gut dysfunction.
GI, gastrointestinal; GLP, glucagon-like peptide; HPA, hypothalamic–pituitary–adrenal;
SCFA, short-chain fatty acid; TBI, traumatic brain injury.
Clinical trial data reveal a drastic reduction of intestinal bacteria, particularly
anaerobes, and Lactobacillus spp., immediately after severe TBI, with the flora and major short-chain fatty acids
(SCFAs) not fully recovering after 2 weeks. Conversely, harmful Enterococcus and Pseudomonas levels increase gradually.[20] Chronic TBI is marked by elevated Actinobacteria, Firmicutes, and Ruminococcaceae
and reduced Bacteroidetes and Prevotella.[16]
[21] Significant post-TBI reductions in Lactobacillus gastricus, Ruminococcus flavus, and Eubacterium gastroensis, and increase in Eubacterium sulci and Marvinbryantia formatexigens have been reported in mouse models.[22] Seven days postinjury, elevation in Firmicutes, Proteobacteria, Ruminococcus, Bacteroidetes, Lactobacillus, and Clostridium difficile in rodents has been observed.[22]
[23] These microbes stimulate the innate immune system through toll-like receptor (TLR)
signaling, leading to increased intestinal motility, enhanced epithelial integrity,
and greater production of metabolites, which enter the bloodstream and impact extraintestinal
organs.[24] Bacterial translocation through an altered intestinal barrier contributes to systemic
chronic inflammation. Nicholson et al, in their animal model study, observed that
the evolution of the TBI lesion directly correlated with changes in the GI microbiome.
Reductions in beneficial commensal bacteria, Firmicutes, Anaeroplasmataceae, and Verrucomicrobiaceae
and increase in pathogenic bacteria Proteobacteria were associated with larger brain lesion.[25]
Microbiota–Brain–Gut Axis in Traumatic Brain Injury
Microbiota–Brain–Gut Axis in Traumatic Brain Injury
The BGA–CNS dysfunction impacts the gut microbiome through two-way vagal pathways
linking neuroendocrine and immunologic signaling[26] ([Fig. 2]). Gut microbial metabolites, such as methane, SCFAs, tryptamine, butyrate, cholic
acid, and chenodeoxycholic acid, bind to receptors on vagal afferent fibers in the
gut mucosa. This interaction stimulates changes in microbial composition and pathogenicity.[27]
[28]
Fig. 2 Mechanistic pathways through which gut microbiota influence the microbiota–brain–Gut
axis. CNS, central nervous system; GABA, gamma-aminobutyric acid; HPA, hypothalamic–pituitary–adrenal;
IL, interleukin; SCFA, short-chain fatty acid; TNF, tumor necrosis factor.
The gut microbiota metabolites also affect the brain influencing the BGA, through
astrocytes, microglia, and neuronal cells. Gut microbiota produce various metabolites
and neurotransmitters that have significant roles in maintaining gut and brain health.
SCFAs, produced by Faecalibacterium and Clostridium, support colonic host energy, reinforce intestinal and BBB, and exhibit anti-inflammatory
effects in the GI and CNS. Tryptophan metabolites, from genera such as Lactobacillus and Escherichia, impact neurogenesis, motor activity, and mood regulation, while also linking to
conditions such as autism and depression. Gamma-aminobutyric acid (GABA) from Lactobacillus and Bifidobacterium modulates immune response and mitigates anxiety and depression. Dopamine and norepinephrine
from Bacillus and Escherichia influence immune cell function, reduce inflammation, and help in managing neurodegenerative
conditions. Finally, serotonin produced by Streptococcus and Enterococcus plays a role in immune modulation, reducing cytokine production and managing inflammatory
conditions.[29]
Post-TBI phylogenetic changes in gut microbial populations have been reported in some
clinical studies with small sample sizes, but they lack sufficient power and clinical
intervention analysis to draw firm conclusions.[30] Zhu et al suggested that TBI-induced disruption of BGA leads to abdominal pain,
altered intestinal motility, and gastric ulcers.[26] Olsen et al noted significant contractile dysfunction in the ileum due to an inflammatory
response in smooth muscle, resulting in delayed intestinal transit in moderate TBI.
[6] Recently, Paneth cell modulation, decreased lysozyme antimicrobial peptide expression,
and increased translocation of pathogenic microbiota have been reported across a compromised
epithelial barrier.[12] However, larger clinical studies are required to enhance our understanding of gut
microbiome alterations following injury, particularly regarding early resuscitation.
