Does the vaginal microbiota play a role in the development of cervical cancer?

  • Maria Kyrgiou
    Institute of Reproductive and Developmental Biology, Department of Surgery & Cancer, Faculty of Medicine, Imperial College, London, UK

    Queen Charlotte's & Chelsea – Hammersmith Hospital, Imperial Healthcare NHS Trust, London, UK
    Search for articles by this author
  • Anita Mitra
    Institute of Reproductive and Developmental Biology, Department of Surgery & Cancer, Faculty of Medicine, Imperial College, London, UK
    Search for articles by this author
  • Anna-Barbara Moscicki
    Reprint requests: Anna-Barbara Moscicki, Chief, Division of Adolescent and Young Adult Medicine, Ronald Reagan UCLA Medical Center, UCLA Medical Center, 10833 Le Conte Ave MD 22-432, Los Angeles, California 90095.
    Department of Pediatrics, University of California, Los Angeles
    Search for articles by this author
      Persistent infection with oncogenic human papillomavirus (HPV) is necessary but not sufficient for the development of cervical cancer. The factors promoting persistence as well those triggering carcinogenetic pathways are incompletely understood. Rapidly evolving evidence indicates that the vaginal microbiome (VM) may play a functional role (both protective and harmful) in the acquisition and persistence of HPV, and subsequent development of cervical cancer. The first studies examining the VM and the presence of an HPV infection using next-generation sequencing techniques identified higher microbial diversity in HPV-positive as opposed to HPV-negative women. Furthermore, there appears to be a temporal relationship between the VM and HPV infection in that specific community state types may be correlated with a higher chance of progression or regression of the infection. Studies describing the VM in women with preinvasive disease (squamous intraepithelial neoplasia [SIL]) consistently demonstrate a dysbiosis in women with the more severe disease. Although it is plausible that the composition of the VM may influence the host’s innate immune response, susceptibility to infection, and the development of cervical disease, the studies to date do not prove causality. Future studies should explore the causal link between the VM and the clinical outcome in longitudinal samples from existing biobanks.


      8-OHdG (8-hydroxy-2' -deoxyguanosine), ASCUS (atypical squamous cells of uncertain significance), BV (bacterial vaginosis), CST (community state type), HNCF (human normal fibroblast-like cervical), HPV (human papillomavirus), HSIL (high-grade squamous intraepithelial lesion), IUD (intrauterine device), LSIL (low-grade squamous intraepithelial lesion), MPA (medroxyprogesterone acetate), NGS (next-generation sequencing), OC (oral contraceptive), OTU (operational taxonomic unit), SIL (squamous intraepithelial lesion), STI (sexually transmitted infection), VM (vaginal microbiome)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Ferlay J.
        • Soerjomataram I.
        • Dikshit R.
        • et al.
        Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
        Int J Cancer. 2015; 136: E359-E386
      1. Cervical Cancer. Estimated Incidence, Mortality and Prevalence Worldwide in 2012. GLOBOCAN 2012. International Agency for Research on Cancer. World Health Organization, Lyon, France2012
        • Peto J.
        • Gilham C.
        • Fletcher O.
        • et al.
        The cervical cancer epidemic that screening has prevented in the UK.
        Lancet. 2004; 364: 249-256
        • Walboomers J.M.
        • Jacobs M.V.
        • Manos M.M.
        • et al.
        Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.
        J Pathol. 1999; 189: 12-19
        • Dunne E.F.
        • Unger E.R.
        • Sternberg M.
        • et al.
        Prevalence of HPV infection among females in the United States.
        JAMA. 2007; 297: 813-819
        • Moscicki A.B.
        • Palefsky J.
        • Gonzales J.
        • et al.
        Human papillomavirus infection in sexually active adolescent females: prevalence and risk factors.
        Pediatr Res. 1990; 28: 507-513
        • Edelman S.M.
        • Lehti T.A.
        • Kainulainen V.
        • et al.
        Identification of a high-molecular-mass Lactobacillus epithelium adhesin (LEA) of Lactobacillus crispatus ST1 that binds to stratified squamous epithelium.
        Microbiology. 2012; 158: 1713-1722
        • Hampras S.S.
        • Giuliano A.R.
        • Lin H.Y.
        • et al.
        Natural history of cutaneous human papillomavirus (HPV) infection in men: the HIM study.
