Neurotrauma and the Gut–Brain Axis: Mechanistic Insights and Therapeutic Implications

Abstract

The gut–brain axis (GBA) represents a complex bidirectional communication network linking the gastrointestinal tract and the central nervous system through neural, immune, endocrine, and metabolic pathways. Increasing evidence indicates that traumatic brain injury (TBI) and spinal cord injury (SCI) disrupt gut microbial homeostasis, resulting in dysbiosis, increased intestinal permeability, systemic inflammation, and secondary neurological injury. Alterations in microbial composition, depletion of short-chain fatty acid–producing bacteria, and dysregulated immune signaling contribute to neuroinflammation and multisystem dysfunction following neurotrauma. Experimental studies highlight the role of microbial metabolites, inflammatory mediators, enteroendocrine signaling, and vagal pathways in modulating neurological outcomes. Emerging therapeutic strategies targeting the GBA, including probiotics, prebiotics, dietary modification, short-chain fatty acid supplementation, fecal microbiota transplantation, amino acid supplementation, and judicious antibiotic use have shown promise in attenuating inflammation and supporting recovery. However, robust clinical evidence remains limited. This narrative review synthesizes current knowledge on the pathophysiological mechanisms linking the gut and brain in neurotrauma, evaluates existing and emerging therapeutic interventions, and identifies key gaps in knowledge that must be addressed to translate microbiome-based strategies into effective clinical therapies.

Keywords

gut–brain axis - neurotrauma - gut microbiota - dysbiosis - neuro-immuno-endocrine pathways

Introduction

Since ancient times, humans have recognized that the gastrointestinal system and the mind are connected in some form. Early medical records from the nineteenth century document the gradual elucidation of both the beneficial and adverse health effects arising from bidirectional communication between the brain and the gut.[1] Since then, understanding of the interactions between the enteric nervous system (ENS) and the central nervous system (CNS) has evolved rapidly. The molecular and cellular basis of neuro-immuno-endocrine pathways, the role of gut microbiota, and the microbial metabolites regulating these interactions are now well documented. The term gut–brain axis (GBA) was coined to describe this complex crosstalk.[2] Recent advances have revealed that the GBA plays a significant role in a wide range of neurological conditions, behaviors, and cognitive processes. Dysregulation of the GBA has been linked to multiple neuropathologies, including Parkinson's disease, autism, Guillain–Barré syndrome, anxiety, and depression, underscoring its broad neurological relevance.[2] Traumatic brain and spinal injuries can disrupt gastrointestinal homeostasis through multiple mechanisms, and derangement of the GBA is well recognized in the setting of neurotrauma.[3] However, translation of these discoveries into effective diagnostic tools and novel therapeutic interventions remains limited. This review aims to summarize recent and relevant research findings to provide an integrated understanding of the role of the GBA in neurotrauma, with the goal of stimulating further investigation into its impact on patient outcomes and addressing existing knowledge gaps.

Methodology

To conduct this narrative review, a literature search was performed to identify relevant articles published till December 2025. The PubMed, Scopus, Google Scholar, and EMBASE databases were searched using the keywords “brain,” “gut,” “gut–brain axis,” “gut microbiome,” “probiotics,” “traumatic brain injury,” “traumatic spine injury,” “brain injury,” “spine injury,” “neurotrauma,” “TBI,” “TSI,” “SCI,” and “spinal cord injury.” Following comprehensive screening, high-quality articles addressing the molecular mechanisms, clinical impact, and therapeutic approaches related to the GBA in traumatic brain and spinal cord injury were included.

Pathophysiological Understanding of GBA in Neurotrauma

Under physiological conditions, beneficial and potentially harmful gut microbiota exist in a dynamic equilibrium. Following traumatic brain injury (TBI), this balance undergoes a marked disruption.[4] Pathogenic bacterial populations, including members of the Verrucomicrobiaceae family, proliferate at the expense of beneficial taxa such as Bacteroidaceae, Lachnospiraceae, and Ruminococcaceae.[5] Certain bacterial species increase intestinal mucosal permeability, resulting in a “leaky gut” phenotype.[3] Similar dysbiosis has been observed in patients with spinal cord injury (SCI) characterized by depletion of butyrate and other short-chain fatty acid (SCFA) producing bacteria, particularly Lachnospiraceae and Ruminococcaceae.[6] Preliminary evidence suggests that age and sex may influence these interactions, with adolescents and females potentially experiencing more prolonged and severe dysbiosis.[7] [8] Microbial metabolites interact with receptors on vagal afferent nerve endings, providing a rapid sensory neural connection between the gut, predominantly the colon, and the brain. Following TBI or SCI, sustained activation of the stress response, marked by elevated cortisol and catecholamines, disrupts gut barrier integrity, promotes bacterial translocation, and drives systemic inflammation while suppressing immune function and contributing to neuroinflammation. Concurrently, TBI reduces enteroendocrine cell expression and differentiation, altering the gastrointestinal endocrine milieu. Impaired gut–brain hormonal communication involved in the regulation of cognition and inflammation may further exacerbate neurological dysfunction, highlighting a potential therapeutic target.[9] [10] [11]

