The Gut–Brain Axis in Brain Tumors: Insights into Tumor Development, Progression, and Therapy

Astrocytomas are primary brain tumors arising from astrocytes, a type of glial cell [11]. Astrocytes are involved in neurotransmitter regulation, ion homeostasis, and synaptic support [11]. In their neoplastic state, these cells lose regulatory control, which contributes to tumor growth and the eventual malignant transformation observed in higher-grade astrocytomas [20]. Astrocytomas exhibit a broad spectrum of behavior ranging from low-grade lesions to highly aggressive malignancies. In detail, astrocytomas are classified as follows: pilocytic astrocytoma and subependymal giant cell (Grade I), diffuse astrocytomas (Grade II), pleomorphic xanthastrocytomas (Grades II and III), anaplastic astrocytoma (Grade III), and glioblastoma (GBM) (Grade IV) [11]. These various degrees of histological variability correspond to different degrees of malignancy, which is given both by the speed of growth and the ability to reform themselves after surgical removal [11]. Therefore, the evaluation of the degree is an important parameter for both prognosis and therapy.

Meningiomas are the most common primary brain tumors, originating from the arachnoid cap cells of the meninges [35]. Meningothelial cells are specialized cells that form the arachnoid layer of the meninges, the protective coverings of the brain and spinal cord. These cells play a role in the production and regulation of cerebrospinal fluid, as well as in forming a barrier that helps protect the central nervous system [36]. When these cells undergo neoplastic transformation, they give rise to meningiomas [37]. This kind of tumor accounts for approximately one-third of all primary intracranial neoplasms and is most frequently diagnosed in middle-aged and elderly populations, with a higher prevalence in females. Although the majority of meningiomas are benign (Grade I) and exhibit slow growth, there exists a subset that demonstrates atypical (Grade II) or anaplastic (Grade III) behavior, which is associated with increased recurrence rates and poorer outcomes [38].

Meningiomas are often discovered incidentally during neuroimaging performed for unrelated reasons due to their typically indolent nature [39]. When symptomatic, patients may experience headaches, seizures, or focal neurological deficits, depending on the tumor's size and location. Despite their benign nature, meningiomas can cause significant morbidity by exerting mass effect on adjacent brain structures, particularly when located at skull base regions or in proximity to critical neurovascular bundles [39].

Recent advancements in molecular diagnostics have shed light on the genetic alterations underlying meningioma pathogenesis. Mutations in the neurofibromin 2 (NF2) gene are common, especially in sporadic meningiomas of the fibrous subtype, and are believed to play a pivotal role in tumor initiation [40,41]. Additionally, alterations in other genes such as SMO, AKT1, TRAF7, and KLF4 have been identified, particularly in non-NF2 mutant meningiomas, indicating a heterogeneous molecular landscape that may influence both prognosis and treatment response [42].

The primary treatment for symptomatic meningiomas remains surgical resection, which is often curative for benign lesions [43]. However, complete resection may be challenging when tumors are located in eloquent brain areas or the skull base. In cases where the tumor is atypical or anaplastic, or when a subtotal resection is achieved, adjuvant radiotherapy is frequently employed to reduce the risk of recurrence [43].

Immunotherapeutic approaches are also emerging as potential adjuncts in treating high-grade or recurrent meningiomas, although these strategies are still in the early stages of clinical evaluation [44].

The integration of molecular profiling into routine clinical practice holds promise for refining the classification and management of meningiomas [14]. A better understanding of the molecular drivers of tumor progression and recurrence, such as the roles of NF2, SMO, AKT1, TRAF7, and KLF4 mutations, will facilitate the development of targeted therapies, potentially improving outcomes for patients with atypical and anaplastic meningiomas [45]. Moreover, ongoing research is needed to elucidate the contributions of the TME, including immune cell infiltration and angiogenesis, to meningioma pathobiology, which may reveal novel therapeutic targets and strategies to overcome resistance to current treatments [14]. These research efforts are critical for developing more effective, personalized treatment approaches that not only improve long-term outcomes but also enhance the quality of life for patients afflicted with this diverse group of neoplasms.

Ongoing research is essential to address the intrinsic heterogeneity of these tumors and to translate molecular discoveries into effective treatments.

Pediatric brain tumors represent a distinct category of CNS neoplasms, differing significantly from adult brain tumors in terms of histology, molecular profile, clinical behavior, and treatment response [46]. The most common types in children include medulloblastomas, ependymomas, atypical teratoid/rhabdoid tumors (AT/RT), pilocytic astrocytomas, and diffuse midline gliomas [47]. These tumors often arise in different anatomical locations compared to adults, with a predilection for the posterior fossa and brainstem, which can complicate surgical approaches. Molecular characterization has revealed unique alterations in pediatric tumors, such as mutations in the SMARCB1 gene in AT/RT, and H3K27M mutations in diffuse midline gliomas [48,49].

