RBIO-14. Plasma gut microbial metabolites associate with glioblastoma risk and response to chemoradiation

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. Emerging evidence suggests that gut microbes may indirectly influence brain tumor behavior by releasing microbial metabolites that alter metabolism and immune activity. These metabolites act as signaling molecules that can promote or suppress tumor progression, implicating the gut-brain axis in GBM pathogenesis. This study investigated whether plasma levels of metabolites are associated with GBM susceptibility and response to treatment. METHODS From 2016 to 2020, 100 healthy individuals and 87 GBM patients were recruited at the Cleveland Clinic. All GBM patients received six weeks of radiation with concurrent chemotherapy. Patients were matched by age, surgical management, genomic profile, and treatment regimen. Response was defined as progression-free survival beyond 9 months, based on median time to progression from date of diagnosis. Plasma levels of 60 gut microbiota-associated metabolites were quantified by stable isotope dilution UHPLC with on-line tandem mass spectrometry and compared between healthy controls and GBM patients, and between responders and non-responders within the GBM cohort. Hierarchical clustering was used to visualize group-level differences. RESULTS Tryptophan-related metabolites were significantly decreased in GBM patients compared to healthy controls, including tryptophan, serotonin, indole-3-propionic acid, and indole-acetic acid, along with reduced phenylalanine and tyrosine-derived products, such as 4-ethylphenylsulfate and phenol sulfate. Metabolites linked to serotonin breakdown (5-OH-indole acetic acid), detoxification (hippuric acid, indoxyl-glucuronide), and carnitine metabolism (carnitine, TMAO) were elevated in GBM patients compared to healthy controls. Among GBM patients, non-responders had increased levels of amino acid metabolism-related metabolites, including phenylalanine, 4-hydroxyphenyllactic acid, C-mannosyltryptophan, symmetric dimethylarginine, and asymmetric dimethylarginine. CONCLUSIONS Several metabolites differed significantly between GBM patients and healthy individuals, and between responders and non-responders within the GBM cohort. These findings highlight the potential of circulating microbial metabolites as noninvasive biomarkers for GBM risk, response to therapy, and prognosis.