Microbiota-Neuroinflammation Crosstalk in Primary Brain Tumors: Focus on Glioblastoma

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains difficult to treat because of diffuse invasion, immunosuppression, metabolic adaptability, and therapy resistance. This review evaluates how gut microbiota and microbiota-associated neuroinflammatory signaling may contribute to GBM biology and therapeutic response.

We synthesized mechanistic, preclinical, translational, and emerging clinical evidence on microbiota-neuroinflammation interactions in GBM. The review focused on gut-brain axis pathways, microbial metabolites, blood-brain barrier (BBB) regulation, glial and myeloid immune activity, tumor-associated microbial signatures, microbial peptide-HLA presentation, and microbiome-informed biomarker or therapeutic strategies.

Current evidence suggests that microbiota-related signals may influence GBM through systemic immune modulation, short-chain fatty acids, tryptophan-derived metabolites, polyamines, BBB effects, and altered microglial and tumor-associated myeloid cell function. Polyamine metabolism may sustain myeloid-cell-mediated immunosuppression in the acidic GBM tumor microenvironment, whereas microglial GLUT5-dependent fructose metabolism may limit inflammatory antigen presentation and adaptive antitumor immunity. Sequencing-based studies have reported bacterial and fungal nucleic acid signatures in brain tumor specimens, but these findings require careful interpretation because of low biomass, contamination risk, and methodological variability. Preclinical models further indicate that microbiome modulation can alter inflammatory tone, tumor growth, immune-cell infiltration, and response to immune checkpoint blockade.

Microbiota-regulated neuroinflammation is a biologically plausible contributor to GBM progression, immune suppression, and treatment resistance. However, most evidence remains preclinical or early translational. Well-controlled, spatially resolved, multi-omic studies are required before microbiome-based biomarkers or interventions can be clinically implemented for patient stratification and future precision clinical neuro-oncology applications.