The role of microbiota in the etiology of dysplastic and oncological diseases of the cervix, vagina, and vulva: A review

Cover Page

Cite item

Full Text

Abstract

The vaginal microbiota of a healthy woman is a unique microecosystem comprising more than 300 bacterial species. The main vaginal bacteria of a healthy woman are Lactobacillus spp. (90–95%), with the most common being L. crispatus, L. iners, L. jensenii, and L. gasseri. Based on the dominant Lactobacillus species, five types of communities are distinguished: CST I, II, III, IV, and V. Lactobacilli ensure a normal vaginal pH (3.8–4.4) and inhibit the growth of other microorganisms, particularly Escherichia coli, Trichomonas vaginalis, Gardnerella vaginalis, Prevotella bivia, etc. Different lactobacilli species produce different levels of reactive oxygen species. Many studies demonstrated a close relationship between vaginal microbiota disturbance and the development of malignancies, particularly cervical, vagina, and vulvar cancer. This review analyzes published studies, which showed a positive correlation between a low content of lactobacilli, an increase in the abundance of pathogenic bacteria, and cancer of the anogenital region; the association between some bacteria, the persistence of the human papillomavirus, and the development of dysplasia of the lower reproductive system was demonstrated. Timely diagnosis and treatment of vulvovaginal infections and vaginal dysbiosis would reduce the risk of human papillomavirus persistence and, consequently, the development of dysplasia and cancers of the lower genital tract.

About the authors

A. N. Mgeryan

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Author for correspondence.
Email: docanna@mail.ru
ORCID iD: 0000-0003-0574-1230

Cand. Sci. (Med.)

Russian Federation, Moscow

V. N. Prilepskaya

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: docanna@mail.ru
ORCID iD: 0000-0003-3993-7629

D. Sci. (Med.), Prof., Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Russian Federation, Moscow

E. R. Dovletkhanova

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: docanna@mail.ru
ORCID iD: 0000-0003-2835-6685

Cand. Sci. (Med.), Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Russian Federation, Moscow

P. R. Abakarova

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: docanna@mail.ru
ORCID iD: 0000-0002-8243-5272

Cand. Sci. (Med.), Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Russian Federation, Moscow

E. A. Mejevitinova

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: docanna@mail.ru
ORCID iD: 0000-0003-2977-9065