The clinical course of pediatric brain tumors also differs from adults: low-grade tumors, such as pilocytic astrocytomas, may have excellent long-term survival with complete resection, whereas high-grade tumors, including diffuse intrinsic pontine gliomas, carry a very poor prognosis despite aggressive therapy [50]. Treatment strategies often combine surgery, radiotherapy, and chemotherapy, tailored to tumor type, molecular features, and the child's age, with special attention to minimizing long-term neurocognitive and developmental side effects. Emerging therapies, including targeted agents, immunotherapies, and, in selected high-grade cases, tumor treating fields, are under investigation to improve outcomes while reducing toxicity [51].

Overall, pediatric brain tumors require a multidisciplinary approach integrating neuroimaging, molecular diagnostics, and individualized treatment planning, highlighting the importance of understanding tumor biology.

Recent research has explained the profound influence that gut microbiota exerts on brain health [,,,,]. The human gut is home to trillions of microorganisms, including bacteria, fungi, and viruses, that form a diverse and dynamic microbiome. These microbes are involved in numerous physiological functions, ranging from nutrient metabolism to immune modulation []. The microbiota plays a crucial role in the synthesis and regulation of key neurotransmitters that are essential for brain function [,]. For instance, the gut microbiota influences the production and release of serotonin, a neurotransmitter that regulates mood, sleep, and appetite, which can impact mood and emotional responses [,]. Dysregulation of the microbiota–brain axis has been implicated in the development of several neurological and psychiatric disorders, including depression, anxiety, migraine, and autism spectrum disorders (ASD) [,]. ^{2 53 54 55 56 57 58 59 60 61 61 62}

Moreover, studies have shown that an imbalance in gut microbial communities, known as dysbiosis, is associated with the development of neurogenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) [,,,] (). ^{3 63 64 65} Figure 1

Inflammatory responses triggered by an imbalanced gut microbiota are believed to contribute to brain inflammation, which can exacerbate neurodegenerative processes. The interaction between gut-derived inflammatory mediators and the brain's immune system can lead to chronic low-grade inflammation, which is often observed in conditions like AD and PD. In the context of AD, a systematic review conducted by Manfredi et al. [] showed a decreased abundance ofand, and an increase in Bacteroidetes andin both human and mouse AD models. These alterations in gut microbiota were found to exacerbate AD pathology by increasing also BBB permeability []. Another report on Egyptian patients with PD (= 30) showed significant alterations in gut microbiota composition compared to healthy controls (= 35) []. PD patients displayed a reduction inand, and an increase in. The/ratio was markedly lower in PD patients (0.62) than the healthy control (1.32) []. Importantly, microbial profiles correlated with clinical PD subtypes: tremors predominant had lowerand/ratio, while both tremors and postural instability and gait disability (PIGD) phenotypes had lower[]. ^{66 66 67 67 67} Firmicutes Bifidobacteria Proteobacteria n n Firmicutes Bifidobacteria Bacteroides Firmicutes Bacteroidetes Firmicutes Firmicutes Bacteroidetes Bifidobacteria

As mentioned earlier, the gut microbiota can influence the integrity of the BBB, which controls the entry of substances into the brain []. The BBB's integrity is maintained by tight junction (TJ) proteins, such as claudin-5, occludin, and ZO-1 [], which form the structural basis of its selective permeability []. Disruptions in the microbiota can compromise BBB function, potentially allowing harmful substances, such as pathogens or toxins, to cross into the brain and damage neural tissue, thereby promoting a neuroinflammatory state []. ^{7 7 7 7}

The gut microbiota also has a direct role in regulating the autonomic nervous system (ANS), which in turn controls several functions such as heart rate, digestion, and respiratory rate. By influencing the ANS, the gut microbiome can affect not just brain function but also the physical aspects of brain health, such as blood flow and cellular repair mechanisms []. Additionally, microbiota-derived metabolites, such as SCFAs, play a key role in maintaining brain health by supporting neuronal survival and modulating neuroinflammation [,]. ^{68 62 69}

