Vaginal microbiota and HPV-associated cervical diseases: Established relationship

This review is aimed to analyse research data on the lower genital tract microbiome and factors effecting its composition, as well as the relationship with HPV-associated cervical diseases. Modern studies show that certain types of lactobacilli can play a protective role by reducing the likelihood of human papillomavirus (HPV) infection and contributing to its elimination. At the same time, dysbiotic changes, including decreased levels of lactobacilli and increased levels of opportunistic pathogens, are associated with the development of bacterial vaginosis and other abnormal vaginal biocenosis. These conditions can contribute to the persistence of HPV, increasing the risk of cervical intraepithelial neoplasia and cervical cancer. Most studies show significant differences in the vaginal microbiome composition in women with cervical intraepithelial neoplasia and malignant cervix neoplasms as compared to healthy patients. Anaerobic bacteria such as Gardnerella vaginalis, Mobiluncus spp., Peptoniphilus spp., Parvimonas micra, Prevotella spp. that can inhibit the growth of lactobacilli and disrupt the normal balance of microflora play an important role in this process. In addition, decreased levels of Lactobacillus crispatus are associated with a higher probability of HPV persistence and dysplasia progression. Studying mechanisms of interaction between vaginal microbiota and HPV is critically important to understand the mechanisms of pathogenesis of precancerous and malignant processes of the cervix. Further study of these aspects will allow the development of new prevention and treatment strategies to modulate vaginal microflora and reduce the risk of disease progression.

1. Audirac-Chalifour A, Torres-Poveda K, Bahena-Roman M, Tellez-Sosa J, Martinez-Barnetche J et al. Cervical microbiome and cytokine profile at various stages of cervical cancer: a pilot study. PloS ONE. 2016;11(4):e0153274. https://doi.org/10.1371/journal.pone.0153274.

2. Castle PE, Hillier SL, Rabe LK, Hildesheim A, Herrero R, Bratti MC et al. An association of cervical inflammation with highgrade cervical neoplasia in women infected with oncogenic human papillomavirus (HPV). Cancer Epidemiol Biomarkers Prev. 2001;10(10):1021–1027. Available at: https://pubmed.ncbi.nlm.nih.gov/11588127/.

3. Castellsagué X. Natural history and epidemiology of HPV infection and cervical cancer. Gynecol Oncol. 2008;110(3 Suppl 2):S4–7. https://doi.org/10.1016/j.ygyno.2008.07.045.

4. Chase D, Goulder A, Zenhausern F, Monk B, Herbst-Kralovetz M. The vaginal and gastrointestinal microbiomes in gynecologic cancers: a review of applications in etiology, symptoms and treatment. Gynecol Oncol. 2015;138(1):190–200. https://doi.org/10.1016/j.ygyno.2015.04.036.

5. Komesu YM, Dinwiddie DL, Richter HE, Lukacz ES, Sung VW, Siddiqui NY et al. Defining the relationship between vaginal and urinary microbiomes. Am J Obstet Gynecol. 2020;222(2):154.e1–154.e10. https://doi.org/10.1016/j.ajog.2019.08.011.

6. Chen C, Song X, Wei W, Zhong H, Dai J, Lan Z et al. The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases. Nat Commun. 2017;8(1):875. https://doi.org/10.1038/s41467-017-00901-0.

7. Brusselaers N, Shrestha S, van de Wijgert J, Verstraelen H. Vaginal dysbiosis and the risk of human papillomavirus and cervical cancer: systematic review and meta-analysis. Am J Obstet Gynecol. 2019;221(1):9–18. https://doi.org/10.1016/j.ajog.2018.12.011.

8. Greenbaum S, Greenbaum G, Moran-Gilad J, Weintraub AY. Ecological dynamics of the vaginal microbiome in relation to health and disease. Am J Obstet Gynecol. 2019;220(4):324–335. https://doi.org/10.1016/j.ajog.2018.11.1089.

9. Mitra A, MacIntyre DA, Ntritsos G, Smith A, Tsilidis KK, Marchesi JR et al. The vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions. Nat Commun. 2020;11(1):1999. https://doi.org/10.1038/s41467-020-15856-y.

10. Amabebe E, Anumba DO. The Vaginal Microenvironment: The Physiologic Role of Lactobacilli. Front Med. 2018;5:181. https://doi.org/10.3389/fmed.2018.00181.

11. Mitra A, MacIntyre DA, Marchesi JR, Lee YS, Bennett PR, Kyrgiou M. The vaginal micro- biota, human papillomavirus infection and cervical intraepithelial neoplasia: what do we know and where are we going next? Microbiome. 2016;4(1):58. https://doi.org/10.1186/s40168-016-0203-0.

