Prevotella bivia promotes cervical cancer progression and modulates macrophage polarization, while Lactobacillus iners suppresses these processes: evidence from multiomics analysis.

内容摘要

The incidence and mortality rates of cervical cancer are high among women. Growing evidence suggests the key roles of the intratumor microbiome in various solid tumors. However, the intratumoral microbiome in patients with cervical cancer has not been well characterized. In this study, 16S rRNA sequencing was performed on 76 tissues to reveal the features of the intratumoral microbiome, and the highly differentially abundant bacteria Lactobacillus iners/Prevotella bivia were selected for functional verification. Flow cytometry, transwell migration, and invasion experiments, among others, were performed in vitro; subcutaneous tumor formation and lung metastasis experiments were performed in vivo. Additionally, macrophages were cocultured with the L. iners/P. bivia supernatant to evaluate how the intratumoral microbiome affects their polarization, and tumor cell and macrophage transcriptome sequencing was subsequently performed to explore the potential molecular mechanisms involved. Metabolomic analysis of tissues and bacterial supernatants was performed to search for potential carcinogens and cancer suppressors. We determined that the abundance of microbes was greater in cervical cancer tissues than in normal cervical and paracancerous tissues. The relative abundance of Prevotella was correlated with deep stromal invasion, tumor size, clinical stage, and poor survival prognosis in cervical cancer patients. L. iners inhibited the proliferation and promoted the apoptosis of tumor cells, whereas P. bivia significantly promoted cervical cancer cell migration and invasion. Mechanistically, the modulation of phosphorylated PI3K/AKT/mTOR signaling may be involved in the observed effects. P. bivia promoted M2 macrophage polarization by activating phosphorylated STAT3 and NF-κB, but the role of L. iners remains unknown. The amino acid metabolism, carbohydrate metabolism, and lipid metabolism pathways were enriched in differentially abundant metabolites such as glycine, which may be a key molecule. This study provides evidence that the intratumoral microbiome, represented by L. iners/P. bivia, affects tumor biology and macrophage polarization in patients with cervical cancer.IMPORTANCEThe microbiome in cervical cancer tissues significantly differed from that in normal cervical tissues and showed significant correlations with clinicopathological features and survival prognosis. The tumor microbiome affects the biological behavior of cervical tumor cells and the polarization of macrophages through metabolite production, thus playing an important role in the occurrence and development of cervical cancer.