Uncovering the mediating role of CSF metabolites in the gut microbiota–glioblastoma axis via causal mediation analysis

BACKGROUND: Glioblastoma is a lethal brain tumor with poor prognosis and limited early diagnostic tools. The gut microbiota and its metabolites may influence glioblastoma progression through the gut-brain axis. METHODS: We employed Mendelian randomization and Generalized Summary-data-based Mendelian Randomization to explore causal relationships among 473 gut microbial taxa, 338 cerebrospinal fluid metabolites, and glioblastoma risk in Finnish individuals. Mediation analysis was conducted to identify key pathways linking gut microbes, metabolites, and glioblastoma development. RESULTS: Coprobacillus cateniformis was positively associated with glioblastoma (OR = 1.7363,95%CI:1.0541–2.8600,P = 0.030). The cerebrospinal fluid metabolite S-1-pyrroline-5-carboxylate was negatively associated with glioblastoma (OR = 0.7270,95%CI:0.5506–0.9598,P = 0.024). Additionally, Coprobacillus cateniformis was negatively associated with S-1-pyrroline-5-carboxylate (OR = 0.8933, 95%CI:0.7994–0.9982,P = 0.046). Mediation analysis indicated that S-1-pyrroline-5-carboxylate served as a mediator in the pathway through which Coprobacillus cateniformis promotes glioblastoma development, with a mediation effect ratio of 6.1%. CONCLUSION: This study reveals a potential causal pathway linking Coprobacillus cateniformis to glioblastoma through S-1-pyrroline-5-carboxylate. These findings highlight a novel gut–cerebrospinal fluid–brain axis and suggest potential microbial and metabolic biomarkers for glioblastoma diagnosis and therapy.