Gut and oral microbiota in gynecological cancers: interaction, mechanism, and therapeutic value

Abstract

Gynecologic cancers develop from the female reproductive organs. Microbial dysbiosis in the gut and oral cavity can communicate with each other through various ways, leading to mucosal destruction, inflammatory response, genomic instability, and ultimately inducing cancer and worsening. Here, we introduce the mechanisms of interactions between gut and oral microbiota and their changes in the development of gynecologic tumors. In addition, new therapeutic approaches based on microbiota modulation are discussed.

Fig. 1. Gut and oral microbiota in the tumorigenesis.

MAMP microbial-associated molecular patterns, PXR pregnane X receptor, FXR farnesoid X receptor, TGR5 Takeda G protein-coupled receptor 5, MAPK mitogen-protein kinases, NF-κB nuclear factor kappa-light-chain-enhancer in activated B cells, IGF-1 insulin-like growth factor 1, EGF epidermal growth factor. Alterations in oral/gut microbiota composition may impact the development of gynecological cancers via changes in pathogen translocation, metabolite release, and modulation of estrogen levels. Dysbiosis within the gut/oral microbiome represents a consistent hallmark among gynecological cancer patients; distinct diseases exhibit varying increases in specific bacterial species while universally displaying reduced levels of beneficial bacterium Lactobacillus. Anatomically, the mouth and gut are closely connected, and pathogens that colonize these two sites can migrate to various parts of the body. Immune cells recognize pathogens’ MAMPs through NODs and LTRs, producing a strong inflammatory response that induces gene mutations. Metabolites produced by intestinal microbes, including short-chain fatty acids (SCFAs), bile acids (BAs), and lactic acids (LAs), are crucial for cellular homeostasis. SCFAs are ligands for GPCRs, while BAs are ligands for PXR, TGR5, and FXR, which play roles in various cellular pathways, controlling cell adhesion, cell apoptosis, and the formation of various cytokines. Furthermore, estrogen receptors are highly expressed in the mouth and intestines, where estrogen compounds can shape the gut and oral microbiomes. On the other hand, there are genes encoding β-glucuronidase in the human gut microbiome, which regulates endogenous estrogen metabolism and affects downstream MAPK, NF-κB, IGF-1, and EGF pathways.

Fig. 2. Gut and oral microbiota in the development of cervical cancer (CC).

HPV is the main cause of CC, and evidence of HPV colonization has been found on the mucous membranes of the oral and gastrointestinal tracts. Integration of HPV DNA into the genome of cervical epithelial cells leads to sustained expression of viral oncogenes E6 and E7, ultimately leading to abnormal cell proliferation and carcinogenic induction. In addition to HPV infection, bacterial dysbiosis caused by abnormal bacterial proliferation in the gastrointestinal tract and oral mucosa is also a major cause of CC, with a reduction in Lactobacillus and an advantage of anaerobic bacteria being characteristic of CC patients’ microbiome. Disruption of the microbiome triggers an inflammatory response, which can lead to DNA damage and carcinogenic mutations. HPV may also interact with the microbiome, with a reduction in Lactobacillus induced by HPV infection, and an increase in the abundance of Sneathia spp. and Clostridium also potentially contributing to the development of CC.