The microbiome and gynaecological cancer development, prevention and therapy

Abstract

The female reproductive tract (FRT), similar to other mucosal sites, harbours a site-specific microbiome, which has an essential role in maintaining health and homeostasis. In the majority of women of reproductive age, the microbiota of the lower FRT (vagina and cervix) microenvironment is dominated by Lactobacillus species, which benefit the host through symbiotic relationships. By contrast, the upper FRT (uterus, Fallopian tubes and ovaries) might be sterile in healthy individuals or contain a low-biomass microbiome with a diverse mixture of microorganisms. When dysbiosis occurs, altered immune and metabolic signalling can affect hallmarks of cancer, including chronic inflammation, epithelial barrier breach, changes in cellular proliferation and apoptosis, genome instability, angiogenesis and metabolic dysregulation. These pathophysiological changes might lead to gynaecological cancer. Emerging evidence shows that genital dysbiosis and/or specific bacteria might have an active role in the development and/or progression and metastasis of gynaecological malignancies, such as cervical, endometrial and ovarian cancers, through direct and indirect mechanisms, including modulation of oestrogen metabolism. Cancer therapies might also alter microbiota at sites throughout the body. Reciprocally, microbiota composition can influence the efficacy and toxic effects of cancer therapies, as well as quality of life following cancer treatment. Modulation of the microbiome via probiotics or microbiota transplant might prove useful in improving responsiveness to cancer treatment and quality of life. Elucidating these complex host-microbiome interactions, including the crosstalk between distal and local sites, will translate into interventions for prevention, therapeutic efficacy and toxic effects to enhance health outcomes for women with gynaecological cancers.

Fig. 1.. Microbial communities associated with health and gynaecological cancers.

Microbiota composition and other features of the local microenvironment associated with health and gynaecological cancers across the female reproductive tract (FRT). In healthy reproductive-age women, the majority of bacteria reside in the lower FRT (vagina and cervix). The vaginal microbiota exhibits low microbial diversity and is dominated by Lactobacillus species, which acidify the local microenvironment through the production of lactic acid. By contrast, the upper FRT (endometrium, Fallopian tubes and ovaries) might contain no to low microbial biomass. The normal upper FRT microbiota is still not well characterized and is considered sterile by some groups. Available data suggest that the upper FRT microbiome exhibits higher microbial diversity than the lower FRT microbiome, especially in diseased states. The presence of Lactobacillus species and other microorganisms has been reported in the endometrium, Fallopian tubes and ovaries. In women with gynaecological malignancies (cervical, endometrial and ovarian cancer), the local microbiota composition and biomass loads change considerably. In women with cervical cancer, the vaginal microbiome exhibits high microbial diversity and is characterized by an overgrowth of diverse anaerobic bacteria, particularly Sneathia. Lactobacillus depletion results in elevated vaginal pH. In women with endometrial cancer, the simultaneous presence of Atopobium and Porphyromonas has been associated with disease. In women with ovarian cancer, potential intracellular pathogens, such as Brucella, Mycoplasma and Chlamydia, and pathobionts, such as Acinetobacter, were reported. Overall, these dysbiotic microbiomes might contribute to the aetiology, disease severity and/or treatment of gynaecological cancers. TBD, to be determined.

Fig. 2.. Behavioural, socioeconomic, genetic and environmental factors contributing to genital dysbiosis and cancer.

Complex interactions between the microbiome and host that increase the risk of gynaecological cancer can be influenced by behavioural factors (sexual orientation, sexual activity, number of sexual partners, use of lubricants and sex toys, contraception, feminine hygiene practices, smoking and vaping, alcohol consumption, diet and nutrition, obesity and physical activity), socioeconomic factors (education, income, structured racism or segregation, social policy and access to health care), genetic and host factors (age, genome and epigenome, hormonal status, pregnancy, altered immunity or other comorbidities (cardiometabolic, neuroendocrine and immuno-inflammatory)) and environmental factors (sexually transmitted infection (STI) status (including bacterial, viral, fungal and parasitic infections), human papilloma virus (HPV) vaccination, stress, antibiotics, probiotics, xenobiotics, toxins, carcinogens, geography and early life factors such as gestation, birth route and infancy).