Role of Inflammatory Markers

Levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interferon-γ (IFN-γ), and monocyte chemoattractant protein-1 (MCP-1), along with several other pro-inflammatory mediators, are elevated following TBI.[12] [13] Increased concentrations of these cytokines and chemokines have been linked to TBI-induced alterations in gut microbiota, accompanied by a reduction in beneficial short-chain fatty acids (SFCAs) producing bacteria. Acetate, butyrate, and propionate are the predominant SCFAs that play a critical role in limiting immune overactivation and maintaining mucosal barrier integrity. Their depletion results in an exaggerated inflammatory response after TBI, adversely affecting both short- and long-term outcomes.[12]

In SCI, inflammatory pathways are broadly similar to those observed in TBI. Damage-associated molecular patterns (DAMPs) released from necrotic cells play a pivotal role in initiating the pro-inflammatory state.[14] Activation of glial cells and astrocytes through toll-like receptor (TLR) signaling pathways by DAMPs leads to the release of mediators such as matrix metalloproteinase-8 (MMP-8), cyclooxygenase-2 (COX-2), and IFN-γ. These converging pathways culminate in a vicious cycle characterized by increased apoptosis and disruption of the blood–brain and blood–spinal cord barriers. ([Figure 1])[15]

Figure 1 Gut-Brain Axis in Neurotrauma. IL-1β, interleukin-1β; IL6, interleukin-6; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; MCP-1, monocyte chemoattractant protein-1 (MCP-1); DAMP, damage-associated molecular pattern; SCFAs, short-chain fatty acids.

Impact of Inflammation on Organ Systems

The inflammatory cascades initiated and amplified by the mechanisms described above are not confined to the gut and the CNS. Instead, the acute systemic inflammatory response undergoes both spatial and temporal expansion, progressively evolving into subacute and chronic phases. During the acute phase, inflammation may contribute to hemodynamic instability and exacerbate secondary brain and spinal cord injury. Over the longer term, involvement of multiple organ systems becomes increasingly evident, including impaired wound healing, immune suppression, neuropathic pain, hematological and coagulation abnormalities, gastrointestinal motility and secretory disturbances, and autonomic dysfunction. Collectively, these systemic effects adversely affect recovery and pose a substantial challenge to clinicians.[15] [16]

Different Therapeutic Targets in the Gut–Brain Axis

The foregoing discussion highlights that restoration of the disrupted gut microbiota is critical for mitigating inflammatory multisystem injury following TBI and SCI. Given that therapeutic strategies targeting apoptotic pathways remain largely ineffective and elusive, increasing attention has been directed toward reversing dysbiotic alterations within the GBA as a relatively simple and potentially effective approach.[17] Several pathways, through which gut–brain crosstalk may be modulated, have been explored and are summarized below.

Inflammatory Mediators

Several therapeutic interventions targeting inflammatory pathways have been investigated, including antagonists and inhibitors of interleukin-1 (IL-1; anakinra), IL-6 (tocilizumab), and TNF-α (etanercept). Elevated IL-1β levels have been associated with a higher incidence of post-traumatic seizures.[18] [19] Increased intestinal mucosal permeability facilitates enhanced absorption of pro-inflammatory lipopolysaccharide (LPS) derived from gut microbes, and experimental LPS administration in healthy volunteers has been shown to increase anxiety.[20] Anti-inflammatory polyphenols such as paeonol, enzogenol, and resveratrol have demonstrated preliminary benefits, including improvements in memory and cognition, in small studies involving TBI.[21] [22]

Endocrine Pathways

In animal models, administration of ghrelin has been shown to improve motor deficits after TBI by downregulating cortical expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor–binding protein (FGF-BP).[23] Vasoactive intestinal peptide has been associated with reduced microglial activation and consequent attenuation of inflammatory responses.[24] These findings provide early evidence that gastrointestinal endocrine pathways may represent additional therapeutic targets in neurotrauma. However, conclusive human studies exploring this aspect are currently lacking.