        PLoS One. 2014; 9: e104843
        • Dona M.G.
        • Gheit T.
        • Latini A.
        • 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; 71: 74-84
        • Bottalico D.
        • Chen Z.
        • Dunne A.
        • et al.
        The oral cavity contains abundant known and novel human papillomaviruses from the Betapapillomavirus and Gammapapillomavirus genera.
        J Infect Dis. 2011; 204: 787-792
        • National Cancer Institute
        SEER Stat Fact Sheets: Cervix Uteri Cancer.
        2012 (Available at:) (Accessed March 31, 2016)
        • McCann M.F.
        • Irwin D.E.
        • Walton L.A.
        • et al.
        Nicotine and cotinine in the cervical mucus of smokers, passive smokers, and nonsmokers.
        Cancer Epidemiol Biomarkers Prev. 1992; 1: 125-129
        • Barton S.E.
        • Maddox P.H.
        • Jenkins D.
        • et al.
        Effect of cigarette smoking on cervical epithelial immunity: a mechanism for neoplastic change?.
        Lancet. 1988; 2: 652-654
        • Remoue F.
        • Jacobs N.
        • Miot V.
        • et al.
        High intraepithelial expression of estrogen and progesterone receptors in the transformation zone of the uterine cervix.
        Am J Obstet Gynecol. 2003; 189: 1660-1665
        • Hwang L.Y.
        • Ma Y.
        • Benningfield S.M.
        • et al.
        Factors that influence the rate of epithelial maturation in the cervix in healthy young women.
        J Adolesc Health. 2009; 44: 103-110
        • Jensen K.E.
        • Schmiedel S.
        • Norrild B.
        • et al.
        Parity as a cofactor for high-grade cervical disease among women with persistent human papillomavirus infection: a 13-year follow-up.
        Br J Cancer. 2013; 108: 234-239
        • Moscicki A.B.
        • Schiffman M.
        • Burchell A.
        • et al.
        Updating the natural history of human papillomavirus and anogenital cancers.
        Vaccine. 2012; 30: F24-F33
        • Stanley M.A.
        Epithelial cell responses to infection with human papillomavirus.
        Clin Microbiol Rev. 2012; 25: 215-222
        • Rose 2nd, W.A.
        • McGowin C.L.
        • Spagnuolo R.A.
        • et al.
        Commensal bacteria modulate innate immune responses of vaginal epithelial cell multilayer cultures.
        PLoS One. 2012; 7: e32728
        • Doorbar J.
        Molecular biology of human papillomavirus infection and cervical cancer.
        Clin Sci (Lond). 2006; 110: 525-541
        • Wise-Draper T.M.
        • Wells S.I.
        Papillomavirus E6 and E7 proteins and their cellular targets.
        Front Biosci. 2008; 13: 1003-1017
        • Bercik P.
        • Denou E.
        • Collins J.
        • et al.
        The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.
        Gastroenterology. 2011; 141 (609 e1–3): 599-609
        • Ohland C.L.
        • Kish L.
        • Bell H.
        • 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; 38: 1738-1747
        • McDonald D.
        • Hornig M.
        • Lozupone C.
        • et al.
        Towards large-cohort comparative studies to define the factors influencing the gut microbial community structure of ASD patients.
        Microb Ecol Health Dis. 2015; 26: 26555
        • van de Wijgert J.H.
        • Borgdorff H.
        • Verhelst R.
        • et al.
        The vaginal microbiota: what have we learned after a decade of molecular characterization?.
        PLoS One. 2014; 9: e105998
        • Brotman R.M.
        Vaginal microbiome and sexually transmitted infections: an epidemiologic perspective.
        J Clin Invest. 2011; 121: 4610-4617
        • Boskey E.R.
        • Cone R.A.
        • Whaley K.J.
        • et al.
        Origins of vaginal acidity: high D/L lactate ratio is consistent with bacteria being the primary source.
        Hum Reprod. 2001; 16: 1809-1813
        • McMillan A.
        • Dell M.
        • Zellar M.P.
        • et al.
        Disruption of urogenital biofilms by Lactobacilli.
        Colloids Surf B Biointerfaces. 2011; 86: 58-64
        • Boris S.
        • Barbes C.
        Role played by Lactobacilli in controlling the population of vaginal pathogens.