12. Zhou X, Brown CJ, Abdo Z, Davis CC, Hansmann MA, Joyce P et al. Differences in the composition of vaginal microbial communi- ties found in healthy Caucasian and black women. ISME J. 2007;1(2):121–133. https://doi.org/10.1038/ismej.2007.12.

13. Łaniewski P, Barnes D, Goulder A, Cui H, Roe DJ, Chase DM, Herbst-Kralovetz MM. Linking cervicovaginal immune signatures, HPV and microbiota composition in cervical carcinogenesis in non-Hispanic and Hispanic women. Sci Rep. 2018;8(1):7593. https://doi.org/10.1038/s41598-018-25879-7.

14. Green KA, Zarek SM, Catherino WH. Gynecologic health and disease in relation to the microbiome of the female reproductive tract. Fertil Steril. 2015;104(6):1351–1357. https://doi.org/10.1016/j.fertnstert.2015.10.010.

15. Chico RM, Mayaud P, Ariti C, Mabey D, Ronsmans C, Chandramohan D. Prevalence of malaria and sexually transmitted and re- productive tract infections in pregnancy in sub-Saharan Africa: a systematic review. JAMA. 2012;307(19):2079–2086. https://doi.org/10.1001/jama.2012.3428.

16. Gosmann C, Anahtar MN, Handley SA, Farcasanu M, Abu-Ali G, Bowman BA et al. Lactobacillus-Deficient Cervicovaginal Bacterial Communities Are Associated with Increased HIV Acquisition in Young South African Women. Immunity. 2017;46(1):29–37. https://doi.org/10.1016/j.immuni.2016.12.013.

17. 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 symp- toms, sexual behaviors, and reproductive health. Sex Transm Dis. 2007;34(11):864–869. https://doi.org/10.1097/olq.0b013e318074e565.

18. Spear GT, French AL, Gilbert D, Zariffard MR, Mirmonsef P, Sullivan TH et al. Human α-amylase present in lower-genital-tract mu- cosal fluid processes glycogen to support vaginal colonization by Lactobacillus. J Infect Dis. 2014;210(7):1019–1028. https://doi.org/10.1093/infdis/jiu231.

19. Vodstrcil LA, Hocking JS, Law M, Walker S, Tabrizi SN, Fairley CK, Bradshaw CS. Hormonal con- traception is associated with a reduced risk of bacterial vaginosis: a systematic review and meta-analysis. PLoS ONE. 2013;8(9):e73055. https://doi.org/10.1371/journal.pone.0073055.

20. Jespers V, van de Wijgert J, Cools P, Verhelst R, Verstraelen H, Delany-Moretlwe S et al. The signif-icance of Lactobacillus crispatus and L. vagi- nalis for vaginal health and the negative effect of recent sex: a cross-sectional descriptive study across groups of African women. BMC Infect Dis. 2015;15(1):115. https://doi.org/10.1186/s12879-015-0825-z.

21. Prokopczyk B, Cox JE, Hoffmann D, Waggoner SE. Identification of tobaccospecific carcinogen in the cervical mucus of smokers and nonsmokers. J Natl Cancer Inst. 1997;89(12):868–873. https://doi.org/10.1093/jnci/89.12.868.

22. Wei L, Griego AM, Chu M, Ozbun MA. Tobacco exposure results in increased E6 and E7 oncogene expression, DNA damage and mu- tation rates in cells maintaining episomal hu- man papillomavirus 16 genomes. Carcinogenesis. 2014;35(10):2373–2381. https://doi.org/10.1093/carcin/bgu156.

23. Hill GB. The microbiology of bacterial vaginosis. Am J Obstet Gynecol. 1993;169(2 Pt 2):450–454. https://doi.org/10.1016/0002-9378(93)90339-k.

24. Winters AD, Romero R, Gervasi MT, Gomez-Lopez N, Tran MR, Garcia-Flores V et al. Does the endometrial cavity have a molecu lar microbial signature? Sci Rep. 2019;9(1):9905. https://doi.org/10.1038/s41598-019-46173-0.

25. Chen Y, Qiu X, Wang W, Li D, Wu A, Hong Z et al. Human papillomavirus infection and cervical intraepithelial neoplasia progression are associated with increased vaginal microbiome diversity in a Chinese cohort. BMC Infect Dis. 2020;20(1):629. https://doi.org/10.1186/s12879-020-05324-9.

26. So KA, Yang EJ, Kim NR, Hong SR, Lee JH, Hwang CS et al. Changes of vaginal microbiota during cervical carcinogenesis in women with human papillomavirus infection. PLoS ONE. 2020;15(9):e0238705. https://doi.org/10.1371/journal.pone.0238705.

27. Łaniewski P, Cui H, Roe DJ, Barnes D, Goulder A, Monk BJ et al. Features of the cervicovaginal microenvironment drive cancer biomarker signatures in patients across cervical carcinogenesis. Sci Rep. 2019;9(1):7333. https://doi.org/10.1038/s41598-019-43849-5.