Neural Pathways

Multiple neurotransmitters are involved in gut–brain crosstalk. Among these, tryptophan is the most extensively studied and serves as a precursor to serotonin, a key neurotransmitter influencing memory, mood, and multiple neural pathways. Modulation of dietary tryptophan intake is currently being explored as a potential therapeutic strategy to enhance neurological recovery.[25] In addition, vagal nerve stimulation has demonstrated early potential to ameliorate secondary brain injury by reducing inflammation, enhancing recovery, and promoting neuroplasticity.[10]

Current Therapeutic Interventions

Dietary interventions aimed at modulating the gut microbiota and, consequently, positively influencing the GBA are gradually being incorporated into clinical practice. The commonly employed strategies are outlined below.([Figure 2])

Figure 2 Therapeutic interventions for positive modulation on the gut–brain axis in Neurotrauma. BCCAs, branched-chain amino acids; SCFAs, short-chain fatty acids.

Probiotics

In a recently conducted clinical trial, a seven-strain probiotic supplement was evaluated in patients with TBI. Although markers of oxidative stress did not decrease significantly, probiotic supplementation was associated with increased intake of energy, macronutrients, vitamin E, and other essential nutrients. Antibiotic-induced depletion of commensal gut microbiota has been linked to worsened outcomes after TBI. Lactobacillus acidophilus and Clostridium butyricum are among the probiotics most commonly evaluated in animal models of TBI.[26] [27] Enterogermina, a widely used probiotic containing Bacillus clausii, has demonstrated anti-inflammatory and gut-protective effects in preclinical TBI models.[28] Treatment with Lactobacillus helveticus has been shown to alleviate neurological deficits and correct gut dysbiosis, characterized by increased Lactobacillus abundance and reduced inflammatory markers.[29]

In a murine SCI model, prolonged treatment with the medical-grade probiotic VSL#3, which contains eight lactic acid–producing bacterial strains, was associated with improved restoration of locomotor performance and immune function following SCI.[30] However, conflicting evidence also exists, with some studies failing to demonstrate similar benefits.[31] There are several human studies exploring the effect of probiotics in TBI patients. Clinical studies suggest that probiotic supplementation in hospitalized TBI patients improves outcomes by restoring gut microbiota, reducing infections and gastrointestinal complications, and shortening ICU stay and ventilation duration. Probiotics also appear to lower the risk of severe complications such as sepsis and multiple organ failure.[32] Probiotics are believed to exert their effects through multiple mechanisms, including preservation of epithelial barrier integrity, modulation of gut-associated lymphoid tissue (GALT) and mucosa-associated lymphoid tissue (MALT), and attenuation of systemic inflammatory responses. Although these mechanisms are biologically plausible at the molecular level, it remains unclear whether probiotic therapy consistently confers neuroprotection or significantly reduces morbidity associated with TBI and SCI.

Disruption of the GBA is also recognized in cardiometabolic disorders, depression, fatigue, mood disturbances, and cognitive impairment. Many individuals with TBI and SCI experience conditions within this spectrum; fatigue and cognitive dysfunction, in particular, are highly prevalent among survivors. How insights into the gastrointestinal basis of neurological and metabolic disorders can be effectively translated into the context of neurotrauma requires further investigation.[33] [34]

Short-chain Fatty Acids

As discussed earlier, SCFAs produced through fermentation of dietary fibers by gut bacteria play an instrumental role in maintaining the integrity of the GBA. In a rat study, reduced fecal SCFA levels were observed following TBI, and supplementation with soluble SCFAs resulted in improved spatial learning compared with placebo.[35] In another study, SCFA supplementation attenuated neurocognitive deficits, limited cortical and white matter damage, and reduced neuroinflammation, underscoring their neuroprotective role after TBI. The authors suggested that these effects likely result from both direct SCFA replacement and indirect mechanisms, including restoration of butyrate-producing microbial populations, activation of heat shock responses, and downregulation of genes associated with neurodegeneration.[36] Collectively, these findings highlight the potential role of soluble dietary fiber in improving neurological outcomes following TBI.

Dietary Modifications

Diets rich in antioxidants, omega-3 fatty acids, phytonutrients, and micronutrients have been evaluated for their potential to minimize neural injury, support adequate energy repletion, and reduce free radical mediated damage following neurotrauma.[37] However, high-quality evidence demonstrating a clear clinical benefit remains limited. The MIND diet, which integrates elements of the Mediterranean and DASH dietary patterns and emphasizes plant-based foods, whole grains, and lean proteins, has been associated with neuroprotective effects that may support cognitive outcomes after TBI.[38] The ketogenic diet, originally developed for the management of refractory epilepsy, is a high-fat, low-carbohydrate dietary approach that has more recently been explored in the context of TBI. By providing ketone bodies as an alternative cerebral energy substrate and attenuating neuroinflammatory pathways, this diet may contribute to improved neurological outcomes following TBI.[39]