        Microbes Infect. 2000; 2: 543-546
        • Aroutcheva A.
        • Gariti D.
        • Simon M.
        • et al.
        Defense factors of vaginal Lactobacilli.
        Am J Obstet Gynecol. 2001; 185: 375-379
        • Reid G.
        • Heinemann C.
        • Velraeds M.
        • et al.
        Biosurfactants produced by Lactobacillus.
        Methods Enzymol. 1999; 310: 426-433
        • Ocana V.S.
        • Pesce De Ruiz Holgado A.A.
        • Nader-Macias M.E.
        Characterization of a bacteriocin-like substance produced by a vaginal Lactobacillus salivarius strain.
        Appl Environ Microbiol. 1999; 65: 5631-5635
        • Verstraelen H.
        • Verhelst R.
        • Claeys G.
        • et al.
        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. 2009; 9: 116
        • Ravel J.
        • Gajer P.
        • Abdo Z.
        • et al.
        Vaginal microbiome of reproductive-age women.
        Proc Natl Acad Sci U S A. 2011; 108: 4680-4687
        • Human Microbiome Project Consortium
        Structure, function and diversity of the healthy human microbiome.
        Nature. 2012; 486: 207-214
        • Gajer P.
        • Brotman R.M.
        • Bai G.
        • et al.
        Temporal dynamics of the human vaginal microbiota.
        Sci Transl Med. 2012; 4: 132ra52
        • Bradshaw C.S.
        • Walker J.
        • Fairley C.K.
        • et al.
        Prevalent and incident bacterial vaginosis are associated with sexual and contraceptive behaviours in young Australian women.
        PLoS One. 2013; 8: e57688
        • Chico R.M.
        • Mayaud P.
        • Ariti C.
        • et al.
        Prevalence of malaria and sexually transmitted and reproductive tract infections in pregnancy in sub-Saharan Africa: a systematic review.
        JAMA. 2012; 307: 2079-2086
        • Ness R.B.
        • Kip K.E.
        • Hillier S.L.
        • et al.
        A cluster analysis of bacterial vaginosis-associated microflora and pelvic inflammatory disease.
        Am J Epidemiol. 2005; 162: 585-590
        • Leitich H.
        • Bodner-Adler B.
        • Brunbauer M.
        • et al.
        Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis.
        Am J Obstet Gynecol. 2003; 189: 139-147
        • Brotman R.M.
        • Klebanoff M.A.
        • Nansel T.R.
        • et al.
        Bacterial vaginosis assessed by gram stain and diminished colonization resistance to incident gonococcal, chlamydial, and trichomonal genital infection.
        J Infect Dis. 2010; 202: 1907-1915
        • Atashili J.
        • Poole C.
        • Ndumbe P.M.
        • et al.
        Bacterial vaginosis and HIV acquisition: a meta-analysis of published studies.
        AIDS. 2008; 22: 1493-1501
        • Dewhirst F.E.
        • Chen T.
        • Izard J.
        • et al.
        The human oral microbiome.
        J Bacteriol. 2010; 192: 5002-5017
        • Srinivasan S.
        • Hoffman N.G.
        • Morgan M.T.
        • et al.
        Bacterial communities in women with bacterial vaginosis: high resolution phylogenetic analyses reveal relationships of microbiota to clinical criteria.
        PLoS One. 2012; 7: e37818
        • MacIntyre D.A.
        • Chandiramani M.
        • Lee Y.S.
        • et al.
        The vaginal microbiome during pregnancy and the postpartum period in a European population.
        Sci Rep. 2015; 5: 8988
        • Romero R.
        • Hassan S.S.
        • Gajer P.
        • et al.
        The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women.
        Microbiome. 2014; 2: 4
        • Plummer M.
        • Herrero R.
        • Franceschi S.
        • et al.
        Smoking and cervical cancer: pooled analysis of the IARC multi-centric case–control study.
        Cancer Causes Control. 2003; 14: 805-814
        • Moreno V.
        • Bosch F.X.
        • Munoz N.
        • et al.
        Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study.
        Lancet. 2002; 359: 1085-1092
        • Fichorova R.N.
        • Chen P.L.
        • Morrison C.S.
        • et al.
        The contribution of cervicovaginal infections to the immunomodulatory effects of hormonal contraception.
        MBio. 2015; 6 (e00221–15)
        • Round J.L.