Given the significant effects of the gut microbiota on brain health, researchers are exploring probiotic and prebiotic therapies to promote a healthy gut microbiota as potential treatments for various neurological and psychological conditions. Probiotics, which are live beneficial bacteria, and prebiotics, which are compounds that promote the growth of beneficial gut bacteria, are being tested for their ability to restore balance to the gut microbiota and alleviate symptoms of mental health disorders [,,]. Emerging findings suggest that modulating the microbiota through diet, supplements, and lifestyle changes could be a promising strategy to prevent or treat mental health disorders and neurodegenerative diseases [,,,]. For instance, diets rich in fiber, fermented foods, and polyphenols have been shown to support the growth of beneficial gut bacteria, while reducing the abundance of harmful bacteria linked to conditions like depression and anxiety []. ^{62 69 70 62 71 72 73 73}

In addition to diet, recent studies are investigating the use of FMT as a potential treatment for restoring gut health in certain neurological conditions [,,]. By transferring healthy microbiota from a donor to a recipient, FMT aims to re-establish microbial balance and alleviate symptoms associated with neurological dysfunction. ^{9 65 74}

While microbiota-based therapies hold promise, their effectiveness ultimately depends on the molecular pathways by which gut microbes shape brain function, many of which converge on key immune and inflammatory signaling cascades and are promising for the development of future treatments.

For instance, emerging evidence supports a central role for the NLRP3 inflammasome as a molecular hub in the gut-microbiota–brain axis, mediating the bidirectional crosstalk between dysbiosis and neuroinflammation []. Gut-derived signals, such as LPS, extracellular ATP, reactive oxygen species (ROS), β-amyloid, and α-synuclein aggregates, can trigger NLRP3 activation via pattern recognition receptor (PRR)-mediated pathways in both intestinal and central innate immune cells, including macrophages and microglia []. ^{75 76}

Once activated, the NLRP3 inflammasome assembles a complex with ASC and pro-caspase-1, leading to caspase-1 cleavage and maturation of IL-1β and IL-18, culminating in neuroinflammation and pyroptotic cell death, which exacerbate BBB disruption and neuronal injury []. ⁷⁷

This activation loop is further compounded by gut dysbiosis: in animal models, NLRP3 knockout or caspase-1 deficiency alters microbiota composition, behavioral outcomes, and gut motility, underscoring a mutual regulatory feedback loop between microbiota and the inflammasome []. ⁷⁸

In pathological contexts such as AD, PD, major depressive disorder (MDD), and intracerebral hemorrhage (ICH), microbiota-driven activation of NLRP3 promotes peripheral and central inflammation, compromises gut barrier integrity, and leads to white matter injury and neurodegeneration []. ⁷⁹

Notably, in models of ICH, dysbiosis-induced NLRP3 activation mediates secondary injury by disrupting the BBB, inducing neuroinflammation, and hindering nerve regeneration []; pharmacological inhibition of NLRP3 (e.g., with MCC950) has shown protective effects on white matter integrity and cognitive function []. ^{80 6}

Collectively, current evidence suggests that gut dysbiosis may drive NLRP3 over-activation, fostering the release of pro-inflammatory cytokines, which in turn may further alter gut microbial composition, thus perpetuating a vicious cycle of dysbiosis and neuroinflammation []. ⁸¹

As the understanding of the gut–brain connection deepens, researchers continue to explore novel ways to leverage the gut microbiome in the treatment and prevention of a wide range of neurological and psychological disorders. The emerging field of microbiome-based medicine may offer new hope for improving brain health.

The interplay between gut microbiota, inflammatory state and brain tumor development is complex and multifactorial [2,82]. Recent studies suggest that microbial communities in the gut influence the onset of cancer, including brain tumors, through various mechanisms [2,8,85,88]. Tumor cells within the brain can alter the local microenvironment, and emerging evidence suggests that microbial imbalances may influence tumor growth indirectly by affecting systemic inflammation, immune responses, and metabolic pathways [89]. One of the key mechanisms through which the gut microbiota might influence brain tumor development is via the modulation of the immune system. An imbalance in the gut microbiota can lead to immune system dysfunction and chronic inflammation, which is a known contributor to the development of many cancers, including gliomas [2,90]. Studies have shown that a dysregulated microbiota promotes an inflammatory state that may support the initiation of tumorigenesis [82,91]. For example, an overgrowth of pro-inflammatory bacteria or the depletion of beneficial bacteria might result in an immune response that fosters the growth of abnormal cells in the brain [92]. Gut-derived metabolites such as SCFAs, which are produced by beneficial gut bacteria, may have tumor-suppressive properties [93]. SCFAs play a key role in modulating immune responses and neuroinflammation, even influencing tumor suppressor gene expression [72,93,94,95]. Dysbiosis in the gut microbiota may disrupt the production of these metabolites, potentially creating a microenvironment conducive to the initiation of brain tumors [96].

