Gut and Oral Microbes Emerge as Hidden Players in Brain Tumour Biology

Brain tumours remain among the most lethal forms of cancer, and decades of intensive research have yielded only incremental improvements in survival. Now, a comprehensive review published in Nature Reviews Neurology argues that a largely overlooked dimension of brain tumour biology may have been hiding in plain sight: the trillions of microbes that inhabit the human body. The review, led by Golnaz Morad of the H. Lee Moffitt Cancer Center and Research Institute together with Rebecca A. Soto, Nadim J. Ajami, Sherise D. Ferguson and Jennifer A. Wargo of The University of Texas MD Anderson Cancer Center, synthesizes a rapidly expanding literature suggesting that microbial communities in the gut and oral cavity, and even microbial elements residing within tumours themselves, can shape the initiation, growth and treatment response of primary and metastatic brain tumours.

The rationale for this line of inquiry rests on a well-established foundation. Microbes and their by-products are known to shape systemic immunity, and microbial metabolites can circulate far beyond the organs in which they are produced. The authors describe a gut–oral–brain axis through which distant microbial communities could conceivably influence the central nervous system and the tumour microenvironment within it. Because the brain was long considered a sterile, immune-privileged organ shielded by the blood–brain barrier, the idea that gut bacteria might affect gliomas or brain metastases once sounded far-fetched. Yet the microbiota–gut–brain axis has been firmly implicated in neurodevelopment, neuroinflammation and behaviour, and the immune cells that patrol brain tumours are demonstrably responsive to microbial signals originating elsewhere in the body.

A growing body of preclinical evidence now supports this framework. In mouse models, alterations of the gut microbiome have been shown to affect glioma development, growth and the composition of immune cells within the tumour microenvironment. Studies have reported that gut dysbiosis can promote glioblastoma progression, and that short-chain fatty acids—metabolites produced by beneficial gut bacteria—can reverse this effect by shifting macrophage polarization toward an anti-tumour phenotype. Other work has identified specific bacterial genera with decisive roles: intestinal Bacteroides has been shown to drive glioma progression by regulating the infiltration of CD8-positive T cells, while supplementation with Bifidobacterium lactis and Lactobacillus plantarum inhibited glioma growth in mice through modulation of the PI3K/AKT pathway. Even dietary interventions appear to act partly through the microbiome: a 2025 study in Cancer Cell reported that a ketogenic diet inhibited glioma progression by promoting the production of gut microbiota-derived butyrate.

Human data, though still preliminary, point in the same direction. Pilot studies have detected distinct gut microbial signatures in patients with benign and malignant brain tumours, and glioma patients show measurable alterations in faecal short-chain fatty acids and neurotransmitters. Case–control studies have associated specific oral microbiota profiles with glioma grade, and gender-specific salivary microbial signatures have been linked to glioma pathogenesis. These findings raise the intriguing possibility that periodontal disease and oral dysbiosis—well-documented sources of systemic inflammation—might influence brain tumour risk or progression, echoing earlier discoveries of periodontopathic bacteria such as Porphyromonas gingivalis in Alzheimer’s disease brain tissue.

Perhaps most strikingly, recent work suggests that brain tumours themselves may harbour microbes. Emerging clinical data indicate that primary and metastatic brain tumours can contain intracellular microbial elements, consistent with pan-cancer analyses showing that tumours across the body host type-specific bacterial communities. Multi-omics studies have revealed an interplay between intratumoral bacteria and glioma biology, and a landmark 2023 study in Nature demonstrated that microbial peptides presented on tumour cells can activate tumour-infiltrating lymphocytes in glioblastoma—direct evidence that microbial antigens within brain tumours are immunologically visible. A 2025 characterization of the tumour microbiome of brain metastases and glioblastoma further revealed tumour-type-specific and location-specific microbial signatures, hinting that the anatomical position of a brain lesion may shape its resident microbial community.

