Restorative Microbiota-Based Therapies for Traumatic Brain Injury: A Systematic Review of Preclinical Studies

Abstract

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, characterized by complex neurological impairments and systemic consequences. The objective of this systematic review is to assess studies on gut microbiota modulation as a therapy in animal TBI models. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. To be eligible for inclusion, publications needed to (1) report original research involving preclinical animal subjects; (2) evaluate the impact of TBI on the microbiome; (3) be written in English; and (4) be published in a peer-reviewed journal. All studies reviewed found changes in the gut microbiome following TBI, with similar alterations in bacterial populations observed across the research. Of 125 records, 9 studies (mice/rats; fluid percussion, Controlled Cortical Impact, and weight-drop models) were included after screening. TBI consistently induces dysbiosis, leaky gut, inflammation, and impaired recovery. Microbiota therapies restore homeostasis, reduce neuroinflammation, and improve outcomes. Microbiota-targeted interventions show significant potential in preclinical models of TBI, effectively mitigating dysbiosis and reducing inflammation. However, translating these findings into clinical settings requires further investigation to establish efficacy and safety in human populations.

Graphical abstract

Keywords

restorative therapy / microbiota / traumatic brain injury / systematic review / preclinical studies

Introduction

Traumatic brain injury (TBI) encompasses a wide clinical spectrum ranging from mild concussive events to severe injuries associated with enduring cognitive, emotional, and physical impairments[1]. Current epidemiological estimates suggest that approximately 50 million new cases occur globally each year, indicating that nearly half of the world’s population is likely to experience TBI at some point during their lifetime[2]. Severe TBI, conventionally defined by a Glasgow Coma Scale (GCS) score ranging from 3 to 8, is typically associated with profound alterations in consciousness, frequently manifesting as coma or progressive loss of awareness following the insult[2,3]. The prognosis in severe TBI remains poor, with mortality rates approaching 30%, while nearly half of survivors develop moderate-to-severe long-term disabilities within the first year post-injury. Only a minority (10%–20%) demonstrate substantial neurological recovery[4]. The heterogeneous and multifaceted nature of TBI, along with its persistent neurological and systemic sequelae, has prompted increasing research interest in the contributions of neuroinflammation and the gut–brain axis to its pathophysiology, defined as brain damage resulting from the application of an external mechanical force to the cranium[5,6]. Recent studies explore the therapeutic potential of targeting the gut–brain axis in TBI. Probiotic supplementation, dietary modulation, and microbiota-derived metabolites such as short-chain fatty acids (SCFAs) have been shown to attenuate microglial activation, suppress secondary neuroinflammatory cascades, and improve cognitive outcomes in preclinical models[7,8]. Recent studies show that probiotic supplementation with beneficial bacteria can restore microbial balance, reduce systemic inflammation, and enhance neuroprotection[9]. Consequently, modulating the gut microbiota through dietary interventions, probiotics, or prebiotics holds promise for mitigating neuroinflammation and improving recovery after TBI by lowering pro-inflammatory cytokines and boosting anti-inflammatory mediators such as interleukin-10 (IL-10)[10]. The current review synthesizes findings from preclinical studies that investigate alterations in the gut microbiome following TBI and explores therapeutic interventions targeting the microbiota. The primary objective of the review is to evaluate the efficacy of restorative microbiota-based therapies (probiotics and fecal microbiota transplantation (FMT)) in improving neurological outcomes following TBI in preclinical models, to understand the characteristics and impact of the restorative interventions on gut microbiota composition and gut barrier function, and to explore reported key mechanisms of action, including the reduction of neuroinflammation and the modulation of the immune and metabolic pathways of the gut–brain axis in order to understand the quality and limitations of the current evidence so the scope and opportunities for future studies can be anticipated.