Once a brain tumor has developed, the role of the gut microbiota in tumor progression becomes even more pronounced. The gut microbiota can impact tumor growth, metastasis, and the immune landscape of the brain TME through several mechanisms [84,97]. The immune system plays a dual role in cancer as it can suppress or promote tumor growth by allowing for immune evasion or aiding in tumor immune tolerance [89,98]. In gliomas, for example, immune checkpoints such as PD-1/PD-L1 and CTLA-4 are often upregulated, suggesting a worse outcome [99,100]. It is believed that the gut microbiota can influence the expression of these checkpoints by modulating systemic inflammation and immune cell activity [101]. Certain gut bacteria, including Bifidobacterium and Akkermansia, have been found to enhance the efficacy of immunotherapies by stimulating anti-tumor immune responses [5]. Moreover, microbiota can impact the TME by the production of metabolites like SCFAs that regulate cellular metabolism and inflammation [56,86,93]. For example, butyrate, a major SCFA, has been shown to inhibit tumor proliferation and reduce invasiveness through modulation of cell cycle progression and even affecting extracellular matrix substrates [102,103].

The influence of the gut microbiota on brain tumor treatment is an emerging area of research with significant implications for therapeutic strategies. Traditional treatments for brain tumors, such as surgery, radiation, and chemotherapy, have limited success due to the BBB and the complexity of the TME [104].

The gut microbiota contributes to human health through multiple mechanisms, such as the digestion of complex carbohydrates, modulation of nutrient absorption, secretion of microbial metabolites (e.g., SCFAs, lipopolysaccharide (LPS)), and the production of vitamins and neurotransmitters [105]. Increasing evidence indicates that these processes extend beyond the intestine, influencing CNS function and brain physiology. In particular, the gut microbiota plays a critical role in maintaining immune homeostasis in the brain by modulating the activity of microglia, T cells, dendritic cells (DCs), macrophages, and other immune cells [106].

In the oncological context, alterations in gut microbiota composition have been shown to influence tumor progression and therapeutic outcomes [2,10,87,107,108].

Notably, previous studies have suggested an association between commensal gut microbe's alterations and brain tumors, including GBM [96,109]. For instance, Wang et al. [109] reported that higher abundances of Ruminococcaceae were associated with a reduced risk of developing GBM. Members of this family synthesize the metabolite isoamylamine (IAA), which promotes microglia activation by enhancing the recruitment of p53, a key transcription factor involved in cell cycle regulation, DNA repair, and apoptosis, to the S100A8 promoter region [110].

Probiotics, particularly those containing Lactobacillus and Bifidobacterium strains, are being investigated for their potential to enhance anti-tumor response [70,111,112].

A study by Wang et al. [88] demonstrated that supplementation with Bifidobacterium lactis and Lactobacillus plantarum reduced tumor volume, prolonged survival, and improved intestinal barrier integrity by modulating TJs expression in an orthotopic glioma mouse model.

Among the most promising avenues of investigation is the role of the gut microbiota in enhancing the efficacy of immunotherapies for brain tumors [87,107].

By modulating innate and adaptive immune responses through metabolite production and other regulatory pathways, the microbiota has been shown to influence the effectiveness of immune checkpoint inhibitors (ICIs) and related therapies [2].

For example, Dees and colleagues [113] demonstrated in a murine glioma model with a humanized microbiome that microbial composition influences the success of anti-PD-1 therapy.

In detail, fecal material from five healthy human donors was transplanted into gnotobiotic mice [113]. Once the transplanted microbiomes stabilized, the mice were bred to generate five independent humanized mouse lines (HuM1–HuM5). All HuM lines were susceptible to GBM transplantation and exhibited comparable median survival times ranging from 19 to 26 days. The response to anti-PD-1 treatment varied among the lines: HuM1, HuM4, and HuM5 were non-responders, whereas HuM2 and HuM3 were responsive, showing a significantly prolonged survival compared with isotype-treated controls. Bray–Curtis cluster analysis revealed that the gut microbial communities of responder lines HuM2 and HuM3 were closely related [113]. Further taxonomic comparison identified Bacteroides cellulosilyticus as a common species enriched in HuM2 and HuM3, suggesting a potential role in mediating sensitivity to immune checkpoint inhibition [113].

Commensal bacteria shape both innate and adaptive immunity, with microbial metabolites such as SCFAs, which in turn modulate inflammatory pathways and immune cell recruitment [103].

SCFAs, including acetate, propionate, and butyrate, are produced by the fermentation of dietary fibers. SCFAs are known to exert beneficial effects in the context of neuroinflammatory diseases [62,69,114,115,116,117] as well as in brain tumors, reducing GBM cells proliferation by modulating several signaling pathways [72,106,118].

