A Comprehensive Review of the Brain–Gut Microbiota System in Traumatic Brain Injury: Mechanisms, Outcomes, and Emerging Interventions

Abstract

Traumatic brain injury (TBI) has profound effects that extend beyond the brain, affecting other body systems via secondary pathways and leading to various complications, including gastrointestinal (GI) dysfunction during and after hospitalization. While advances in TBI management have improved overall outcomes, the absence of effective treatments for these systemic effects highlights the urgent need for innovative therapeutic strategies. A critical aspect in this context is the brain–gut axis (BGA), a bidirectional communication network connecting the brain and GI system through complex neuronal, hormonal, and immune pathways. TBI results in increased intestinal permeability and a hypercatabolic state leading to bacterial translocation, immune dysregulation, septic complications, and multiorgan failure. These complications significantly heighten the risk of morbidity and mortality in TBI patients. Emerging evidence suggests that gut dysbiosis plays a pivotal role in post-TBI complications. The gut microbiome, a diverse community of commensal microorganisms, is integral to gut physiology, performing key functions such as metabolic regulation, maintaining the intestinal barrier, and modulating immune responses. Disruptions to this microbiota can exacerbate GI and immune system dysfunction, potentially leading to severe outcomes. This review examines the mechanisms underlying BGA dysfunction following TBI, focusing on the pathways contributing to this dysregulation. Additionally, it discusses therapeutic strategies aimed at mitigating gut microbiota dysbiosis. Potential interventions include approaches to restore microbial balance, enhance gut barrier integrity, and support immune modulation. By targeting these areas, therapies may reduce the systemic effects of TBI and improve patient outcomes.

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

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

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

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

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

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.

Conflict of Interest

None declared.

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Publication History

Article published online:
02 April 2025