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to conduct the current review[11]. The selected electronic databases PubMed, Scopus, the Cochrane Central Register of Controlled Trials (CENTRAL), and ScienceDirect were searched with the search terms outlined in Table 1. Two investigators independently screened all titles and abstracts for relevance, and the reference lists of all included articles and relevant reviews were also manually screened to identify any additional studies. The full texts of potentially eligible articles were then retrieved and assessed against the refined eligibility criteria. Any disagreements regarding study selection were resolved by discussion and consensus with a third reviewer, and the authors were contacted for missing data. The inclusion criteria were original preclinical studies involving an animal model of TBI, published in the English language. Based on the population, intervention, comparator and outcome (PICO) framework, the inclusion criteria were defined as follows: animal models of TBI (P); restorative microbiota-based therapies, defined as probiotics (administration of live beneficial microorganisms) or FMT (I); placebo, vehicle, or sham-treated control groups (C); and (O): improvement in neurological functions (e.g., motor and cognitive recovery), reduction in neuroinflammation (e.g., microglial activation, inflammatory cytokines), restoration of gut microbial composition (e.g., diversity, key taxa), improvement in gut barrier integrity, or modulation of systemic markers as reported. Reviews, editorials, commentaries, letters, case reports, and conference abstracts were excluded. Additionally, human observational or clinical studies, preclinical non-interventional studies (i.e., studies describing the effects of TBI on the gut without testing a therapeutic intervention), and studies where the intervention was not a probiotic or FMT were excluded. Two investigators independently extracted data from the included studies using a standardized data extraction form, and discrepancies were resolved through discussion and consensus. The data extraction details included study author, year of publication, country, demographic details (species, age, and sex), TBI model and methodology, sample size for each experimental group, details of the intervention (e.g., probiotic strain(s) and FMT protocol), microbiota-related outcomes (e.g., diversity indices and changes in specific taxa), neurological outcomes (e.g., behavioral scores, lesion volume, and neuroinflammation markers), systemic and gut-related outcomes (e.g., gut barrier integrity, and serum biomarkers), and any other details relevant to PICO. The quality and risk of bias of all included preclinical animal studies were assessed using Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias tool for animal studies[12].

Results

Study selection

The PRISMA flow chart showing the study selection process is presented in Figure 1. Electronic database search resulted in 125 results, after removing duplicates 76 studies were screened, 9 studies[13–21] were excluded with reasons, and 9 studies[22–30] were included in qualitative result synthesis.

Search strategy and study selection

The search strategy outlined in the methods identified a total of 7 trials in the Cochrane database, 53 articles in the PubMed NLM database, 54 articles in the Scopus database, 10 entries in the ScienceDirect database and one entry in others (Table 1). In total, 125 records were found. Of these, 49 records were duplicates across multiple databases and were removed from further screening. Consequently, 76 articles remained, from which 58 records were excluded based on a review of the relevant abstracts. Ultimately, 18 articles were selected for a full-text review. Following a thorough analysis of the full texts, 9 were excluded for specific reasons (Table 2). A systematic review was conducted with the remaining 9 articles. The results of this process are presented in a PRISMA flow diagram (Figure 1). The characteristics of the included studies are detailed in Tables 3 and 4.

The reviewed studies comprise nine investigations focused on animal models of TBI, all utilizing a true experimental design. Among these studies, four employed the C57BL/6 mouse model[22,25–27] and one of the studies utilized 5xFAD transgenic mice while the other four utilized rat models, specifically the Sprague-Dawley strain[23,24,28,30].The ages of the mice in the studies varied between 8 and 12 weeks, with one study utilizing mice that were 21 weeks old[29] and the other one 112 weeks old[22]. In the case of the studies involving a rat model, the ages ranged from 8 to 13 weeks; however, one of the studies did not specify the age of the animals used[23]. In the animal studies, researchers employed various techniques to model TBI, including the fluid percussion injury model[22], the weight-drop method[26], the gas explosion-induced TBI model[23], and controlled cortical impact (CCI)[24,25,29,30]. Additionally, they utilized the lateral fluid percussion injury (LFPI) model[28]. The study by Ma et al. 2019 did not specify the mechanism for inducing TBI; however, a reference within their methodology suggests they employed a modified weight drop method[31]. Microbiome diversity was assessed through stool sampling across the studies. Of the nine animal studies reviewed, one collected sample on day 8 following TBI induction, while another study collected fecal samples from each rat on the 21st day post-gavage[23]. In a separate investigation, fecal samples were taken from the sham, TBI, TBI + saline, and TBI + FMT groups 1 day prior to TBI (pre-TBI) and again 8 days post-injury[24]. Other studies documented the collection of fecal samples[28], and stool samples[29] from the beginning of antibiotic administration until study completion. In few studies, fecal stool pellets were collected aseptically at 3 days post-injury (acute group) and 35 days post-injury (chronic group)[25,30]. Two studies focused on collection of cecal contents[22,32], while one focused on colon contents[26]. DNA isolation was performed on all samples, and most studies were profiled using 16S rRNA sequencing of the V3–V4 region.