D. Sci. (Med.), Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Russian Federation, Moscow

References

  1. Hickey RJ, Zhou X, Pierson JD, et al. Understanding vaginal microbiome complexity from an ecological perspective. Translational Res. 2012;160(4):267-82.
  2. Tachedjian G, O’Hanlon DE, Ravel J. The implausible in vivo role of hydrogen peroxide as an antimicrobial factor produced by vaginal microbiota. Microbiome. 2018;6(1):1-5.
  3. Gajer P, Brotman RM, Bai G, et al. Temporal dynamics of the human vaginal microbiota. Sci Transl Med. 2012;4(132):ra13252-52.
  4. Younes, JA, Lievens E, Hummelen R, et al. Women and their microbes: the unexpected friendship. Trends Microbiol. 2018;26:16-32.
  5. Tachedjian G, Aldunate M, Bradshaw CS, Cone RA. The role of lactic acid production by probiotic Lactobacillus species in vaginal health. Res Microbiol. 2017;168:782-92.
  6. Srinivasan S, Fredricks DN. The human vaginal bacterial biota and bacterial vaginosis. Interdisciplinary Perspectives Infect Dis. 2008:750479-22.
  7. Punzón-Jiménez P, Labarta E. The impact of the female genital tract microbiome in women health and reproduction: a review. J Assist Reprod Genet. 2021;38(10):2519-41.
  8. Tuniyazi M, Zhang N. Possible therapeutic mechanisms and future perspectives of vaginal microbiota transplantation. Microorganisms. 2023;11(6):1427.
  9. Beghini J, Linhares I, Giraldo P, et al. Differential expression of lactic acid isomers, extracellular matrix metalloproteinase inducer, and matrix metalloproteinase-8 in vaginal fluid from women with vaginal disorders. BJOG: Int J Obstet Gynecol. 2015;122(12):1580-5.
  10. Ravel J, Gajer P, Abdo Z, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A. 2011;108(suppl._1):4680-7.
  11. Doyle R, Gondwe A, Fan Y-M, et al. A Lactobacillus-deficient vaginal microbiota dominates postpartum women in rural Malawi. Appl Environ Microbiol. 2018;84(6):e02150-17.
  12. Chee WJY, Chew SY, Than LTL. Vaginal microbiota and the potential of Lactobacillus derivatives in maintaining vaginal health. Microb Cell Fact. 2020;19(1):203.
  13. Zheng J, Wittouck S, Salvetti E, et al. A taxonomic note on the genus Lactobacillus: description of 23 novel genera, emended description of the genus Lactobacillus Beijerinck 1901, and union of Lactobacillaceae and Leuconostocaceae. Int J Syst Evol MicroBiol. 2020;70(4):2782-58.
  14. De Seta F, Campisciano G, Zanotta N, et al. The vaginal community state types microbiome-immune network as key factor for bacterial vaginosis and aerobic vaginitis. Front Microbiol. 2019:2451.
  15. Atassi F, Pho Viet Ahn DL, Lievin-Le Moal V. Diverse expression of antimicrobial activities against bacterial vaginosis and urinary tract infection pathogens by cervicovaginal microbiota strains of Lactobacillus gasseri and Lactobacillus crispatus. Front Microbiol. 2019;10:2900.
  16. Brotman RM, Shardell MD, Gajer P, et al. Interplay between the temporal dynamics of the vaginal microbiota and human papillomavirus detection. J Infect Dis. 2014;210(11):1723-33.
  17. Witkin SS, Mendes-Soares H, Linhares IM, et al. Influence of vaginal bacteria and D-and L-lactic acid isomers on vaginal extracellular matrix metalloproteinase inducer: implications for protection against upper genital tract infections. MBio. 2013;4(4).
  18. Ragaliauskas T, Plečkaitytė M, Jankunec M, et al. Inerolysin and vaginolysin, the cytolysins implicated in vaginal dysbiosis, differently impair molecular integrity of phospholipid membranes. Sci Rep. 2019;9(1):10606.
  19. Rampersaud R, Planet PJ, Randis TM, et al. Inerolysin, a cholesterol-dependent cytolysin produced by Lactobacillus iners. J Bacteriol. 2011;193(5):1034-41.
  20. Macklaim JM, Fernandes AD, Di Bella JM, et al. Comparative meta-RNA-seq of the vaginal microbiota and differential expression by Lactobacillus iners in health and dysbiosis. Microbiome. 2013;1(1):12.
  21. Zheng N, Guo R, Wang J, et al. Contribution of Lactobacillus iners to vaginal health and diseases: a systematic review. Front Cell Infect Microbiol. 2021;11:792787.
  22. Spurbeck RR, Arvidson CG. Lactobacillus jensenii surface-associated proteins inhibit Neisseria gonorrhoeae adherence to epithelial cells. Infect Immun. 2010;78(7):3103-11.
  23. Shannon B, Yi TJ, Perusini S, et al. Association of HPV infection and clearance with cervicovaginal immunology and the vaginal microbiota. Mucosal Immunol. 2017;10:1310-9.