The therapeutic implications are potentially profound. In humanized microbiome mouse models of glioma, the gut microbial communities of the donor mice dictated the efficacy of anti-PD-1 immunotherapy, one of the most transformative cancer treatments of the past decade. In the clinical setting, a prospective phase I/II trial of anti-PD-L1 therapy in newly diagnosed glioblastoma found that improved overall survival was associated with distinct immune, mutation and gut microbiome features. Gut microbiota composition has also been linked to the efficacy of oncolytic virus therapy in malignant gliomas, and gut microbes have been shown to mediate individual variation in response to temozolomide, the backbone chemotherapy for glioma, via immunomodulation. Together, these findings suggest that the microbiome may partly explain why immunotherapy, so successful in many other cancers, has struggled in brain tumours—and why responses vary so widely between patients.

The review also highlights a bold frontier: engineered bacteria as anti-cancer agents. Attenuated Salmonella strains have been designed to penetrate the blood–brain barrier, home to glioma tumours, and regulate the tumour microenvironment; engineered strains carrying siRNA against PD-L1 and endostatin have enhanced the efficacy of radiation therapy against glioblastoma in preclinical models. Bacteriotherapy has been shown to stimulate tumoricidal immunity and inhibit glioblastoma relapse in animal studies, while engineered skin bacteria capable of inducing anti-tumour T cell responses against melanoma demonstrate the broader potential of microbial engineering in oncology. Although such approaches remain far from the clinic for brain tumours, they illustrate how microbes might eventually be transformed from bystanders into delivery vehicles and drug factories within the central nervous system.

Yet the authors are emphatic that the field must proceed with rigor. Brain tumour tissue is inherently low in microbial biomass, making it exceptionally vulnerable to contamination from reagents, surgical instruments and environmental sources. Several high-profile cancer microbiome findings have been invalidated by major data analysis errors, and host variables such as diet, medication and comorbidities can confound associations between microbiota and disease. Compounding the challenge, glioma patients routinely receive corticosteroids, antibiotics and anticonvulsants—each capable of reshaping the microbiome—while surgical antibiotic prophylaxis is standard practice. The review therefore lays out detailed clinical, experimental and computational considerations for rigorous study design, including standardized sampling protocols, appropriate contamination controls, validation across independent cohorts and methods to distinguish true intratumoural microbes from artefacts. Techniques such as culturomics, germ-free and humanized microbiome mouse models, and autofluorescence-reducing staining approaches are presented as key tools for strengthening the evidence base.

Looking forward, the authors identify several translational opportunities with genuine clinical potential. Microbial signatures could eventually serve as biomarkers for predicting treatment response or monitoring disease progression through non-invasive sampling of stool, saliva or blood. Microbiota modulation—through diet, probiotics, faecal microbiota transplantation or targeted metabolite supplementation—could be combined with existing therapies to improve outcomes, and microbiome-informed strategies might finally unlock the promise of immunotherapy in glioma. The review also points toward precision interventions: if specific bacterial metabolites such as butyrate or indole demonstrably influence tumour immunity, manipulating their production could become a therapeutic goal in its own right.

The broader message of the review is a call to reframe brain tumour biology. Glioblastoma and brain metastases have historically been studied as problems of mutated cells, aberrant vasculature and immunosuppression confined within the skull. The emerging evidence suggests that the disease must instead be understood as part of a whole-body ecosystem in which microbes in the mouth and gut continuously calibrate the immune forces that battle tumours in the brain. If ongoing and future studies validate these associations under rigorous conditions, neuro-oncology may gain an entirely new class of therapeutic targets—ones that live not within the tumour, but within us. For patients facing some of the worst prognoses in medicine, that shift in perspective could not come soon enough.

Subject of Research: The role of gut, oral and intratumoural microbiota in primary and metastatic brain tumour biology and treatment response.

Article Title: The emerging role of microbiota in neuro-oncology

Article References: Morad, G., Soto, R. A., Ajami, N. J., Ferguson, S. D., & Wargo, J. A. (2026). The emerging role of microbiota in neuro-oncology. Nature Reviews Neurology. https://doi.org/10.1038/s41582-026-01266-z

Image Credits: AI Generated

DOI: 10.1038/s41582-026-01266-z

Keywords: neuro-oncology, microbiome, glioblastoma, gut-brain axis, brain metastases, tumour microenvironment, immunotherapy, oral microbiota, short-chain fatty acids, bacteriotherapy, temozolomide, tumour microbiome