Review ArticleDoes the vaginal microbiota play a role in the development of cervical cancer?
Introduction
Although cervical cancer is largely preventable through detection and treatment of the preinvasive precursor, high-grade squamous intraepithelial lesions (HSILs), it remains the commonest female malignancy in virtually all low-resource countries and the seventh more frequent malignancy in females worldwide.1 It is estimated that, globally, almost 530,000 women develop cervical invasive disease annually and more than 265,000 die from the disease.2 The comparatively low incidence of cervical cancer in affluent societies is largely related to the presence of population-based screening programs and education that led to a dramatic decrease in the incidence and mortality from the disease.3 Although the human papillomavirus (HPV) vaccine has the potential to dramatically decrease these rates, introduction into most developing countries has been slow, so these changes are not expected to impact cervical cancer rates for at least 1 to 2 decades.
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HPV and Cervical Carcinogenesis
There is strong evidence that infection with HPV is necessary but not sufficient for the development of cervical preinvasive and invasive disease. With more than 200 HPV subtypes recognized today, it is only a fraction of these that has been found to have a carcinogenic potential.4 Of these, subtypes HPV-16 and HPV-18 are most commonly associated with invasive cancers and are thought to cause approximately 65–75% of the cases. It is now recognized that it is the persistence of infection by
The Vaginal Microbiome
Much of the work to date on mucosal microbiota has been focused on the gut including its influence on immune function, behavior as well as local and systemic inflammatory diseases.22, 23, 24 The Human Microbiome Project has extensively examined the vaginal microbiota although in contrast to the gut, less is understood about the role of the VM in human disease. A detailed description of the VM is outside the scope of this article and can be found in several review articles.25, 26 In the
Vaginal Microbiome, HPV, and Immune Response
There are no good direct data that show how altered VM influences local immune function. However, it is plausible that the stability and composition of the VM may play an important role in determining host innate immune response and susceptibility to infection as well as playing a role further downstream regarding the development of cervical disease.
Several studies have shown that BV and BV-associated bacteria effect immune parameters within the vagina including cytokines/chemokines,
HPV Infection and the Vaginal Microbiome
Several pieces of evidence suggest that HPV is affected by the VM. In meta-analyses of mostly cross-sectional studies, the presence of BV was associated with higher rates of HPV infection (12 studies; odds ratio [OR]: 1.43, 95% confidence interval (CI): 1.11–1.84)74 suggesting that a diverse, Lactobacillus-depleted microbiome may contribute to HPV persistence. There is also evidence to suggest that persistence is more likely in those with altered microbiome. In one study, women with persistent
Preinvasive and Invasive Cervical Cancer and the Vagina Microbiome
More recently, we published the first study describing the VM in 169 women with biopsy-proven cervical preinvasive and invasive disease and compared them to healthy HPV-negative controls.81 We found that the rate of Lactobacillus-depleted high-diversity microbiome (CST IV) was increased 2 fold in women with low-grade squamous intraepithelial neoplasia (LSIL), 3 fold in women with high-grade squamous intraepithelial neoplasia (HSIL), and 4 fold in women with invasive disease (normal = 2/20, 10%;
Barriers and Limitations of the Existing Literature
Rapidly evolving evidence suggests the importance of the interactions between the human host, the innate immunity, the microbiome and virome in the genital tract with health and disease. Despite variations among the studies, the results consistently demonstrate differences in the microbiota noted in women with cervical disease that appear to correlate with the severity of the disease. Lactobacilli produce hydrogen peroxide and preserve an acid protective environment in the vagina with low pH.
Future Directions
There appears to be a complex relationship between the host and the VM, and composition of the VM may play a role in host susceptibility to HPV infection, its persistence, and subsequent development of dysplastic and ultimately neoplastic lesions. The evaluation of all these interactions can be challenging, as the VM shows significant intraindividual variability, whereas different HPV subtypes that may be present at a given time may follow a different independent course, and these shifts in
Conclusion
There is a wealth of emerging evidence to suggest that the cervico-vaginal bacterial population plays a substantial role in the persistence of the virus and the presence of subsequent cervical preinvasive disease. The role of the microbiome in other HPV-related cancers such as vulvar, anal, and oropharyngeal cancers has not yet been explored but likely play important roles. Future studies assessing the impact of the VM in cervical carcinogenesis should explore the causal link in longitudinal
Acknowledgments
Conflicts of Interest: All authors have read the journal's policy on disclosure of potential conflicts of interest and have none to declare.
The article conforms to the relevant ethical guidelines for human and animal research.
British Society of Colposcopy Cervical Pathology Jordan/Singer Award (P47773, M. Kyrgiou); Imperial College Healthcare Charity (M. Kyrgiou, A. Mitra; P47907); Genesis Research Trust (M. Kyrgiou; P55549); Imperial Healthcare NHS Trust NIHR Biomedical Research Centre (M.
References (123)
- et al.
The cervical cancer epidemic that screening has prevented in the UK
Lancet
(2004) - et al.