Among SCFAs, butyrate accounts for approximately 20% of the total SCFAs in the gut and plays key roles in energy supply to intestinal epithelial cells, as well as in cellular regulation, proliferation, and differentiation [106]. Most butyrate-producing bacteria belong to the phyla Firmicutes, Actinobacteria, Bacteroidetes, Fusobacteria, and Proteobacteria. Butyrate is known to influence innate immunity by promoting monocyte differentiation into macrophages, which can polarize into pro-inflammatory M1 or immunosuppressive M2 phenotypes, contributing to tumor progression [119]. In this context, Zhou et al. [56] demonstrated by using an orthotopic GBM model that gut dysbiosis caused by antibiotic treatment accelerated glioma growth by increasing the percentage of M2-like macrophage populations and reducing the levels of gut microbial metabolites SCFAs in the TME. In detail, 21 days after tumor implantation, the authors performed 16Sr RNA sequencing on fecal samples from the cecum of GL261-bearing mice, showing that the numbers of the most abundant microbiota, like Firmicutes and Bacteroidetes were decreased or vanished, but the numbers of Proteobacteria were increased in the gut microbiota of ABX-treated tumor-bearing mice [56]. However, oral supplementation of SCFAs reversed these effects by shifting macrophages toward an M1-like phenotype, resulting in an enhanced M1/M2 ratio and improving glioma outcomes [56] (Table 3).

Another crucial mediator involved in the gut–brain axis is LPS, a pro-inflammatory endotoxin derived from Gram-negative bacteria, that can trigger systemic inflammation by activating Toll-like receptor 4 (TLR4) [120,121,122]. Elevated LPS levels have been associated with increased inflammation in cancer and brain diseases [121,123,124,125]. Because TLRs can modulate both innate and adaptive immunity, TLR ligands are a promising approach for brain tumor immunotherapy. Accordingly, LPS, as a well-known TLR4 ligand, has been reported to alter the immuno-phenotype of glioma and glioma stem-like cells, and induce anti-tumor effects [126,127].

In recent years, cancer vaccines are an emerging and rapidly evolving area in immuno-oncology, aiming to stimulate the immune system to recognize and eliminate tumor cells by presenting tumor-associated antigens (TAAs) [128]. In GBM, a notoriously immunosuppressive tumor, several vaccine strategies have shown promise in enhancing immune responses. One innovative approach involves the use of an amphiphile-ligand conjugated with a tumor peptide vaccine. In preclinical models of EGFRvIII-positive GBM, this system traffics from the bloodstream to lymph nodes, where it integrates into the membranes of resident antigen-presenting cells (APCs) [128,129]. This process efficiently primes both CD4⁺ and CD8⁺ T cells and promotes antigen spreading, thereby enhancing the efficacy of adoptive cell therapies such as CAR-T cells. Another well-established strategy is the use of DC vaccines, which are generated ex vivo by differentiating monocytes or hematopoietic progenitor cells into mature DCs and loading them with tumor antigens either synthetic peptides or autologous tumor lysates [130]. These antigen-loaded DCs activate CD4⁺ T-helper cells and, through cross-priming, cytotoxic CD8⁺ T cells. Synthetic peptides are particularly efficient at enhancing cytotoxic T lymphocyte (CTL) responses due to their rapid processing and presentation by DCs. Accordingly, clinical trials have demonstrated encouraging outcomes; notably, the phase III DCVax-L trial reported significant improvements in overall survival in both newly diagnosed and recurrent GBM patients [128,131].

Another strategy includes PVSRIPO, a genetically modified, nonpathogenic poliovirus engineered to target CD155, a receptor commonly overexpressed in GBM cells. Upon direct intratumoral administration, PVSRIPO selectively infects and lyses tumor cells, while simultaneously activating strong local and systemic immune responses. This virotherapy not only exerts direct cytotoxicity but also acts as an in situ vaccine by releasing tumor antigens and promoting immune activation [132]. These vaccine-based therapies—whether bacterial, viral, or cell-based—offer a promising complement to conventional GBM treatments, including surgery, radiation, and chemotherapy.

The gut microbiota is increasingly recognized as a critical modulator of therapeutic outcomes. Microbiome-based interventions, such as targeted probiotics, may further enhance the efficacy of cancer vaccines by shaping systemic and intratumoral immunity. As research continues to uncover the complex interplay between the microbiota, the immune system, and tumor biology, microbiota-informed vaccine strategies may open new therapeutic avenues for GBM.