The majority of the animal studies reported changes in microbial alterations following TBI. Studies consistently show that TBI induces dysbiosis, characterized by reduced microbial diversity and shifts in dominant populations; specifically, there is often a decrease in beneficial bacteria such as Lactobacillus and Bifidobacterium and an increase in pathogenic strains from Enterobacteriaceae[23–25,30]. This imbalance compromises gut barrier integrity, leading to increased intestinal permeability, or “leaky gut”, which allows bacterial products such as lipopolysaccharide (LPS) to enter systemic circulation and fuel neuroinflammation[24,25,30]. The resulting systemic inflammation and altered microbial metabolites, such as SCFAs[28], critically modulate the gut–brain axis, further contributing to neuroinflammation and impeding recovery[26]. Given these findings, therapeutic interventions targeting microbiota manipulation, including probiotics, prebiotics, and even fecal microbiota transplantation, are being explored to restore gut homeostasis, reduce neuroinflammation, and improve TBI outcomes, highlighting the gut microbiome as a crucial modifiable factor in TBI pathology and recovery[22,23,25].

Discussion

The gut–brain axis and TBI pathophysiology

Following TBI, the gut microbiota undergoes significant changes that influence neuroinflammation and impede neuronal repair. An acute brain injury compromises the “brain–gut–microbiome axis,” a well-balanced network formed by the brain, gastrointestinal tract, and gut microbiome[32]. This has a complex effect: damage to the brain alters the composition of the microbiome, and the altered microbiome affects TBI severity, neuroplasticity, and metabolic pathways through various bacterial metabolites[32]. The gut–brain axis facilitates communication between the gut microbiota and the brain via neural, immune, and hormonal pathways, influencing brain function and behaviour[9]. The microbiome is defined as the collective genomes of the microbes (composed of bacteria, bacteriophage, fungi, protozoa, and viruses) that colonize the human body[33]. The gut microbiota, encompassing over 1,000 microbial species across major phyla including Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria[34], is integral to host physiology, contributing to nutrient metabolism, immune regulation, neurotransmitter production, and maintenance of the blood–brain barrier[35,36]. The trillions of microbes that exist in the gastrointestinal tract have emerged as pivotal regulators of mammalian development and physiology[37,38]. Studies have reported a direct correlation between the intestinal microbiota and the brain, as co-metabolism between the microbiota and the host results in a mutually beneficial gut microbiota-brain axis[9].

Mechanisms of TBI-induced dysbiosis and neuroinflammation

Recent evidence highlights that TBI induces consistent alterations in gut microbial composition, marked by reduced diversity, depletion of commensals such as Lactobacillus and Bifidobacterium, and overgrowth of potentially pathogenic taxa such as Enterobacteriaceae[23–25,30,39]. TBI induces rapid and sustained dysbiosis within the gut ecosystem, characterized by reduced abundance of commensal taxa such as Lactobacillus and Bifidobacterium, alongside expansion of potentially pathogenic genera including Clostridium and Enterobacteriaceae[40]. The temporal dynamics of bacteriological alterations within the gut microbiota are of significant importance; perturbations in this microbiotic ecosystem often commence within a matter of days and may persist for several weeks, culminating in dysbiosis[37]. Disrupted gut microbial balance increases intestinal permeability, enabling microbial products and metabolites to enter the bloodstream and activate immune cells in the brain, especially microglia and astrocytes[41]. While these glial cells are essential for clearing debris and supporting repair[42], excessive activation leads to the release of pro-inflammatory cytokines, which exacerbate neuronal damage[43]. These microbial shifts compromise intestinal barrier integrity, promote systemic endotoxemia, and exacerbate neuroinflammation through heightened glial activation and pro-inflammatory cytokine release[24,25,44]. This cascade can impair the blood–brain barrier, promote chronic brain inflammation, and result in cognitive and behavioral deficits[45]. Decreased levels of beneficial gut-derived metabolites, such as SCFAs, and altered tryptophan metabolism further enhance neuroinflammatory pathways, disrupt protective signaling mechanisms and impair neural repair[26,28,46,47]. Thus, TBI-induced gut dysbiosis amplifies neuroinflammatory responses, highlighting the therapeutic potential of interventions targeting the gut microbiome to improve neurological recovery. Disruptions to this close relationship between the gut microbiota-brain axis can result in several neurological pathologies, including anxiety and depression, autism spectrum disorder, and multiple sclerosis[35]. The persistent neurological and systemic sequelae have prompted increasing research interest in the contributions of neuroinflammation and the gut–brain axis to its pathophysiology[6,48].

