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

## TL;DR

This study finds that gut microbes, metabolites, and immune cells are linked to osteosarcoma risk, suggesting new ways to understand and treat the disease.

## Contribution

The study identifies causal gut microbial traits, metabolites, and immune cells that mediate the risk of osteosarcoma using Mendelian randomization.

## Key findings

- Six gut microbial traits, including three metabolic pathways and three taxa, are causally linked to osteosarcoma.
- Twelve plasma metabolites are associated with osteosarcoma, with seven being protective and two increasing risk.
- Nine immune cell phenotypes are linked to osteosarcoma, with Flavonifractor plautii increasing risk via CX3CR1+ monocytes.

## Abstract

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).

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.

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 Flavonifractor was linked to a higher risk. MR also identified 12 plasma metabolites associated with OS; seven were protective (including 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoate [CMPF]) and two increased risk. The l‐isoleucine biosynthesis pathway (PWY‐3001) was associated with lower CMPF levels, whereas Flavonifractor was associated with higher CMPF. Mediation analysis showed that CMPF partially mediated the effect of PWY‐3001 on OS (~35%) but not that of Flavonifractor. Nine immune cell phenotypes were linked to OS (five positively, four inversely). Flavonifractor plautii (F. plautii) was associated with an increased proportion of CX3CR1+ monocytes, which in turn increased OS risk; these monocytes mediated ~5% of F. plautii's effect on OS.

This study provides evidence supporting the involvement of GM, plasma metabolites, and immune cells play critical roles in the development of OS.