28. Wiik J, Sengpiel V, Kyrgiou M, Nilsson S, Mitra A, Tanbo T et al. Cervical microbiota in women with cervical intra-epithelial neoplasia, prior to and after local excisional treatment, a Norwegian cohort study. BMC Womens Health. 2019;19(1):30. https://doi.org/10.1186/s12905-019-0727-0.

29. Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SSK, McCulle SL et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci USA. 2011;108(1):4680–4687. https://doi.org/10.1073/pnas.1002611107.

30. Fettweis JM, Brooks JP, Serrano MG, Sheth NU, Girerd PH, Edwards DJ et al. Differences in vaginal microbiome in African American women versus women of European ancestry. Microbiology. 2014;160:2272–2282. https://doi.org/10.1099/mic.0.081034-0.

31. Van de Wijgert JHHM, Jespers V. The global health impact of vaginal dysbiosis. Res Microbiol. 2017;168(9-10):859–864. https://doi.org/10.1016/j.resmic.2017.02.003.

32. White BA, Creedon DJ, Nelson KE, Wilson BA. The vaginal microbiome in health and disease. Trends Endocrinol Metab. 2011;22(10):389–393. https://doi.org/10.1016/j.tem.2011.06.001.

33. Tachedjian G, Aldunate M, Bradshaw CS, Cone RA. The role of lactic acid production by probiotic Lactobacillus species in vaginal health. Res Microbiol. 2017;168(9-10):782–792. https://doi.org/10.1016/j.resmic.2017.04.001.

34. Petrova MI, Reid G, Vaneechoutte M, Lebeer S. Lactobacillus iners: friend or Foe? Trends Microbiol. 2017;25(3):182–191. https://doi.org/10.1016/j.tim.2016.11.007.

35. 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;10:569022. https://doi.org/10.3389/fcimb.2020.569022.

36. Ilhan ZE, Łaniewski P, Thomas N, Roe DJ, Chase DM, Herbst-Kralovetz MM. Deciphering the complex interplay between microbiota, HPV, inflammation and cancer through cervicovaginal metabolic profiling. EBioMedicine. 2019;44:675–690. https://doi.org/10.1016/j.ebiom.2019.04.028.

37. 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;516865. https://doi.org/10.1038/srep16865.

38. Kwasniewski W, Wolun-Cholewa M, Kotarski J, Warchol W, Kuzma D, Kwasniewska A, Gozdzicka-Jozefiak A. Microbiota dysbiosis is associated with HPV-induced cervical carcinogenesis. Oncol Lett. 2018;16(6):7035–7047. https://doi.org/10.3892/ol.2018.9509.

39. Di Paola M, Sani C, Clemente AM, Iossa A, Perissi E, Castronovo G et al. Characterization of cervico-vaginal microbiota in women developing persistent high-risk Human Papillomavirus infection. Sci Rep. 2017;7(1):10200. https://doi.org/10.1038/s41598-017-09842-6.

40. Palma E, Recine N, Domenici L, Giorgini M, Pierangeli A, Panici PB. Long-term Lactobacillus rhamnosus BMX 54 application to restore a balanced vaginal ecosystem: a prom- ising solution against HPV-infection. BMC Infect Dis. 2018;18(1):13. https://doi.org/10.1186/s12879-017-2938-z.

41. Brusselaers N, Shrestha S, van de Wijgert J, Verstraelen H. Vaginal dysbiosis and the risk of human papillomavirus and cervical cancer: systematic review and meta-analysis. Am J Obstet Gynecol. 2019;221(1):9–18.e8. https://doi.org/10.1016/j.ajog.2018.12.011.

42. Walther-Antonio MRS, Chen J, Multinu F, Hokenstad A, Distad TJ, Cheek EH et al. Potential contribution of the uterine microbiome in the development of endometrial cancer. Genome Med. 2016;8(1):122. https://doi.org/10.1186/s13073-016-0368-y.

43. Baker JM, Chase DM, Herbst-Kralovetz MM. Uterine microbiota: residents, tourists, or invaders? Front Immunol. 2018;9:208. https://doi.org/10.3389/fimmu.2018.00208.

44. Baker JM, Al-Nakkash L, Herbst-Kralovetz MM. Estrogen-gut microbiome axis: physiological and clinical implications. Maturitas. 2017;103:45–53. https://doi.org/10.1016/j.maturitas.2017.06.025.

45. Cheng H, Wang Z, Cui L, Wen Y, Chen X, Gong F et al. Opportunities and challenges of the human microbiome in ovarian cancer. Front Oncol. 2020;10:163. https://doi.org/10.3389/fonc.2020.00163.

46. Flores R, Shi J, Fuhrman B, Xu X, Veenstra TD, Gail MH et al. Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study. J Transl Med. 2012;10:253. https://doi.org/10.1186/1479-5876-10-253.

