Unveiling the Gut–Microbiota–Microglia–Glioblastoma Axis: Pharmacological Strategies and Molecular Insights into Neuroinflammation-Driven Brain Tumors

Glioblastoma (GBM) is an aggressive primary malignant brain tumour characterized by extensive cellular heterogeneity, diffuse invasion, metabolic adaptation, and profound immunosuppression. Despite maximal safe surgical resection followed by radiotherapy and temozolomide-based chemotherapy, disease recurrence remains a major therapeutic challenge. Increasing evidence suggests that the gut microbiota can regulate systemic immunity, host metabolism, and inflammatory signalling through the microbiota–gut–brain axis [1–3]. However, the extent to which these mechanisms directly influence human glioblastoma remains incompletely established. This review examines the proposed gut microbiota–microglia–glioblastoma axis through an integrated framework encompassing microbial metabolites, peripheral immune signalling, blood–brain barrier regulation, microglial plasticity, and glioblastoma-associated macrophage (GAM) metabolism. Particular emphasis is placed on short-chain fatty acids, tryptophan–kynurenine metabolism, aryl hydrocarbon receptor signalling, microbial-associated molecular patterns, and inflammatory pathways involving Toll-like receptors, NF-κB, NLRP3 inflammasomes, and colony-stimulating factor 1 receptor (CSF1R). Pharmacological opportunities include myeloid-cell reprogramming, selective inflammatory pathway modulation, microbiome-directed interventions, and rational combinations with standard anticancer therapies. Recent reviews published in 2025–2026 have further highlighted the potential relationship between microbiome-associated signals and glioblastoma immunobiology [4–8]. Nevertheless, evidence differs substantially across human observational studies, experimental models, and mechanistic investigations. Confounding by antibiotics, corticosteroids, diet, treatment exposure, and tumour-associated physiological changes remains important. This review proposes a translational framework integrating longitudinal microbiome profiling, metabolomics, single-cell analysis, spatial transcriptomics, and pharmacological target validation. Establishing whether microbial signals causally modify tumour-associated myeloid cells will be essential before microbiome-informed strategies can be translated into clinical glioblastoma management.