Metabolites and Immune Cells Mediated the Causal Relationship Between the Gut Microbiota and Osteosarcoma: A Mendelian Randomization Study.

Background and Aims: Osteosarcoma (OS) is characterized by a primary malignant bone tumor with high local invasion and metastasis potential. The role of gut microbiota (GM) in the development of OS remains poorly understood. This study aims to investigate the relationship between GM, plasma metabolites, immune cells, and OS utilizing Mendelian randomization (MR). Methods: Summary data from large-scale Genome-Wide Association Studies (GWAS) involving GM, plasma metabolites, immune cells, and OS cases were applied. A two-sample MR approach was used to evaluate the causal effects among these factors. The analysis was performed by using the inverse variance weighting (IVM) method, MR-Egger, and other sensitivity analyses to ensure the reliability of results. Furthermore, mediation analysis was employed to elucidate the mediating roles of metabolites and immune cells in the relationship between GM and OS. Results: MR identified six gut microbial traits that are causally linked to OS, including three metabolic pathways and three taxa. Pathways involved in amino acid metabolism were associated with increased OS risk. In contrast, the Bacteroidaceae family appeared protective, whereas the genus Conclusions: This study provides evidence supporting the involvement of GM, plasma metabolites, and immune cells play critical roles in the development of OS.