  24. Oerlemans E, Ahannach S, Wittouck S, et al. Impacts of menstruation, community type, and an oral yeast probiotic on the vaginal microbiome. Msphere. 2022;7(5):e00239-22.
  25. Nowak RG, Randis TM, Desai P, et al. Higher levels of a cytotoxic protein, vaginolysin, in Lactobacillus-deficient community state types at the vaginal mucosa. Sex Transm Dis. 2018;45(4):e14.
  26. Sharifian K, Shoja Z, Jalilvand S. The interplay between human papillomavirus and vaginal microbiota in cervical cancer development. Virol J. 2023;20(1):73.
  27. Borgdorff H, Gautam R, Armstrong SD, et al. Cervicovaginal microbiome dysbiosis is associated with proteome changes related to alterations of the cervicovaginal mucosal barrier. Mucosal Immunol. 2016;9(3):621-33.
  28. Ma B, Forney LJ, Ravel J. Vaginal microbiome: rethinking health and disease. Annu Rev Microbiol. 2012;66:371-89.
  29. de Abreu AL, Malaguti N, Souza RP, et al. Association of human papillomavirus, Neisseria gonorrhoeae and Chlamydia trachomatis co-infections on the risk of high-grade squamous intraepithelial cervical lesion. Am J Cancer Res. 2016;6(6):1371-83. eCollection 2016.
  30. Verteramo R, Pierangeli A, Mancini E, et al. Human papillomaviruses and genital co-infections in gynaecological outpatients. BMC Infect Dis. 2009;9:16.
  31. Kim SI, Yoon JH, Park DC, et al. Co-infection of Ureaplasma urealyticum and human papilloma virus in asymptomatic sexually active individuals. Int J Med Sci. 2018;15(9):915-920.
  32. Smith SB, Ravel J. The vaginal microbiota, host defence and reproductive physiology. J Physiol. 2017;595(2):451-63.
  33. Byrne EH, Doherty KE, Bowman BA, et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity. 2015;42(5):965-76.
  34. Membrilla-Beltran L, Cardona D, Camara-Roca L, et al. Impact of Cervical Cancer on Quality of Life and Sexuality in Female survivors. Int J Environ Res Public Health. 2023;20(4):3751.
  35. Singh D, Vignat J, Lorenzoni V, et al. Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative. Lancet Global Health. 2023;11(2):e197-206.
  36. Cascardi E, Cazzato G, Daniele A, et al. Association between cervical microbiota and HPV: could this be the key to complete cervical cancer eradication? Biology. 2022;11(8):1114.
  37. Bonab FR, Baghbanzadeh A, Ghaseminia M, et al. Molecular pathways in the development of HPV-induced cervical cancer. EXCLI J. 2021;20:320.
  38. Pappa KI, Lygirou V, Kontostathi G, et al. Proteomic analysis of normal and cancer cervical cell lines reveals deregulation of cytoskeleton-associated proteins. Cancer Genomics Proteomics. 2017;14(4):253-66.
  39. Hong X, Wei Z, Xie M, et al. Ubiquitination of the HPV oncoprotein E6 is critical for E6/E6AP-mediated p53 degradation. Front Microbiol. 2019;10:2483.
  40. Ng DS-C, Yam JC, Chen LJ, et al. Posttranslational modifications on the retinoblastoma protein. J Biomed Sci. 2022;29(1):1-16.
  41. Alimena S, Davis J, Fichorova RN, et al. The vaginal microbiome: a complex milieu affecting risk of human papillomavirus persistence and cervical cancer. Curr Probl Cancer. 2022;46(4):100877.
  42. Kwasniewski W, Wolun-Cholewa M, Kotarski J, et al. Microbiota dysbiosis is associated with HPV-induced cervical carcinogenesis. Oncol Lett. 2018;16(6):7035-47.
  43. Curty G, de Carvalho PS, Soares MA. The role of the cervicovaginal microbiome on the genesis and as a biomarker of premalignant cervical intraepithelial neoplasia and invasive cervical cancer. Int J Mol Sci. 2019;21(1):222.
  44. Muhleisen AL, Herbst-Kralovetz MM. Menopause and the vaginal microbiome. Maturitas. 2016;91:42-50.
  45. Audirac-Chalifour A, Torres-Poveda K, Bahena-Román M, et al. Cervical microbiome and cytokine profile at various stages of cervical cancer: a pilot study. PLoS One. 2016;11(4):e0153274.
  46. Di Paola M, Sani C, Clemente AM, et al. Characterization of cervicovaginal microbiota in women developing persistent high-risk Human Papillomavirus infection. Sci Rep. 2017;7(1):10200.
  47. Mitra A, MacIntyre DA, Lee YS, et al. Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity. Sci Rep. 2015;5:16865.
  48. Łaniewski P, Barnes D, Goulder A, et al. Linking cervicovaginal immune signatures, HPV and microbiota composition in cervical carcinogenesis in non-Hispanic and Hispanic women. Sci Rep. 2018;8:7593.
