A critical review of the vaginal microbiota and its relationship with human papillomavirus


  • Chaharzad Said Abdallah Department of Obstetrics and Gynecology, 2nd Hospital of Jilin University, Changchun, Jilin, China
  • Tianmin Xu Department of Obstetrics and Gynecology, 2nd Hospital of Jilin University, Changchun, Jilin, China
  • Cong Wang Department of Obstetrics and Gynecology, 2nd Hospital of Jilin University, Changchun, Jilin, China




Vaginal microbiota, Human papillomavirus, CIN


The study of bacterial 16S rRNA genes is facilitated with the assistance of next-generation sequencing methods (NGS) which allow a thorough investigation of vaginal microbial community makeup to an extent not achievable with regular culture-supported microbiological methods. The human papillomavirus (HPV) triggers cervical intraepithelial neoplasia (CIN), the precursor of cervical malignancy. Vaginal microbiota has a mutualistic symbiotic connection with their host and has a significant influence on health and disease. Surging proof points to a likely connection between the vaginal microbiota and repeated HPV infections. Some vaginal microbial types can be either prophylactic or pathogenic in cancer development of the cervix after repeated HPV infection. In this review, we discussed the composition and structure of the vaginal microbiota as well as the relationship between HPV infection and the vaginal microbiota. We also covered the link between the vaginal microbiome, HPV, and immune response.


Cash HL, Whitham CV, Behrendt CL, Hooper LV. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science. 2006;313(5790):1126-30.

Dethlefsen L, McFall-Ngai M, Relman DA. An ecological and evolutionary perspective on humang-microbe mutualism and disease. Nature. 2007;449:811-8.

Peterson J, Garges S, Giovanni M, McInnes P, Wang L, Schloss JA, et al. The NIH Human Microbiome Project. Genome Res. 2009;19(12):2317-23.

Trends in HIV and STD-related risk behaviors among high school students-United States, 1991-2007. JAMA. 2008;300(14):1643.

Clifford GM, Gallus S, Herrero R, Muñoz N, Snijders PJF, Vaccarella S, et al. Worldwide distribution of human papillomavirus types in cytologically normal women in the International agency for research on cancer HPV prevalence surveys: a pooled analysis. Lancet. 2005;366(9490):991-8.

Dols JAM, Reid G, Kort R, Schuren FHJ, Tempelman H, Bontekoe TR, et al. PCR-based identification of eight lactobacillus species and 18 hr-HPV genotypes in fixed cervical samples of South African women at risk of HIV and BV. Diagn Cytopathol. 2012:472-7.

Clarke MA, Rodriguez AC, Gage JC, Herrero R, Hildesheim A, Wacholder S, et al. A large, population-based study of age-related associations between vaginal pH and human papillomavirus infection. BMC Infect Dis. 2012;12.

Hausen HZ. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst. 2000;92(9):690-8.

Bosch FX, deSanjosé S. Chapter 1: Human papillomavirus and cervical cancer--burden and assessment of causality. Journal of the National cancer institute. Monographs. 2003:3-13.

Muñoz N, Bosch FX, deSanjosé S, Herrero R, Castellsagué X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348(6):518-27.

Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SSK, McCulle SL, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A. 2011;108(1):4680-7.

Gajer P, Brotman RM, Bai G, Sakamoto J, Schütte UME, Zhong X, et al. Temporal dynamics of the human vaginal microbiota. Sci Transl Med. 2012;4(132).

Bakken LR. Separation and purification of bacteria from soil. Appl Environ Microbiol. 1985;49(6):1482-7.

Amann RI, Ludwig W, Schleifer KH. Phylogenetic identification and in situ detection of individual microbial cells without cultivation. Microbiolog Rev. 1995;59:143-69.

Hugenholtz P, Goebel BM, Pace NR. Impact of culture-independent studies on the emerging phylogenetic view of bacterial diversity. J Bacteriol. 1998;180:4765-74.

Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, et al. Microbiology: diversity of the human intestinal microbial flora. Science. 2005;308(5728):1635-8.

Sobel JD. Is there a protective role for vaginal flora? Curr Infect Dis Rep. 1999;1(4):379-83.

Selle KM, Klaenhammer TR, Russell WM. Lactobacillus: Lactobacillus acidophilus. 2nd ed. In: Encyclopedia of Food Microbiology; 2014: 412-7.

Alakomi HL, Skyttä E, Saarela M, Mattila-Sandholm T, Latva-Kala K, Helander IM. Lactic acid permeabilizes gram-negative bacteria by disrupting the outer membrane. Appl Environ Microbiol. 2000;66(5):2001-5.