        • Mazmanian S.K.
        The gut microbiota shapes intestinal immune responses during health and disease.
        Nat Rev Immunol. 2009; 9: 313-323
        • Balkwill F.
        • Mantovani A.
        Inflammation and cancer: back to Virchow?.
        Lancet. 2001; 357: 539-545
        • Achilles S.L.
        • Hillier S.L.
        The complexity of contraceptives: understanding their impact on genital immune cells and vaginal microbiota.
        AIDS. 2013; 27: S5-S15
        • van de Wijgert J.H.
        • Verwijs M.C.
        • Turner A.N.
        • et al.
        Hormonal contraception decreases bacterial vaginosis but oral contraception may increase candidiasis: implications for HIV transmission.
        AIDS. 2013; 27: 2141-2153
        • Vodstrcil L.A.
        • Hocking J.S.
        • Law M.
        • et al.
        Hormonal contraception is associated with a reduced risk of bacterial vaginosis: a systematic review and meta-analysis.
        PLoS One. 2013; 8: e73055
        • Borgdorff H.
        • Gautam R.
        • Armstrong S.D.
        • et al.
        Cervicovaginal microbiome dysbiosis is associated with proteome changes related to alterations of the cervicovaginal mucosal barrier.
        Mucosal Immunol. 2016; 9: 621-633
        • Mitchell C.M.
        • McLemore L.
        • Westerberg K.
        • et al.
        Long-term effect of depot medroxyprogesterone acetate on vaginal microbiota, epithelial thickness and HIV target cells.
        J Infect Dis. 2014; 210: 651-655
        • Vogtmann E.
        • Flores R.
        • Yu G.
        • et al.
        Association between tobacco use and the upper gastrointestinal microbiome among Chinese men.
        Cancer Causes Control. 2015; 26: 581-588
        • Ahn J.
        • Chen C.Y.
        • Hayes R.B.
        Oral microbiome and oral and gastrointestinal cancer risk.
        Cancer Causes Control. 2012; 23: 399-404
        • Bradshaw C.S.
        • Walker S.M.
        • Vodstrcil L.A.
        • et al.
        The influence of behaviors and relationships on the vaginal microbiota of women and their female partners: the WOW Health Study.
        J Infect Dis. 2014; 209: 1562-1572
        • Brotman R.M.
        • He X.
        • Gajer P.
        • et al.
        Association between cigarette smoking and the vaginal microbiota: a pilot study.
        BMC Infect Dis. 2014; 14: 471
        • Onderdonk A.B.
        • Delaney M.L.
        • Fichorova R.N.
        The human microbiome during bacterial vaginosis.
        Clin Microbiol Rev. 2016; 29: 223-238
        • Mitchell C.
        • Marrazzo J.
        Bacterial vaginosis and the cervicovaginal immune response.
        Am J Reprod Immunol. 2014; 71: 555-563
        • Libby E.K.
        • Pascal K.E.
        • Mordechai E.
        • et al.
        Atopobium vaginae triggers an innate immune response in an in vitro model of bacterial vaginosis.
        Microbes Infect. 2008; 10: 439-446
        • Doerflinger S.Y.
        • Throop A.L.
        • Herbst-Kralovetz M.M.
        Bacteria in the vaginal microbiome alter the innate immune response and barrier properties of the human vaginal epithelia in a species-specific manner.
        J Infect Dis. 2014; 209: 1989-1999
        • Anahtar M.N.
        • Byrne E.H.
        • Doherty K.E.
        • et al.
        Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract.
        Immunity. 2015; 42: 965-976
        • Anderson B.L.
        • Cu-Uvin S.
        • Raker C.A.
        • et al.
        Subtle perturbations of genital microflora alter mucosal immunity among low-risk pregnant women.
        Acta Obstet Gynecol Scand. 2011; 90: 510-515
        • Hedges S.R.
        • Barrientes F.
        • Desmond R.A.
        • et al.
        Local and systemic cytokine levels in relation to changes in vaginal flora.
        J Infect Dis. 2006; 193: 556-562
        • Novak R.M.
        • Donoval B.A.
        • Graham P.J.
        • et al.
        Cervicovaginal levels of lactoferrin, secretory leukocyte protease inhibitor, and RANTES and the effects of coexisting vaginoses in human immunodeficiency virus (HIV)-seronegative women with a high risk of heterosexual acquisition of HIV infection.