Fecal Microbiota Transplantation

Fecal microbiota transplantation (FMT) involves the transfer of processed stool from a healthy donor to a recipient via oral capsules, nasoenteric tubes, or colonoscopy. By restoring microbial diversity after brain injury, FMT modulates the GBA, leading to reductions in systemic and neuroinflammation and improvements in blood–brain barrier integrity. Emerging evidence suggests that FMT may enhance neurorecovery and cognitive outcomes following TBI.[40]

Prebiotics

Prebiotics are non-digestible fermentable fibers that selectively stimulate the growth and metabolic activity of beneficial gut microbiota, thereby supporting intestinal homeostasis. Common prebiotics include inulin, resistant starch, pectin, β-glucans, xylooligosaccharides, arabinogalactan, and oligofructose, which are abundant in foods such as garlic, onions, leeks, asparagus, Jerusalem artichokes, green bananas, apples, and berries. In the setting of TBI, prebiotic intake along with avoidance of raw sugar, alcohol, and artificial sweeteners promotes the generation of SCFAs, contributing to restoration of gut microbial balance, attenuation of systemic and neuroinflammation, and modulation of the GBA that may support neurological recovery.[38]

Amino Acid Supplements

Amino acids critically modulate neuroinflammation and recovery after TBI, with glutamate, arginine, and tryptophan influencing excitotoxicity, nitric oxide signaling, kynurenine and indole-mediated inflammatory pathways, respectively. Conditionally essential or depleted amino acids such as glutamine, creatine, and branched-chain amino acids support immune function, energy metabolism, neurotransmitter balance, and neuroprotection, though their benefits appear dose- and context-dependent.[38] Although targeted supplementation shows promise in reducing infections, improving metabolic support, and aiding neurological recovery, robust, standardized clinical trials are still needed to define optimal candidates, dosing, and timing.[28]

Judicious Antibiotic Therapy

Ritter et al demonstrated that antibiotic therapy reduced markers of neuroinflammation after TBI, implicating the gut microbiota in early post-injury inflammatory responses and suggesting a potential role for antibiotics in modulating acute inflammation.[13] Similarly, Simon et al showed that microbiome depletion improved neurological and cognitive recovery, indicating that gut microbes may perpetuate inflammation after TBI.[41] However, these findings also highlight a possible tradeoff between reducing inflammation and maintaining gut microbial integrity.

Gaps in Knowledge and Future Research Directions

Despite growing interest in the role of the gut microbiome after neurotrauma, significant gaps remain in understanding the extent, timing, and functional consequences of injury-induced dysbiosis. Current genomic and metagenomic studies are limited in scope, with most relying on fecal samples from a narrow range of injury severities, spinal levels, and experimental models, both in preclinical and clinical settings. The magnitude and composition of microbiota alterations are likely influenced by injury characteristics, biological sex, and time since injury, yet these variables remain insufficiently explored. Moreover, existing studies have largely focused on the large intestine, neglecting the small intestine, which plays a dominant role in nutrient absorption and metabolic regulation. Gut microbiome research in TBI highlights its important role but is limited by wide variability in methodologies, sample sizes, and post-injury sampling time points, making cross-study comparisons difficult. Standardized protocols and integrated multiomics approaches are essential to improve reproducibility and clarify gut–brain communication mechanisms.

Future investigations should integrate comprehensive, longitudinal microbiome profiling across different levels of injury severity and anatomical regions of the gastrointestinal tract. Elucidating the functional implications of microbial shifts, such as alterations in amino acid metabolism, SCFA production, and neurotransmitter synthesis, may help clarify their contribution to common SCI-associated comorbidities, including infection susceptibility, metabolic dysfunction, obesity, and secondary neurological outcomes. Importantly, dysbiosis-associated microbial signatures represent potentially modifiable targets, opening avenues for microbiome-directed interventions such as personalized diets, prebiotics, probiotics, nutraceuticals, bacteriophage-based therapies, and other precision approaches.[11] [17] [33]

Conclusion

Emerging evidence underscores the critical role of the gut microbiome in modulating systemic and neurological outcomes following neurotrauma. Although human studies are constrained by environmental, dietary, and genetic variability, well-controlled preclinical models have demonstrated substantial functional conservation between rodent and human gut microbiomes, supporting the translational relevance of these findings. Nonetheless, species-specific differences, particularly those related to diet, must be carefully considered when extrapolating results to clinical populations. A deeper understanding of neurotrauma-induced microbiome alterations and their mechanistic links to host physiology has the potential to reshape post-injury management strategies. By addressing current knowledge gaps through rigorous, integrative research, microbiome-based interventions may evolve from exploratory concepts into clinically meaningful adjuncts for improving long-term metabolic, immunological, and neurological outcomes after traumatic brain and spinal cord injury.

Conflict of Interest

None declared.

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Publication History

Article published online:
28 January 2026