Lai SK, Hida K, Shukair S, Wang YY, Figueiredo A, Cone R, et al. Human immunodeficiency virus type 1 is trapped by acidic but not by neutralized human cervicovaginal mucus. J Virol. 2009;83(21):11196-200.

Witkin SS, Alvi S, Bongiovanni AM, Linhares IM, Ledger WJ. Lactic acid stimulates interleukin-23 production by peripheral blood mononuclear cells exposed to bacterial lipopolysaccharide. FEMS Immunol Med Microbiol. 2011;61(2):153-8.

Zhou X, Bent SJ, Schneider MG, Davis CC, Islam MR, Forney LJ. Characterization of vaginal microbial communities in adult healthy women using cultivation-independent methods. Microbiology. 2004;150(8):2565-73.

Zhou X, Hansmann MA, Davis CC, Suzuki H, Brown CJ, Schütte U, et al. The vaginal bacterial communities of Japanese women resemble those of women in other racial groups. FEMS Immunol Med Microbiol. 2010;58(2):169-81.

Beres SB, Sylva GL, Barbian KD, Lei B, Hoff JS, Mammarella ND, et al. Genome sequence of a serotype M3 strain of group A Streptococcus: Phage-encoded toxins, the high-virulence phenotype, and clone emergence. Proc Natl Acad Sci U S A. 2002;99(15):10078-83.

Water Aid. Fact sheet: Menstrual Hygiene matters. Available at: http://www.wateraid.org/what-wedo/our-approach/res. Accessed on 15 January 2022.

Koumans EH, Sternberg M, Bruce C, McQuillan G, Kendrick J, Sutton M, et al. The prevalence of bacterial vaginosis in the United States, 2001-2004; associations with symptoms, sexual behaviors, and reproductive health. Sex Transm Dis. 2007;34(11):864-9.

Martino JL, Vermund SH. Vaginal douching: Evidence for risks or benefits to women’s health. Epidemiologic Reviews. 2002;24:109-24.

Sa CR. The biology of the vagina in the human subject. II: The bacterial flora and secretion of the vagina in relation to glycogen in the vaginal epithelium. J Obs Gynecol Br Emp. 1934;41:208-26.

Hickey RJ, Zhou X, Settles ML, Erb J, Malone K, Hansmann MA, et al. Vaginal microbiota of adolescent girls prior to the onset of menarche resemble those of reproductive-age women. MBio. 2015;6(2).

Eschenbach DA, Thwin SS, Patton DL, Hooton TM, Stapleton AE, Agnew K, et al. Influence of the normal menstrual cycle on vaginal tissue, discharge, and microflora. Clin Infect Dis. 2000;30(6):901-7.

Yang C, Tang D. Patient-specific carotid plaque progression simulation. C Model Eng Sci. 2000;1(2):119-31.

MacIntyre DA, Chandiramani M, Lee YS, Kindinger L, Smith A, Angelopoulos N, et al. The vaginal microbiome during pregnancy and the postpartum period in a European population. Sci Rep. 2015;5.

Vodstrcil LA, Hocking JS, Law M, Walker S, Tabrizi SN, Fairley CK, et al. Hormonal contraception is associated with a reduced risk of bacterial vaginosis: a systematic review and meta-analysis. PLoS One. 2013;8(9).

Brotman RM, He X, Gajer P, Fadrosh D, Sharma E, Mongodin EF, et al. Association between cigarette smoking and the vaginal microbiota: a pilot study. BMC Infect Dis. 2014;14(1).

Mändar R, Punab M, Borovkova N, Lapp E, Kiiker R, Korrovits P, et al. Complementary seminovaginal microbiome in couples. Res Microbiol. 2015;166(5):440-7.

Schwebke JR, Desmond RA, Oh MK. Predictors of bacterial vaginosis in adolescent women who douche. Sex Transm Dis. 2004;31(7):433-6.

Brotman RM, Ghanem KG, Klebanoff MA, Taha TE, Scharfstein DO, Zenilman JM. The effect of vaginal douching cessation on bacterial vaginosis: a pilot study. Am J Obstet Gynecol. 2008;198(6):628.

Bui TC, Thai TN, Tran LTH, Shete SS, Ramondetta LM, Basen-Engquist KM. Association between vaginal douching and genital human papillomavirus infection among women in the United States. J Infect Dis. 2016;214(9):1370-5.

Zliang J, Thomas AG, Leybovich E. Vaginal douching and adverse health effects: a meta-analysis. Am J Public Health. 1997;87(7):1207-11.