Preclinical studies on various injury models also support the TBI-linked disruption
of the gut microbiome, which affects outcomes.[5]
[25]
[31] Acute changes in microorganism levels and shifts in α-diversity, including a rise
in Proteobacteria and a fall in Firmicutes, have been linked to the severity of TBI.[21]
[23]
[25]
[26] Concurrently, no significant correlations between TBI severity and preexisting gut
microbiota composition or blood metabolites were observed in a recent study, although
they observed differences between individuals with levels of neurological recovery.[5]
TBI patients are more susceptible to infections, particularly Escherichia coli, due to peripheral immune suppression caused by CNS injury, with risks extending
beyond hospitalization.[32] Experimental TBI studies indicate sustained, bidirectional brain–gut interactions
that worsen long-term outcomes. TBI causes chronic disruption in mucosal barrier integrity
and colonic function at day 28 following brain injury, increasing permeability. EGCs
contribute to prolonged barrier disruption and inflammation in the gut. Mahajan et
al in 2023[33] reported widespread colonization by Proteobacteria, particularly Enterobacteriaceae, within 48 hours postinjury in patients with TBI. Alarmingly, they found that a significant
percentage of these patients had multidrug-resistant organisms (64.1%) and colistin-resistant
strains (16.8%), raising concerns about the potential for increased multidrug resistance
due to indiscriminate antibiotic use. These findings highlight the necessity of using
antibiotics judiciously, unwarranted used antibiotics can lead to pathological overgrowth
and resulting dysbiosis.
Microbiome Dysbiosis and Timing of Injury
Elevation in pathogenic bacteria and a decrease in good bacteria can occur as early
as 2 hours post-TBI[32] and may persist for years.[21]
[25] Nicholson et al demonstrated microbiome alterations within 30 minutes of TBI, with
dysbiosis continuing throughout prolonged hospitalization.[25] This indicates that TBI alters the GI microbiome and creates dysbiosis in the absence
of other injury patterns, resuscitation, antibiotics, and analgesics. Peak magnetic
resonance imaging lesion volume, functional deficits, microbial composition alterations,
and the greatest reduction in α-diversity occurred within 2 and 3 days of injury.[25] Changes in phylogenetic composition and relative abundance were reported within
3 days postinjury.[30] Feighery et al in 2008 demonstrated blunted intestinal villi and increased permeability
in rat models 6 hours after induced TBI.[34] Additionally, Huang et al reported elevation in serum endotoxin and intestinal permeability
within 3 hours of injury, which continues to increase, peaking at 3 days.[31]
Age-Specific Differences
Recently, Davis et al[35] observed an increase in disease-associated microbial species with age, both before
and after TBI. This suggests that age exacerbates TBI-induced dysbiosis, indicating
distinct microbiome responses to TBI based on age and highlighting the potential for
age-tailored treatment approaches to address the role of BGA in TBI recovery.
TBI significantly disrupts GI function, with secondary effects including increased
mucosal permeability, nutrient malabsorption, and mobilization of gut defenses. This
includes reactive gliosis and epithelial repair mechanisms. Dysautonomia, with inflammation,
suppresses smooth muscle contractions, leading to gastroparesis and food intolerance
following TBI. Dysmotility further alters the microbial composition and metabolite
production, impacting gut–brain communication. Secondary infections or inflammation
perpetuate systemic inflammation and dysbiosis, and increase susceptibility to GI
disorders in TBI patients. Additionally, gut microbiota produce essential metabolites
and neurotransmitters (e.g., SCFAs, GABA, and serotonin) that influence recovery outcomes.
Intervention Strategies: Modulating the Microbiome to Improve Brain Injury Outcomes
Intervention Strategies: Modulating the Microbiome to Improve Brain Injury Outcomes
Probiotics and Prebiotics
Patients who received enteral nutrition supplemented with probiotics following severe
craniocerebral injury showed a lower risk of GI complications, infections, and mortality.[36] Probiotics regulate gut microbial populations, increase epithelial cell differentiation,
proliferation, barrier integrity, and limit pathogenic bacterial translocation.[37]
Lactobacillus acidophilus supplementation for 7 days post-TBI was shown to improve intestinal barrier function.[38] Clinical trials with Lactobacillus reuteri demonstrated significant reductions in neuroinflammation compared with a placebo.[39] Probiotics also stimulate SCFA release, which can lower brain inflammation.[40]
Clostridium butyricum supplementation improved neurological outcomes in mice by increasing GLP-1 levels
and enhancing BBB integrity.[41]
Lactobacillus acidophilus also shifted the microbiome to a healthier profile, reduced brain edema, and decreased
TLR4 expression.[38] Probiotic cocktail with Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus for 21 days showed reduced systemic inflammation and infection risk in severe TBI
patients.[42] These findings highlight the connection between GI microbiota and brain immune responses,
indicating that antibiotics and probiotics may be promising therapeutic strategies
in TBI management, warranting further research. Additionally, probiotics may enhance
the production of anti-inflammatory cytokine while simultaneously reducing the production
of proinflammatory cytokines by intestinal epithelial cells.[43] This dual action could help mitigate inflammation and support recovery following
TBI.