  49. Seo SS, Oh HY, Lee JK, et al. Combined effect of diet and cervical microbiome on the risk of cervical intraepithelial neoplasia. Clin Nutr. 2016;35:1434-41.
  50. Oh HY, Kim BS, Seo SS, et al. The association of uterine cervical microbiota with an increased risk for cervical intraepithelial neoplasia in Korea. Clin Microbiol Infect. 2015;21:674.e1-9.
  51. 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. 2018;21:9-18.e8.
  52. Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013;13:800-12. doi: 10.1038/nrc3610
  53. Garrett WS. Cancer and the microbiota. Science. 2015;348:80-6. doi: 10.1126/science.aaa4972
  54. Norenhag J, Du J, Olovsson M, et al. The vaginal microbiota, HPV and cervical dysplasia: a systematic review and network meta-analysis. BJOG. 2020;127(2):171-80.
  55. Wang H, Ma Y, Li R, et al. Associations of cervicovaginal lactobacilli with high-risk HPV infection, cervical intraepithelial neoplasia, and cancer: a systematic review and meta-analysis. J Infect Dis. 2019;220(8):1243-54.
  56. Сhen Y, Qiu X, Wang W, 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;20:1-12.
  57. Wu M, Gao J, Wu Y, et al. Characterization of vaginal microbiota in Chinese women with cervical squamous intra-epithelial neoplasia. Int J Gynecol Cancer. 2020;30(10).
  58. Wu S, Ding X, Kong Y, et al. The feature of cervical microbiota associated with the progression of cervical cancer among reproductive females. Gynecol Oncol. 2021;163(2):348-57.
  59. Nieves-Ramírez M, Partida-Rodríguez O, Moran P, et al. Cervical squamous intraepithelial lesions are associated with differences in the vaginal microbiota of Mexican women. Microbiol Spectr. 2021;9(2):e00143-21.
  60. Wei B, Chen Y, Lu T, et al. Correlation between vaginal microbiota and different progression stages of cervical cancer. Genet Mol Biol. 2022;45:e20200450.
  61. Li X, Wu J, Wu Y, et al. Imbalance of vaginal microbiota and immunity: two main accomplices of Cervical Cancer in Chinese women. Int J Women’s Health. 2023:987-1002.
  62. Adhikari P, Vietje P, Mount S. Premalignant and malignant lesions of the vagina. Diagn Histopathology. 2017;23(1):28-34.
  63. Kulkarni A, Dogra N, Zigras T. Innovations in the management of vaginal cancer. Curr Oncol. 2022;29(5):3082-92.
  64. Bhat R. Vaginal Cancer: Epidemiology and Risk Factors. Prevent Oncol Gynecologist. 2019:309-14.
  65. Łaniewski P, Ilhan ZE, Herbst-Kralovetz MM. The microbiome and gynaecological cancer development, prevention and therapy. Nat Rev Urol. 2020;17(4):232-50.
  66. Gholiof M, Luca A-D, Wessels JM. The female reproductive tract microbiotas, inflammation, and gynecological conditions. Front Reproduct Health. 2022;4:963752.
  67. Gillet E, Meys JF, Verstraelen H, et al. Bacterial vaginosis is associated with uterine cervical human papillomavirus infection: a meta-analysis. BMC Infect Dis. 2011;11:10.
  68. Zhou FY, Zhou Q, Zhu ZY, et al. Types and viral load of human papillomavirus, and vaginal microbiota in vaginal intraepithelial neoplasia: a cross-sectional study. Ann Transl Med. 2020;8(21):1408.
  69. Libby EK, Pascal KE, Mordechai E, et al. Atopobium vaginae triggers an innate immune response in an in vitro model of bacterial vaginosis. Microbes Infect. 2008;10:439-46.
  70. Xie YH, Gao QY, Cai GX, et al. Fecal Clostridium symbiosum for Noninvasive Detection of Early and Advanced Colorectal Cancer: Test and Validation Studies. EBioMedicine. 2017;25:32-40.
  71. Jett BD, Huycke MM, Gilmore MS. Virulence of enterococci. Clin Microbiol Rev. 1994;7:462-78.
  72. Pedrão PG, Guimarães YM, Godoy LR, et al. Management of early-stage vulvar cancer. Cancers. 2022;14(17):4184.
  73. Organization WH. Global Cancer Observatory-estimated number of new cases in 2020, worldwide, females, all ages. Ginebra, Suiza: WHO, 2020.
  74. Pedrão PG, Guimarães YM, Godoy LR, et al. Management of early-stage vulvar cancer. Cancers. 2022;14(17):4184.
  75. Canavan TP, Cohen D. Vulvar cancer. Am Family Phys. 2002;66(7):1269-75.
  76. Wahid M, Dar SA, Jawed A, et al. Microbes in gynecologic cancers: causes or consequences and therapeutic potential. Seminars in cancer biology. Elsevier, 2022.
  77. Rustetska N, Szczepaniak M, Goryca K, et al. The intratumour microbiota and neutrophilic inflammation in squamous cell vulvar carcinoma microenvironment. Transl Med. 2023;21(1):285. doi: 10.1186/s12967-023-04113-7