Torcia MG. Interplay among vaginal microbiome, immune response and sexually transmitted viral infections. Int J Molecul Sci. 2019;20.

Verreck FAW, deBoer T, Langenberg DML, Zanden L, Ottenhoff THM. Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and IFN-γ- and CD40L-mediated costimulation. J Leukoc Biol. 2006;79(2):285-93.

Persson R, Hitti J, Verhelst R, Vaneechoutte M, Persson R, Hirschi R, et al. The vaginal microflora in relation to gingivitis. BMC Infect Dis. 2009;9.

Monaghan KL, Wan ECK. The role of granulocyte-macrophage colony-stimulating factor in murine models of multiple sclerosis. Cells. 2020;9(3):611.

Moscicki AB, Shi B, Huang H, Barnard E, Li H. Cervical-vaginal microbiome and associated cytokine profiles in a prospective study of HPV 16 acquisition, persistence, and clearance. Front Cell Infect Microbiol. 2020;10.

Bokulich NA, Łaniewski P, Chase DM, Caporaso JG, Herbst-Kralovetz MM. Integration of multi-omics data improves prediction of cervicovaginal microenvironment in cervical cancer. medRxiv. 2020.

Vieira V, Calhelha RC, Barros L, Coutinho JAP, Ferreira ICFR, Ferreira O. Insights on the extraction performance of alkanediols and glycerol: using Juglans regia L. Leaves as a source of bioactive compounds. Molecules. 2020;25(11).

Agostini M, Almeida LY, Bastos DC, Ortega RM, Moreira FS, Seguin F, et al. The fatty acid synthase inhibitor orlistat reduces the growth and metastasis of orthotopic tongue oral squamous cell carcinomas. Mol Cancer Ther. 2014;13(3):585-95.

Davis MA, Delaney JR, Patel CB, Storgard R, Stupack DG. Nelfinavir is effective against human cervical cancer cells in vivo: a potential treatment modality in resource-limited settings. Drug Des Devel Ther. 2016;10:1837-46.

Lee JE, Lee S, Lee H, Song YM, Lee K, Han MJ, et al. Association of the vaginal microbiota with human papillomavirus infection in a Korean Twin COHORT. PLoS One. 2013;8(5).

Colbert LE, Medrano AD, Previs RA, Eifel PJ, Jhingran A, Ramondetta LM, et al. Association of changes in vaginal microbiome with oligoclonal T-cell expansion and early response to chemoradiation for cervical cancer. J Clin Oncol. 2018;36(5):8.

Drozhdina MB. Vaginal microbiota, immune response and some sexually transmitted infections: Mechanisms of interaction and regulation of the vaginal ecosystem. Klin Dermatologiya Venerol. 2020;19(6):926-33.

Kyrgiou M, Mitra A, Moscicki AB. Does the vaginal microbiota play a role in the development of cervical cancer? Translational Research. 2017;179:168-82.

Ruler O, Kiewiet JJS, Boer KR, Lamme B, Gouma DJ, Boermeester MA, et al. Failure of available scoring systems to predict ongoing infection in patients with abdominal sepsis after their initial emergency laparotomy. BMC Surg. 2011;11.

Castle PE, Hillier SL, Rabe LK, Hildesheim A, Herrero R, Bratti MC, et al. An association of cervical inflammation with high-grade cervical neoplasia in women infected with oncogenic human papillomavirus (HPV). Cancer Epidemiol Biomarkers Prev. 2001;10(10):1021-7.

Moscicki AB, Hills N, Shiboski S, Powell K, Jay N, Hanson E, et al. Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females. J Am Med Assoc. 2001;285(23):2995-3002.

Mao C, Hughes JP, Kiviat N, Kuypers J, Lee SK, Adam DE, et al. Clinical findings among young women with genital human papillomavirus infection. Am J Obstet Gynecol. 2003;188(3):677-84.

Nam KH, Kim YT, Kim SR, Kim SW, Kim JW, Lee MK, et al. Association between bacterial vaginosis and cervical intraepithelial neoplasia. J Gynecol Oncol. 2009;20(1):39-43.

Rahkola P, Mikkola TS, Ylikorkala O, Vaisanen-Tommiska M. Association between high risk papillomavirus DNA and nitric oxide release in the human uterine cervix. Gynecol Oncol. 2009;114(2):323-6.

Verteramo R, Pierangeli A, Mancini E, Calzolari E, Bucci M, Osborn J, et al. Human papillomaviruses and genital co-infections in gynaecological outpatients. BMC Infect Dis. 2009;9.

Caiyan X, Weiyuan Z, Minghui W, Songwen Z. Prevalence and risk factors of lower genital tract infections among women in Beijing, China. J Obstet Gynaecol Res. 2012;38(1):310-5.