Alpha, beta and gamma human papillomaviruses in the anal canal of HIV-infected and uninfected men who have sex with men
J Infect
(2015) - et al.
Effect of cigarette smoking on cervical epithelial immunity: a mechanism for neoplastic change?
Lancet
(1988) - et al.
High intraepithelial expression of estrogen and progesterone receptors in the transformation zone of the uterine cervix
Am J Obstet Gynecol
(2003) - et al.
Factors that influence the rate of epithelial maturation in the cervix in healthy young women
J Adolesc Health
(2009) - et al.
Updating the natural history of human papillomavirus and anogenital cancers
Vaccine
(2012) - et al.
Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome
Psychoneuroendocrinology
(2013) - et al.
Disruption of urogenital biofilms by Lactobacilli
Colloids Surf B Biointerfaces
(2011) - et al.
Role played by Lactobacilli in controlling the population of vaginal pathogens
Microbes Infect
(2000) - et al.
Defense factors of vaginal Lactobacilli
Am J Obstet Gynecol
(2001)
Biosurfactants produced by Lactobacillus
Methods Enzymol
Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis
Am J Obstet Gynecol
Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study
Lancet
Inflammation and cancer: back to Virchow?
Lancet
Cervicovaginal microbiome dysbiosis is associated with proteome changes related to alterations of the cervicovaginal mucosal barrier
Mucosal Immunol
Atopobium vaginae triggers an innate immune response in an in vitro model of bacterial vaginosis
Microbes Infect
Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract
Immunity
Higher levels of cervicovaginal inflammatory and regulatory cytokines and chemokines in healthy young women with immature cervical epithelium
J Reprod Immunol
Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin
Cell Host Microbe
Where's the high-grade cervical neoplasia? The importance of minimally abnormal Papanicolaou diagnoses
Obstet Gynecol
Is there a local production of nitrosamines by the vaginal microflora in anaerobic vaginosis/trichomoniasis?
Med Hypotheses
DNA damage and repair in Helicobacter pylori-infected gastric mucosa cells
Mutat Res
Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012
Int J Cancer
Cervical Cancer. Estimated Incidence, Mortality and Prevalence Worldwide in 2012
Human papillomavirus is a necessary cause of invasive cervical cancer worldwide
J Pathol
Prevalence of HPV infection among females in the United States
JAMA
Human papillomavirus infection in sexually active adolescent females: prevalence and risk factors
Pediatr Res
Identification of a high-molecular-mass Lactobacillus epithelium adhesin (LEA) of Lactobacillus crispatus ST1 that binds to stratified squamous epithelium
Microbiology
Natural history of cutaneous human papillomavirus (HPV) infection in men: the HIM study
PLoS One
The oral cavity contains abundant known and novel human papillomaviruses from the Betapapillomavirus and Gammapapillomavirus genera
J Infect Dis
SEER Stat Fact Sheets: Cervix Uteri Cancer
Nicotine and cotinine in the cervical mucus of smokers, passive smokers, and nonsmokers
Cancer Epidemiol Biomarkers Prev
Parity as a cofactor for high-grade cervical disease among women with persistent human papillomavirus infection: a 13-year follow-up
Br J Cancer
Epithelial cell responses to infection with human papillomavirus
Clin Microbiol Rev
Commensal bacteria modulate innate immune responses of vaginal epithelial cell multilayer cultures
PLoS One
Molecular biology of human papillomavirus infection and cervical cancer
Clin Sci (Lond)
Papillomavirus E6 and E7 proteins and their cellular targets
Front Biosci
The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice
Gastroenterology
Towards large-cohort comparative studies to define the factors influencing the gut microbial community structure of ASD patients
Microb Ecol Health Dis
The vaginal microbiota: what have we learned after a decade of molecular characterization?
PLoS One
Vaginal microbiome and sexually transmitted infections: an epidemiologic perspective
J Clin Invest
Origins of vaginal acidity: high D/L lactate ratio is consistent with bacteria being the primary source
Hum Reprod
Characterization of a bacteriocin-like substance produced by a vaginal Lactobacillus salivarius strain
Appl Environ Microbiol
Longitudinal analysis of the vaginal microflora in pregnancy suggests that L. crispatus promotes the stability of the normal vaginal microflora and that L. gasseri and/or L. iners are more conducive to the occurrence of abnormal vaginal microflora
BMC Microbiol
Vaginal microbiome of reproductive-age women
Proc Natl Acad Sci U S A
Structure, function and diversity of the healthy human microbiome
Nature
Temporal dynamics of the human vaginal microbiota
Sci Transl Med
Prevalent and incident bacterial vaginosis are associated with sexual and contraceptive behaviours in young Australian women
PLoS One
Prevalence of malaria and sexually transmitted and reproductive tract infections in pregnancy in sub-Saharan Africa: a systematic review
JAMA
A cluster analysis of bacterial vaginosis-associated microflora and pelvic inflammatory disease
Am J Epidemiol
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