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2025 Consilium Medicum

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Согласие на обработку персональных данных с помощью сервиса «Яндекс.Метрика»

1. Я (далее – «Пользователь» или «Субъект персональных данных»), осуществляя использование сайта https://journals.rcsi.science/ (далее – «Сайт»), подтверждая свою полную дееспособность даю согласие на обработку персональных данных с использованием средств автоматизации Оператору - федеральному государственному бюджетному учреждению «Российский центр научной информации» (РЦНИ), далее – «Оператор», расположенному по адресу: 119991, г. Москва, Ленинский просп., д.32А, со следующими условиями.

2. Категории обрабатываемых данных: файлы «cookies» (куки-файлы). Файлы «cookie» – это небольшой текстовый файл, который веб-сервер может хранить в браузере Пользователя. Данные файлы веб-сервер загружает на устройство Пользователя при посещении им Сайта. При каждом следующем посещении Пользователем Сайта «cookie» файлы отправляются на Сайт Оператора. Данные файлы позволяют Сайту распознавать устройство Пользователя. Содержимое такого файла может как относиться, так и не относиться к персональным данным, в зависимости от того, содержит ли такой файл персональные данные или содержит обезличенные технические данные.

3. Цель обработки персональных данных: анализ пользовательской активности с помощью сервиса «Яндекс.Метрика».

4. Категории субъектов персональных данных: все Пользователи Сайта, которые дали согласие на обработку файлов «cookie».

5. Способы обработки: сбор, запись, систематизация, накопление, хранение, уточнение (обновление, изменение), извлечение, использование, передача (доступ, предоставление), блокирование, удаление, уничтожение персональных данных.

6. Срок обработки и хранения: до получения от Субъекта персональных данных требования о прекращении обработки/отзыва согласия.

7. Способ отзыва: заявление об отзыве в письменном виде путём его направления на адрес электронной почты Оператора: info@rcsi.science или путем письменного обращения по юридическому адресу: 119991, г. Москва, Ленинский просп., д.32А

8. Субъект персональных данных вправе запретить своему оборудованию прием этих данных или ограничить прием этих данных. При отказе от получения таких данных или при ограничении приема данных некоторые функции Сайта могут работать некорректно. Субъект персональных данных обязуется сам настроить свое оборудование таким способом, чтобы оно обеспечивало адекватный его желаниям режим работы и уровень защиты данных файлов «cookie», Оператор не предоставляет технологических и правовых консультаций на темы подобного характера.

9. Порядок уничтожения персональных данных при достижении цели их обработки или при наступлении иных законных оснований определяется Оператором в соответствии с законодательством Российской Федерации.

10. Я согласен/согласна квалифицировать в качестве своей простой электронной подписи под настоящим Согласием и под Политикой обработки персональных данных выполнение мною следующего действия на сайте: https://journals.rcsi.science/ нажатие мною на интерфейсе с текстом: «Сайт использует сервис «Яндекс.Метрика» (который использует файлы «cookie») на элемент с текстом «Принять и продолжить».