        Clin Vaccine Immunol. 2007; 14: 1102-1107
        • Valore E.V.
        • Wiley D.J.
        • Ganz T.
        Reversible deficiency of antimicrobial polypeptides in bacterial vaginosis.
        Infect Immun. 2006; 74: 5693-5702
        • Motevaseli E.
        • Shirzad M.
        • Akrami S.M.
        • et al.
        Normal and tumour cervical cells respond differently to vaginal Lactobacilli, independent of pH and lactate.
        J Med Microbiol. 2013; 62: 1065-1072
        • Gomez L.M.
        • Sammel M.D.
        • Appleby D.H.
        • et al.
        Evidence of a gene-environment interaction that predisposes to spontaneous preterm birth: a role for asymptomatic bacterial vaginosis and DNA variants in genes that control the inflammatory response.
        Am J Obstet Gynecol. 2010; 202 (e1–e6): 386
        • Scott M.E.
        • Ma Y.
        • Farhat S.
        • et al.
        Covariates of cervical cytokine mRNA expression by real-time PCR in adolescents and young women: effects of Chlamydia trachomatis infection, hormonal contraception, and smoking.
        J Clin Immunol. 2006; 26: 222-232
        • Hwang L.Y.
        • Scott M.E.
        • Ma Y.
        • et al.
        Higher levels of cervicovaginal inflammatory and regulatory cytokines and chemokines in healthy young women with immature cervical epithelium.
        J Reprod Immunol. 2011; 88: 66-71
        • Gillet E.
        • Meys J.F.
        • Verstraelen H.
        • et al.
        Bacterial vaginosis is associated with uterine cervical human papillomavirus infection: a meta-analysis.
        BMC Infect Dis. 2011; 11: 10
        • Guo Y.
        • You K.
        • Qiao J.
        • et al.
        Bacterial vaginosis is conducive to the persistence of HPV infection.
        Int J STD AIDS. 2012; 23: 581-584
        • King C.C.
        • Jamieson D.J.
        • Wiener J.
        • et al.
        Bacterial vaginosis and the natural history of human papillomavirus.
        Infect Dis Obstet Gynecol. 2011; 2011: 319460
        • Sha B.E.
        • Chen H.Y.
        • Wang Q.J.
        • et al.
        Utility of Amsel criteria, Nugent score, and quantitative PCR for Gardnerella vaginalis, Mycoplasma hominis, and Lactobacillus spp. for diagnosis of bacterial vaginosis in human immunodeficiency virus-infected women.
        J Clin Microbiol. 2005; 43: 4607-4612
        • Lee J.E.
        • Lee S.
        • Lee H.
        • et al.
        Association of the vaginal microbiota with human papillomavirus infection in a Korean twin cohort.
        PLoS One. 2013; 8: e63514
        • Gao W.
        • Weng J.
        • Gao Y.
        • et al.
        Comparison of the vaginal microbiota diversity of women with and without human papillomavirus infection: a cross-sectional study.
        BMC Infect Dis. 2013; 13: 271
        • Brotman R.M.
        • Shardell M.D.
        • Gajer P.
        • et al.
        Interplay between the temporal dynamics of the vaginal microbiota and human papillomavirus detection.
        J Infect Dis. 2014; 210: 1723-1733
        • Mitra A.
        • MacIntyre D.A.
        • Lee Y.S.
        • et al.
        Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity.
        Sci Rep. 2015; 5: 16865
        • Castellarin M.
        • Warren R.L.
        • Freeman J.D.
        • et al.
        Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma.
        Genome Res. 2012; 22: 299-306
        • Yu J.
        • Feng Q.
        • Wong S.H.
        • et al.
        Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer.
        Gut. 2015; ([Epub ahead of print])
        • Mima K.
        • Nishihara R.
        • Qian Z.R.
        • et al.
        Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis.
        Gut. 2015; ([Epub ahead of print])
        • Rubinstein M.R.
        • Wang X.
        • Liu W.
        • et al.
        Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin.
        Cell Host Microbe. 2013; 14: 195-206
        • Mima K.
        • Sukawa Y.
        • Nishihara R.
        • et al.
        Fusobacterium nucleatum and T cells in colorectal carcinoma.
        JAMA Oncol. 2015; 1: 653-661
        • Oh H.Y.