Fecal Microbiota Transplantation
Fecal microbiota transplantation (FMT) is a promising approach for restoration of
normal intestinal microbiome following TBI. FMT involves the transplantation of gut
microbiota from a healthy donor to a patient to replenish gut microbial that may have
been lost due to TBI.[26]
[42] FMT is reported to restore gut microbiota dysbiosis and alleviate neurological deficits
following TBI. Recently, Zhang et al[44] demonstrated that FMT could block the intracerebral TNF signaling pathway, enhance
GLP-1 expression, reduce brain edema, stabilize BBB integrity, and improve neurological
deficits in post-TBI. FMT treatment showed improved neurological deficits and neuropathological
changes by enhancing synaptic plasticity-related proteins, such as postsynaptic density
protein 95 and synapsin I, while also inhibiting microglial activation and reducing
TNF-α production.[45] Davis et al[35] showed significant preservation of cortical volume and white matter connectivity
in FMT-treated mice, along with reduced inflammatory gene expression in microglia.
The enrichment of neuroprotective pathways in the microglia of FMT-treated mice highlights
a promising therapeutic approach for TBI and potentially other neurodegenerative diseases.
While FMT shows considerable potential, the exact mechanisms through which gut microbiota
restoration leads to neuroprotection require further investigation.
Dietary Interventions
The microbiome is particularly responsive to dietary changes. Enteral nutrition and
omega-3 polyunsaturated fatty acids were shown to reduce IL-6 levels and an increase
in glutathione, adjunct to decreased intestinal inflammation bowel dysfunction in
TBI patients, potentially aiding in preserving gut function. A study[46] involving 36 TBI patients found that those receiving immunonutrition had significantly
lower IL-6 levels by day 5, along with higher glutathione and total protein levels.
This suggests that immunonutrition helps mitigate inflammation and oxidative stress,
thereby supporting gut function in TBI patients. Additionally, a high level of nutrition
for 2 weeks in TBI patients has been recommended to reduce inflammation.[26]
Pharmacological Modulation
A study investigating the effects of labetalol in a mouse model following TBI measured
bowel permeability at 3, 6, and 12 hours postinjury. The results showed that labetalol
significantly reduced intestinal permeability, epinephrine, and TNF-α levels compared
with the control group. The findings suggest that labetalol effectively decreased
sympathetic activity induced by TBI.[47] A 2020 study[48] demonstrated that administering a combination of ampicillin, metronidazole, neomycin,
and vancomycin (1 g/L) to male mice 14 days prior to TBI improved intestinal barrier
permeability compared with untreated mice. This suggested that depletion of the intestinal
microbiota provided a neuroprotective effect, whether initiated before or after the
injury in the murine model. In contrast, worsened neuronal loss in the hippocampus
with the same antibiotic regimen also has been reported.[23] This may be due to differences in intestinal flora, diet, injury severity, and analysis
timing. Additionally, 1 week of post-TBI antibiotic treatment reduced peripheral monocyte
and T-lymphocyte infiltration while increasing microglial proinflammatory markers
(TLR4 and major histocompatibility complex class II) levels.
Other Strategies
In 2023, a study found that deficiency in the mitochondrial serine/threonine protein
phosphatase, phosphoglycerate mutase 5, led to an increase in Akkermansia muciniphila abundance. This change helped reduce neuroinflammation and nerve injury, highlighting
new potential therapeutic avenues for managing TBI.[49]
Recently, Yu et al[50] examined the effect of hyperbaric oxygen (HBO) on intestinal dysfunction TBI mouse
model. They observed a significant reduction in histopathological damage and decreased
inflammatory and edema-related proteins in the intestines 10 days post-TBI with HBO
therapy. They also reported enhanced microbiome diversity and increased probiotic
colonization, particularly Bifidobacterium. Additionally, an increase in m6A methylation in injured cortical tissue was observed
in the HBO-treated group, suggesting m6A's potential role in regulating TBI-induced
intestinal dysfunction.
Future Directions and Conclusion
Future Directions and Conclusion
TBI has implications for gut health via the BGA. The potential for GI dysbiosis to
influence TBI recovery through neuroinflammatory pathways underscores the need for
integrated approaches targeting the microbiome. While experimental studies have shown
the potential of gut microbiota as a therapeutic target for TBI, human studies are
needed to establish the mechanisms linking microbiota alterations with injury progression.
Therapeutic strategies, including probiotics and FMT, have the potential for restoration
of microbial balance, potentially enhancing neuroprotection and recovery outcomes.
Future research should prioritize large-scale, longitudinal studies to identify specific
dysbiosis patterns, individual susceptibility factors, and the therapeutic potential
of gut-targeted interventions. Advances in big data analytics and machine learning
may illuminate novel patterns between microbiome changes and TBI outcomes. By integrating
the gut microbiome into diagnostic and therapeutic frameworks, the field holds promise
for more personalized approaches in treating TBI and potentially mitigating the long-term
effects on patient quality of life.