Therapeutic interventions targeting the gut microbiome

Preclinical research has explored a variety of interventions aimed at correcting TBI-induced dysbiosis and restorative microbiota-based therapies—specifically the administration of beneficial bacteria (probiotics) and the transplantation of a complete healthy microbial ecosystem (FMT)—have shown significant promise in animal models[49]. Therapeutic strategies targeting microbiota restoration including probiotics, prebiotics, FMT, and dietary interventions consistently attenuated neuroinflammation and improved cognitive or neurological outcomes in preclinical models[8,22,50,51]. These interventions reduced interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels while enhancing anti-inflammatory mediators such as IL-10, highlighting their immunomodulatory potential[10]. In addition to conventional inflammatory markers, regenerative interventions influence targeted endocrine pathways for example, FMT has demonstrated restoration of circulating ghrelin concentrations, subsequently elevating glucagon-like peptide-1 (GLP-1) expression and attenuating cerebral edema[30]. Notably, findings parallel those observed in other neurological disorders, supporting the therapeutic relevance of targeting the gut–brain axis[7,9]. FMT shows promise in neurological disorders by reinstating healthy microbial communities[49]. Additionally, probiotics and prebiotics help restore microbiota balance, improving gut barrier function and reducing neuroinflammatory markers[51]. Dietary interventions rich in fiber, polyphenols, and omega-3 fatty acids, particularly Mediterranean-style diets, promote beneficial gut bacteria and mitigate neuroinflammation, supporting cognitive health and recovery after brain injury[50]. Together, these data implicate the gut microbiome as a modifiable factor shaping the trajectory of secondary brain injury.

Broader therapeutic context

Therapeutic approaches targeting neuroinflammation include anti-inflammatory agents (NSAIDs, corticosteroids, and minocycline), ion channel modulators (sodium channel blockers such as carbamazepine and lamotrigine)[52], and drugs that balance neurotransmitter systems (NMDA antagonists such as memantine and GABAergic agents such as benzodiazepines)[53,54]. Together, these strategies highlight the significance of the gut–brain axis in neurorehabilitation and offer novel avenues to improve neurological outcomes post-injury.

Limitations

The included studies had significant methodological heterogeneity which was due to variations in TBI models, aged models, animal species, specific probiotic strains or FMT protocols, and the diverse range of reported outcome measures. Although the current evidence has shown the impact and potential protective effects of probiotics in experimental conditions, there is a need for studies where these benefits can be evaluated in clinical scenarios[27]. The information in the included studies was used to conduct a structured narrative synthesis and a quantitative meta-analysis was not performed.

Future direction

Despite these promising findings, translation to clinical practice remains limited. Current evidence from human studies is sparse and heterogeneous, with marked variability in injury models, microbiota assessment methods, and treatment protocols among animal studies. Few investigations employed functional metagenomics or metabolomics, limiting mechanistic insight. Standardization of experimental designs and incorporation of multi-omics approaches are, therefore, essential to strengthen causal links and identify microbial or metabolic biomarkers of recovery. Altogether, TBI consistently induces gut dysbiosis that contributes to systemic inflammation and neuroinflammation. Targeting the gut microbiota through microbiome-based therapies offers a promising avenue to mitigate secondary injury processes and enhance recovery. However, rigorous translational and clinical studies are required to define optimal strategies, establish efficacy in humans, and integrate microbiota modulation into neurocritical care.

Conclusions

Current research suggests that TBI can affect the gut microbiota, disrupt lipid metabolism in the liver, and affect the gut–brain axis. It is postulated that modifying the composition of gut bacteria might protect the brain from the adverse effects of TBI. Studies have described novel mechanisms where controlled alteration of intestinal flora represents a potential therapeutic strategy to attenuate neurological injury in animal models via the brain–gut–microbiome axis. Maintaining a healthy gut microbiome could be beneficial in preventing or improving recovery from TBI. Bioactive agents, including probiotics, prebiotics, or synbiotics, are promising therapeutic tools that can help repair gut dysbiosis and attenuate both gut dysfunction and neurological deficits in TBI. However, research in this field is still in its early stages, and there are currently few comprehensive systematic reviews that thoroughly examine the therapeutic modulation of the bidirectional relationship between TBI and gut microbiota. There is a need for further research to generate evidence that repairing gut dysbiosis via microbiota-targeted interventions (probiotics, prebiotics, or synbiotics) can modulate the gut microbiome, metabolic profiles, and inflammation in TBI patients.

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