        • Kim B.S.
        • Seo S.S.
        • et al.
        The association of uterine cervical microbiota with an increased risk for cervical intraepithelial neoplasia in Korea.
        Clin Microbiol Infect. 2015; 21 (e1–e9): 674
        • Kinney W.K.
        • Manos M.M.
        • Hurley L.B.
        • et al.
        Where's the high-grade cervical neoplasia? The importance of minimally abnormal Papanicolaou diagnoses.
        Obstet Gynecol. 1998; 91: 973-976
        • Nelson T.M.
        • Borgogna J.L.
        • Brotman R.M.
        • et al.
        Vaginal biogenic amines: biomarkers of bacterial vaginosis or precursors to vaginal dysbiosis?.
        Front Physiol. 2015; 6: 253
        • Chen K.C.
        • Forsyth P.S.
        • Buchanan T.M.
        • et al.
        Amine content of vaginal fluid from untreated and treated patients with nonspecific vaginitis.
        J Clin Invest. 1979; 63: 828-835
        • Pavic N.
        Is there a local production of nitrosamines by the vaginal microflora in anaerobic vaginosis/trichomoniasis?.
        Med Hypotheses. 1984; 15: 433-436
        • Bartsch H.
        • Montesano R.
        Relevance of nitrosamines to human cancer.
        Carcinogenesis. 1984; 5: 1381-1393
        • Lidbeck A.
        • Nord C.E.
        • Gustafsson J.A.
        • et al.
        Lactobacilli, anticarcinogenic activities and human intestinal microflora.
        Eur J Cancer Prev. 1992; 1: 341-353
        • Piyathilake C.J.
        • Ollberding N.J.
        • Kumar R.
        • et al.
        Cervical microbiota associated with risk of higher grade cervical intraepithelial neoplasia in women infected with high-risk human papillomaviruses.
        Cancer Prev Res (Phila). 2016; 9: 357-366
        • Srinivasan S.
        • Morgan M.T.
        • Fiedler T.L.
        • et al.
        Metabolic signatures of bacterial vaginosis.
        MBio. 2015; 6: e00204-e00215
        • Romano G.
        • Sgambato A.
        • Mancini R.
        • et al.
        8-hydroxy-2′-deoxyguanosine in cervical cells: correlation with grade of dysplasia and human papillomavirus infection.
        Carcinogenesis. 2000; 21: 1143-1147
        • Arabski M.
        • Klupinska G.
        • Chojnacki J.
        • et al.
        DNA damage and repair in Helicobacter pylori-infected gastric mucosa cells.
        Mutat Res. 2005; 570: 129-135
        • Holmes K.K.
        • Chen K.C.
        • Lipinski C.M.
        • et al.
        Vaginal redox potential in bacterial vaginosis (nonspecific vaginitis).
        J Infect Dis. 1985; 152: 379-382
        • Williams V.M.
        • Filippova M.
        • Filippov V.
        • et al.
        Human papillomavirus type 16 E6* induces oxidative stress and DNA damage.
        J Virol. 2014; 88: 6751-6761
        • Schmitt A.
        • Harry J.B.
        • Rapp B.
        • et al.
        Comparison of the properties of the E6 and E7 genes of low- and high-risk cutaneous papillomaviruses reveals strongly transforming and high Rb-binding activity for the E7 protein of the low-risk human papillomavirus type 1.
        J Virol. 1994; 68: 7051-7059
        • Ling Z.
        • Liu X.
        • Chen X.
        • et al.
        Diversity of cervicovaginal microbiota associated with female lower genital tract infections.
        Microb Ecol. 2011; 61: 704-714
        • Hyman R.W.
        • Fukushima M.
        • Jiang H.
        • et al.
        Diversity of the vaginal microbiome correlates with preterm birth.
        Reprod Sci. 2014; 21: 32-40
        • Swidsinski A.
        • Doerffel Y.
        • Loening-Baucke V.
        • et al.
        Gardnerella biofilm involves females and males and is transmitted sexually.
        Gynecol Obstet Invest. 2010; 70: 256-263
        • Patterson J.L.
        • Stull-Lane A.
        • Girerd P.H.
        • et al.
        Analysis of adherence, biofilm formation and cytotoxicity suggests a greater virulence potential of Gardnerella vaginalis relative to other bacterial-vaginosis-associated anaerobes.
