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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.

Key points

  • The majority of bacteria in the female reproductive tract (FRT) reside in the vagina and cervix; however, the upper FRT might have a distinct low-biomass microbiome and site-specific microenvironmental factors.

  • A vaginal microbiome dominated by Lactobacillus species benefits the host, whereas a dysbiotic vaginal microbiome consisting of anaerobic bacteria is linked to numerous gynaecological and obstetric conditions, including gynaecological cancer.

  • Multiple socioeconomic, behavioural, environmental, hormonal and genetic factors can affect the genital microbiome by disrupting homeostasis and promoting dysbiosis; the FRT microbiome is intimately interconnected with other mucosal sites.

  • Emerging evidence suggests that microbial communities within the FRT might contribute to aetiology, disease severity and/or treatment of gynaecological cancers; however, further well-designed, large-cohort and mechanistic studies are needed.

  • The gut microbiome can modulate oestrogen levels and thereby affect carcinogenesis of oestrogen-mediated cancers, might dictate therapeutic efficacy and toxicity for gynaecological cancer and, ultimately, influence quality of life.

  • Vaginal microbiome modulation via probiotics, novel antimicrobials and/or vaginal microbiota transplantation might be a novel approach to the prevention of gynaecological cancers and/or the reduction of vaginal toxicities related to cancer treatment.

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Fig. 1: Microbial communities associated with health and gynaecological cancers.
Fig. 2: Behavioural, socioeconomic, genetic and environmental factors contributing to genital dysbiosis and cancer.
Fig. 3: Female microbiome axes.
Fig. 4: Effect of microbiota on mucosal homeostasis and hallmarks of cancer.
Fig. 5: An overview of microbiota–cancer therapy interactions.
Fig. 6: Novel approaches for modulating vaginal microbiota.

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Acknowledgements

We would like to acknowledge our clinical colleagues and past and present members of the Herbst-Kralovetz lab for thoughtful discussions on this topic. P.Ł., Z.E.I. and M.M.H.-K. have been supported by the Mary Kay Foundation Translational Research Grant (no. 017-48), the Valley Research Partnership Grant (no. VRP26), the Flinn Foundation Grant (no. 1974), the Alternatives Research and Development Foundation Grant, and the National Institutes of Health Grants from the National Institute of Allergy and Infectious Diseases (1R15AI113457-01A1) and the National Cancer Institute (NCI) and Office for Research on Women’s Health (P30CA023074 and 2U54CA143924-11).

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All authors contributed to researching data for the article, made substantial contributions to discussions of the content, and wrote and edited the manuscript before submission.

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Correspondence to Melissa M. Herbst-Kralovetz.

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M.M.H.-K. has been a consultant for Lupin Pharmaceuticals and Beckton Dickinson. P.Ł. and Z.E.I. declare no competing interests.

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Glossary

Microbiota

A community of microorganisms in a particular environment.

Microbiome

The entire habitat, which includes microorganisms, their genomes, and the surrounding environment.

Metagenome

The collection of genomes and genes from the members of a microbial community.

Pathobionts

Resident microorganisms with pathogenic potential, harmless to the host under normal conditions.

Osmolality

A concentration of osmotic solution expressed as the number of solute particles in 1kg of solvent.

Microbial culturomics

An approach to identifying unknown bacteria that inhabit the human body utilizing bacterial culture techniques to provide unique insights into host–bacteria relationships.

Metagenomics

An approach to characterizing microbial communities at genome and gene level without requiring culturing.

Oestrobolome

The collection of microorganisms (and their genes) that are able to metabolize oestrogens.

Metabolomic studies

Studies of small molecules (metabolites), which are substrates, intermediates and products of metabolism within microorganisms, cells, tissues or body fluids.

Metabolomes

The collections of small molecules (metabolites) and interactions among these molecules within a biological system.

Faecal microbiota transplantation

(FMT). A process of transplantation of faecal material from a healthy individual to a recipient for restoration of the gut microbiota.

Probiotics

Live microorganisms that confer a health benefit on the host when taken as a dietary supplement in adequate amounts.

Biofilm

An assemblage of microbial cells that form on and coat various surfaces.

Vaginal microbiota transplantation

(VMT). A process of transplantation of vaginal secretions from a healthy individual to a recipient for restoration of the vaginal microbiota.

Microbiomics

The study of microbial communities inhabiting a particular environment (for example, the human body).

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Łaniewski, P., Ilhan, Z.E. & Herbst-Kralovetz, M.M. The microbiome and gynaecological cancer development, prevention and therapy. Nat Rev Urol 17, 232–250 (2020). https://doi.org/10.1038/s41585-020-0286-z

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