47. Cicinelli E, De Ziegler D, Nicoletti R, Colafiglio G, Saliani N, Resta L et al. Chronic endometritis: correlation among hystero- scopic, histologic, and bacteriologic findings in a prospective trial with 2190 consecutive office hysteroscopies. Fertil Steril. 2008;89(3):677–684. https://doi.org/10.1016/j.fertnstert.2007.03.074.

48. Dossus L, Rinaldi S, Becker S, Lukanova A, Tjonneland A, Olsen A et al. Obesity, inflammatory markers, and endometrial cancer risk: a prospective case-control study. Endocr Relat Cancer. 2010;17(4):1007–1019. https://doi.org/10.1677/erc-10-0053.

49. Doerflinger SY, Throop AL, Herbst-Kralovetz MM. 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(12):1989–1999. https://doi.org/10.1093/infdis/jiu004.

50. Walsh DM, Hokenstad AN, Chen J, Sung J, Jenkins GD, Chia N et al. Postmenopause as a key factor in the composition of the Endometrial Cancer Microbiome (ECbiome). Sci Rep. 2019;9(1):19213. https://doi.org/10.1038/s41598-019-55720-8.

51. Shanmughapriya S, Senthilkumar G, Vinodhini K, Das BC, Vasanthi N, Natarajaseenivasan K. Viral and bacterial aetiologies of epithelial ovarian cancer. Eur J Clin Microbiol Infect Dis. 2012;31(9):2311–2317. https://doi.org/10.1007/s10096-012-1570-5.

52. Idahl A, Le Cornet C, González Maldonado S, Waterboer T, Bender N, Tjønneland A et al. Serologic markers of Chlamydia trachomatis and other sexually transmitted infections and subsequent ovarian cancer risk: results from the EPIC cohort. Int J Cancer. 2020;147(8):2042–2052. https://doi.org/10.1002/ijc.32999.

53. Fortner RT, Terry KL, Bender N, Brenner N, Hufnagel K, Butt J et al. Sexually transmitted infections and risk of epithelial ovarian cancer: results from the Nurses’ Health Studies. Br J Cancer. 2019;120(8):855–860. https://doi.org/10.1038/s41416-019-0422-9.

54. Banerjee S, Tian T, Wei Z, Shih N, Feldman MD, Alwine JC et al. The ovarian cancer oncobiome. Oncotarget. 2017;8(22):36225–36245. https://doi.org/10.18632/oncotarget.16717.

55. Zhou B, Sun C, Huang J, Xia M, Guo E, Li N et al. The biodiversity composition of microbiome in ovarian carcinoma patients. Sci Rep. 2019;9(1):1691. https://doi.org/10.1038/s41598-018-38031-2.

56. Miao R, Badger TC, Groesch K, Diaz-Sylvester PL, Wilson T, Ghareeb A et al. Assessment of peritoneal microbial features and tumor marker levels as potential diagnostic tools for ovarian cancer. PLoS ONE. 2020;15(1):е0227707. https://doi.org/10.1371/journal.pone.0227707.

57. Xu S, Liu Z, Lv M, Chen Y, Liu Y. Intestinal dysbiosis promotes epithelialmesenchymal transition by activating tumor-associated macrophages in ovarian cancer. Pathog Dis. 2019;77(2):ftz019. https://doi.org/10.1093/femspd/ftz019.

58. Ebner S, Smug LN, Kneifel W, Salminen SJ, Sanders ME. Probiotics in dietary guidelines and clinical recommendations outside the European Union. World J Gastroenterol. 2014;20(43):16095–16100. https://doi.org/10.3748/wjg.v20.i43.16095.

59. Li Y, Yu T, Yan H, Li D, Yu T, Yuan T et al. Vaginal Microbiota and HPV Infection: Novel Mechanistic Insights and Therapeutic Strategies. Infect Drug Resist. 2020;13:1213–20. https://doi.org/10.2147/idr.s210615.

60. Reid G. Has knowledge of the vaginal micro- biome altered approaches to health and dis- ease? F1000 Res. 2018;7(0):460. https://doi.org/10.12688/f1000research.13706.1.

61. Verhoeven V, Renard N, Makar A, Van Royen P, Bogers JP, Lardon F et al. Probiotics enhance the clearance of human papilloma- virus-related cervical lesions: a prospective controlled pilot study. Eur J Cancer Prev. 2013;22(1):46–51. https://doi.org/10.1097/cej.0b013e328355ed23.

62. Savicheva AM, Shalepo KV, Nazarova VV, Menuhova YuN. Monitored, randomized, comparative study assessing the effectiveness of a two-stage treatment of bacterial vaginosis. Gynecology. 2013;15(5):12–15. (In Russ.) Available at: https://mamababy-spb.ru/articles/lactabest/