        Microbiology. 2010; 156: 392-399
        • Verstraelen H.
        • Swidsinski A.
        The biofilm in bacterial vaginosis: implications for epidemiology, diagnosis and treatment.
        Curr Opin Infect Dis. 2013; 26: 86-89
        • Falsetta M.L.
        • Klein M.I.
        • Colonne P.M.
        • et al.
        Symbiotic relationship between Streptococcus mutans and Candida albicans synergizes virulence of plaque biofilms in vivo.
        Infect Immun. 2014; 82: 1968-1981
        • Hillier S.L.
        • Lau R.J.
        Vaginal microflora in postmenopausal women who have not received estrogen replacement therapy.
        Clin Infect Dis. 1997; 25: S123-S126
        • Woodworth C.D.
        HPV innate immunity.
        Front Biosci. 2002; 7: d2058-d2071
        • Garcea G.
        • Dennison A.R.
        • Steward W.P.
        • et al.
        Role of inflammation in pancreatic carcinogenesis and the implications for future therapy.
        Pancreatology. 2005; 5: 514-529
        • Coussens L.M.
        • Werb Z.
        Inflammation and cancer.
        Nature. 2002; 420: 860-867
        • Scott M.
        • Stites D.P.
        • Moscicki A.B.
        Th1 cytokine patterns in cervical human papillomavirus infection.
        Clin Diagn Lab Immunol. 1999; 6: 751-755
        • Borgdorff H.
        • Tsivtsivadze E.
        • Verhelst R.
        • et al.
        Lactobacillus-dominated cervicovaginal microbiota associated with reduced HIV/STI prevalence and genital HIV viral load in African women.
        ISME J. 2014; 8: 1781-1793
        • Smith-McCune K.K.
        • Shiboski S.
        • Chirenje M.Z.
        • et al.
        Type-specific cervico-vaginal human papillomavirus infection increases risk of HIV acquisition independent of other sexually transmitted infections.
        PLoS One. 2010; 5: e10094
        • Gallagher K.E.
        • Baisley K.
        • Grosskurth H.
        • et al.
        The association between cervical human papillomavirus infection and subsequent HIV acquisition in Tanzanian and Ugandan women: a nested case-control study.
        J Infect Dis. 2016; 214: 87-95
        • Thomas R.M.
        • Jobin C.
        The microbiome and cancer: is the ‘oncobiome' mirage real?.
        Trends Cancer. 2015; 1: 24-35
        • Yarbrough V.L.
        • Winkle S.
        • Herbst-Kralovetz M.M.
        Antimicrobial peptides in the female reproductive tract: a critical component of the mucosal immune barrier with physiological and clinical implications.
        Hum Reprod Update. 2015; 21: 353-377
        • Nicholson J.K.
        • Holmes E.
        • Kinross J.M.
        • et al.
        Metabolic phenotyping in clinical and surgical environments.
        Nature. 2012; 491: 384-392
        • Griffin P.M.
        • Tauxe R.V.
        The epidemiology of infections caused by Escherichia coli O157:H7, other enterohemorrhagic E. coli, and the associated hemolytic uremic syndrome.
        Epidemiol Rev. 1991; 13: 60-98
        • Wylie K.M.
        • Mihindukulasuriya K.A.
        • Zhou Y.
        • et al.
        Metagenomic analysis of double-stranded DNA viruses in healthy adults.
        BMC Biol. 2014; 12: 71
        • Vujic G.
        • Jajac Knez A.
        • Despot Stefanovic V.
        • et al.
        Efficacy of orally applied probiotic capsules for bacterial vaginosis and other vaginal infections: a double-blind, randomized, placebo-controlled study.
        Eur J Obstet Gynecol Reprod Biol. 2013; 168: 75-79
        • Kyrgiou M.
        • Koliopoulos G.
        • Martin-Hirsch P.
        • et al.
        Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis.
        Lancet. 2006; 367: 489-498
        • Kyrgiou M.
        • Mitra A.
        • Arbyn M.
        • et al.
        Fertility and early pregnancy outcomes after treatment for cervical intraepithelial neoplasia: systematic review and meta-analysis.
        BMJ. 2014; 349: g6192
        • Arbyn M.
        • Kyrgiou M.
        • Simoens C.
        • et al.
        Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis.
        BMJ. 2008; 337: a1284