Wiley DJ, Masongsong EV, Lu S, Heather LS, Salem B, Giuliano AR, et al. Behavioral and sociodemographic risk factors for serological and DNA evidence of HPV6, 11, 16, 18 infections. Cancer Epidemiol. 2012;36(3).

Oakeshott P, Aghaizu A, Reid F, Howell-Jones R, Hay PE, Sadiq ST, et al. Frequency and risk factors for prevalent, incident, and persistent genital carcinogenic human papillomavirus infection in sexually active women: Community based COHORT study. BMJ. 2012;345(7864).

Lazenby GB, Taylor PT, Badman BS, McHaki E, Korte JE, Soper DE, et al. An association between trichomonas vaginalis and high-risk human papillomavirus in rural tanzanian women undergoing cervical cancer screening. Clin Ther. 2014;36(1):38-45.

Watson-Jones D, Baisley K, Brown J, Kavishe B, Andreasen A, Changalucha J, et al. High prevalence and incidence of human papillomavirus in a COHORT of healthy young African female subjects. Sex Transm Infect. 2013;89(5):358-65.

Brotman RM, Shardell MD, Gajer P, Tracy JK, Zenilman JM, Ravel J, et al. Interplay between the temporal dynamics of the vaginal microbiota and human papillomavirus detection. J Infect Dis. 2014;210(11):1723-33.

Caixeta RCA, Ribeiro AA, Segatti KD, Saddi VA, Alves RR, Carneiro MA, et al. Association between the human papillomavirus, bacterial vaginosis and cervicitis and the detection of abnormalities in cervical smears from teenage girls and young women. Diagn Cytopathol. 2015;43(10):780-5.

Liu J, Liu W, Liu Y, Zhou X, Zhang Z, Sun Z. Prevalence of microorganisms co-infections in human papillomaviruses infected women in Northern China. Arch Gynecol Obstet. 2016;293(3):595-602.

Marks MA, Gupta S, Liaw KL, Tadesse A, Kim E, Phongnarisorn C, et al. Prevalence and correlates of HPV among women attending family-planning clinics in Thailand. BMC Infect Dis. 2015;15(1).

Mitra A, MacIntyre DA, Lee YS, Smith A, Marchesi JR, Lehne B, et al. Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity. Sci Rep. 2015;5.

Oh HY, Kim BS, Seo SS, Kong JS, Lee JK, Park SY, et al. The association of uterine cervical microbiota with an increased risk for cervical intraepithelial neoplasia in Korea. Clin Microbiol Infect. 2015;21(7):674.

Peres AL, Camarotti JRSL, Cartaxo M, Alencar N, Stocco RC, Beçak W, et al. Molecular analysis and conventional cytology: Association between HPV and bacterial vaginosis in the cervical abnormalities of a Brazilian population. Genet Mol Res. 2015;14(3):9497-505.

Gao W, Weng J, Gao Y, Chen X. Comparison of the vaginal microbiota diversity of women with and without human papillomavirus infection: a cross-sectional study. BMC Infect Dis. 2013;13(1).

Brotman RM, Shardell MD, Gajer P, Fadrosh D, Chang K, Silver MI, et al. Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy. Menopause. 2018;25(11):1321-30.

Mitra A, MacIntyre DA, Marchesi JR, Lee YS, Bennett PR, Kyrgiou M. The vaginal microbiota, human papillomavirus infection and cervical intraepithelial neoplasia: what do we know and where are we going next? Microbiome. 2016;4.

Audirac-Chalifour A, Torres-Poveda K, Bahena-Román M, Téllez-Sosa J, Martínez-Barnetche J, Cortina-Ceballos B, et al. Cervical microbiome and cytokine profile at various stages of cervical cancer: a pilot study. PLoS One. 2016;11(4).

Allsworth JE, Lewis VA, Peipert JF. Viral sexually transmitted infections and bacterial vaginosis: 2001-2004 national health and nutrition examination survey data. Sex Transm Dis. 2008;35(9):791-6.

Piyathilake CJ, Ollberding NJ, Kumar R, Macaluso M, Alvarez RD, Morrow CD. Cervical microbiota associated with higher grade cervical intraepithelial neoplasia in women infected with high-risk human papillomaviruses. Cancer Prev Res. 2016;9(5):357-66.

Chandiramani M, Bennett PR, Brown R, Lee YS, Macintyre DA. Vaginal microbiome-pregnant host interactions determine a significant proportion of preterm labour. Fetal Matern Med Rev. 2014;25(1):73-8.






Review Articles