Bidirectional Causal Effect Between Gut Microbiota and Glioma Risk: A Systematic Review‐Based Mendelian Randomization and Immune‐Mediated Effect Analysis

ABSTRACT Background Glioma is the most common malignant tumor in the central nervous system, with unclear pathogenesis and poor treatment outcomes. Recent research reveals that the brain–gut axis—involving gut microbiota and immune activity—influences central nervous system tumors. Given the pivotal role of the brain–gut axis in glioma, our study aimed to elucidate the causal association between gut microbiota and glioma, and to identify potential immune‐mediated effects and therapeutic targets. Methods Based on publicly available genome‐wide association study data, our research employed multi‐subgroup, replicated, Bayesian weighted, and summary statistics‐based two‐sample Mendelian randomization (MR) studies, combined with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) systematic review strategy, to systematically evaluate the potential causal effects of gut microbiota on glioma and their immune‐mediated traits. Results The initial screening identified 53 gut microbiota and 58 plasma immune traits with potential causal associations with glioma. Through external data and systematic review from six studies, we ultimately confirmed five gut microbiota‐plasma immune trait‐glioma pathways. CD28 + CD45RA − CD8dim Treg (OR = 0.019, p = 0.007) mediated the risk of Bacteroides A plebeius A (OR = 0.149, p = 0.036) on glioma, accounting for 2.99% of the effect; the proportion of CD4 + memory T cells in whole blood (OR = 0.066, p = 0.029) mediated the risk of Bacteroides sp002160055 (OR = 0.158, p = 0.024) on non‐glioblastoma(GBM), accounting for 8.51% of the effect, while the risk of Faecalicoccus (OR = 0.345, p = 0.005) on non‐GBM was jointly mediated by the absolute number of Naive CD8br and the expression of CD19 in IgD + CD38br B cells. The protective effect of Faecalibacterium sp002160895 on GBM was mediated by 7.59% of the expression level of CD4 in Treg cells. Conclusion Our study, through MR analysis, revealed the causal relationship between gut microbiota and the susceptibility to glioma, and for the first time proposed the important role of circulating immune cells in this process, providing new potential biomarkers for the early diagnosis and treatment of glioma.