Fig. 3.. Female microbiome axes.

The female reproductive tract (FRT) microbiota interacts with the gut (vagina–gut axis) and the urinary tract microbiota (vagina–bladder axis) and possibly other distal mucosal sites (for example, the oral cavity) through direct or oestrogen-mediated mechanisms. The bacteria residing in the lower FRT, including Lactobacillus species and dysbiotic anaerobes, can ascend to the upper FRT. Common vaginal bacteria, such as Lactobacillus species, are components of the urinary tract microbiota. Vaginal Lactobacillus species can also colonize the rectum. Furthermore, gut microbiota can indirectly influence genital microbiota through the oestrobolome. Finally, haematogenous spread of bacteria (for example, from the oral cavity) might be a putative seeding route for the upper FRT microbiome. Potential extravaginal reservoirs of genital microorganisms are depicted with arrows.

Fig. 4.. Effect of microbiota on mucosal homeostasis and hallmarks of cancer.

a) Health-associated Lactobacillus spp. have a number of roles in homeostasis of the cervicovaginal microenvironment, including anti-inflammatory properties and improving barrier function. Lactobacillus species produce lactic acid, which acidifies the local microenvironment to pH <4.5 and protects the host from invading pathogens with a physiological level of inflammation. In addition, metabolites produced by Lactobacillus species can stimulate the host to produce antimicrobial peptides and anti-inflammatory cytokines. b) Dysbiotic genital bacteria might affect hallmarks of cancer, including chronic inflammation, barrier disruption, genomic instability, altered proliferation and/or apoptosis and angiogenesis. When dysbiosis occurs, Lactobacillus species are replaced with a diverse mixture of anaerobic bacteria (such as Anaerococcus, Atopobium, Dialister, Fusobacterium, Gardnerella, Gemella, Prevotella, Megasphaera, Parvimonas, Peptoniphilus, Peptostreptococcus, Porphyromonas, Shuttleworthia and Sneathia). These microorganisms induce the production of proinflammatory immune mediators and reactive oxygen species (ROS). Oxidative damage by ROS can exhibit genotoxic effects on epithelial cells or alter the proliferation of epithelial cells, which can consequently lead to cell apoptosis. Putative microbial products or metabolites might also directly affect cell proliferation and cause barrier disruption. Bacterial enzymes (for example, sialidase) can degrade the protective mucous layer. Finally, the vaginal bacteria might affect angiogenesis, for example, via stimulation of the Janus kinase (JAK)– signal transducer and activator of transcription (STAT) pathway and the production of angiogenic factors such as vascular endothelial growth factor. TNF, tumour necrosis factor. AMPs, antimicrobial peptides.

Fig. 5.. An overview of microbiota–cancer therapy interactions.

a) Gynaecological cancer therapies (surgery, radiotherapy, chemotherapy and immunotherapy) can affect microbial diversity and composition. The first line of treatment for gynaecological cancers is surgery (for example, hysterectomy); however, data are lacking regarding hysterectomy and modulation of the gut microbiome. The adverse effects of radiation and chemotherapies on gut microbiota are well characterized, whereas the effects of immunotherapy need further characterization. Toxic effects of chemotherapy and radiotherapy on the gut and vaginal ecosystems include diarrhoea or constipation, nausea, vomiting, abdominal pain, gastrointestinal bleeding, mucositis, vaginal stenosis and vulvovaginal atrophy (VVA). b) Modulation of the gut microbiota has been shown to alter the toxic effects and efficacy of cancer treatments. Diminishing the gut microbiota via antibiotics or other inhibitory agents, replenishing the microbiota via faecal microbiota transplantation (FMT) or vaginal microbiota transplantation (VMT) and supplementing the microbiota with prebiotics or probiotics might drive response to cancer therapy.

Fig. 6.. Novel approaches for modulating vaginal microbiota.

Combining current and experimental protocols for modulating the vaginal microbiota from dysbiotic to optimal Lactobacillus-dominant community state could affect carcinogenesis, therapeutic efficacy, toxicity and quality of life for women. Current and experimental protocols include existing antimicrobials, probiotics, intravaginally delivered vaginal lactobacilli formulations, novel antimicrobials, biofilm disruptors and vaginal microbiota transplantation (VMT).