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Towards a deeper understanding of the vaginal microbiota

Abstract

The human vaginal microbiota is a critical determinant of vaginal health. These communities live in close association with the vaginal epithelium and rely on host tissues for resources. Although often dominated by lactobacilli, the vaginal microbiota is also frequently composed of a collection of facultative and obligate anaerobes. The prevalence of these communities with a paucity of Lactobacillus species varies among women, and epidemiological studies have associated them with an increased risk of adverse health outcomes. The mechanisms that drive these associations have yet to be described in detail, with few studies establishing causative relationships. Here, we review our current understanding of the vaginal microbiota and its connection with host health. We centre our discussion around the biology of the vaginal microbiota when Lactobacillus species are dominant versus when they are not, including host factors that are implicated in shaping these microbial communities and the resulting adverse health outcomes. We discuss current approaches to modulate the vaginal microbiota, including probiotics and vaginal microbiome transplants, and argue that new model systems of the cervicovaginal environment that incorporate the vaginal microbiota are needed to progress from association to mechanism and this will prove invaluable for future research.

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Fig. 1: Effect of the menstrual cycle on the vaginal microenvironment.
Fig. 2: The biology of L.crispatus in the vaginal microbiota.
Fig. 3: The CST IV vaginal microbiota.
Fig. 4: Vaginal microbiota interventions to treat bacterial vaginosis.

References

  1. The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

    Article  PubMed Central  CAS  Google Scholar 

  2. Ravel, J. et al. Vaginal microbiome of reproductive-age women. Proc. Natl Acad. Sci. USA 108, 4680–4687 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Antonio, M. A., Hawes, S. E. & Hillier, S. L. The identification of vaginal Lactobacillus species and the demographic and microbiologic characteristics of women colonized by these species. in. J. Infect. Dis. 180, 1950–1956 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Zhou, X. et al. Characterization of vaginal microbial communities in adult healthy women using cultivation-independent methods. Microbiology 150, 2565–2573 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Döderlein, A. Das Scheidensekret und seine Bedeutung für das Puerperalfieber (Verlag Von Eduard Besold, 1892).

  6. Galask, R. P., Larsen, B. & Ohm, M. J. Vaginal flora and its role in disease entities. Clin. Obset. Gynceol. 19, 61–81 (1976).

    Article  CAS  Google Scholar 

  7. Hillier, S. L., Krohn, M. A., Rabe, L. K., Klebanoff, S. J. & Eschenbach, D. A. The normal vaginal flora, H202-producing lactobacilli, and bacterial vaginosis in pregnant women. Clin. Infect. Dis. 16, S273–S281 (1993).

    Article  PubMed  Google Scholar 

  8. Sobel, J. D. Is there a protective role for vaginal flora? in. Curr. Infect. Dis. Rep. 1, 379–383 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Ma, B., Forney, L. J. & Ravel, J. Vaginal microbiome: rethinking health and disease. Annu. Rev. Microbiol. 66, 371–389 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Boskey, E. R., Teslch, K. M., Whaley, K. J., Moench, T. R. & Cone, R. A. Acid production by vaginal flora in vitro is consistent with the rate and extent of vaginal acidification. Infect. Immun. 67, 5170–5175 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. O’Hanlon, D. E., Moench, T. R. & Cone, R. A. Vaginal pH and microbicidal lactic acid when lactobacilli dominate the microbiota. PLoS ONE 8, e80074 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Aldunate, M. et al. Antimicrobial and immune modulatory effects of lactic acid and short chain fatty acids produced by vaginal microbiota associated with eubiosis and bacterial vaginosis. Front. Physiol. 6, 164 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Delgado-Diaz, D. J. et al. Distinct immune responses elicited from cervicovaginal epithelial cells by lactic acid and short chain fatty acids associated with optimal and non-optimal vaginal microbiota. Front. Cell Infect. Microbiol. 9, 446 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Zhou, X. et al. Differences in the composition of vaginal microbial communities found in healthy Caucasian and black women. ISME J. 1, 121–133 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Zhou, X. et al. The vaginal bacterial communities of Japanese women resemble those of women in other racial groups. FEMS Immunol. Med. Microbiol. 58, 169–181 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Verstraelen, H., Verhelst, R., Claeys, G., Temmerman, M. & Vaneechoutte, M. Culture-independent analysis of vaginal microflora: the unrecognized association of Atopobium vaginae with bacterial vaginosis. Am. J. Obstet. Gynecol. 191, 1130–1132 (2004).

    Article  PubMed  Google Scholar 

  17. Peebles, K., Velloza, J., Balkus, J. E., McClelland, R. S. & Barnabas, R. V. High global burden and costs of bacterial vaginosis: a systematic review and meta-analysis. Sex. Transm. Dis. 46, 304–311 (2019).

    Article  PubMed  Google Scholar 

  18. Allsworth, J. E. & Peipert, J. F. Prevalence of bacterial vaginosis: 2001–2004 National Health and Nutrition Examination Survey. Obstet. Gynecol. 109, 114–120 (2007).

    Article  PubMed  Google Scholar 

  19. Ravel, J. & Brotman, R. M. Translating the vaginal microbiome: gaps and challenges. Genome Med. 8, 35 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Reid, G. Is bacterial vaginosis a disease? Appl. Microbiol. Biotechnol. 102, 553–558 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Brotman, R. M. et al. Bacterial vaginosis assessed by Gram stain and diminished colonization resistance to incident gonococcal, chlamydial, and trichomonal genital infection. J. Infect. Dis. 202, 1907–1915 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Brotman, R. M. et al. Association between Trichomonas vaginalis and vaginal bacterial community composition among reproductive-age women. Sex. Transm. Dis. 39, 807–812 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Martin, H. L. et al. Vaginal lactobacilli, microbial flora, and risk of human immunodeficiency virus type 1 and sexually transmitted disease acquisition. J. Infect. Dis. 180, 1863–1868 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Gosmann, C. et al. Lactobacillus-deficient cervicovaginal bacterial communities are associated with increased HIV acquisition in young South African women. Immunity 46, 29–37 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Feehily, C. et al. Shotgun sequencing of the vaginal microbiome reveals both a species and functional potential signature of preterm birth. NPJ Biofilms Microbiomes 6, 50 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Brown, R. G. et al. Establishment of vaginal microbiota composition in early pregnancy and its association with subsequent preterm prelabor rupture of the fetal membranes. Transl. Res. 207, 30–43 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Elovitz, M. A. et al. Cervicovaginal microbiota and local immune response modulate the risk of spontaneous preterm delivery. Nat. Commun. 10, 1305 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Brown, R. G. et al. Vaginal dysbiosis increases risk of preterm fetal membrane rupture, neonatal sepsis and is exacerbated by erythromycin. BMC Med. 16, 9 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Freitas, A. C. et al. Increased richness and diversity of the vaginal microbiota and spontaneous preterm birth. Microbiome 6, 117 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Stafford, G. P. et al. Spontaneous preterm birth is associated with differential expression of vaginal metabolites by lactobacilli-dominated microflora. Front. Physiol. 8, 615 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kindinger, L. M. et al. The interaction between vaginal microbiota, cervical length, and vaginal progesterone treatment for preterm birth risk. Microbiome 5, 6 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Callahan, B. J. et al. Replication and refinement of a vaginal microbial signature of preterm birth in two racially distinct cohorts of US women. Proc. Natl Acad. Sci. USA 114, 9966–9971 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kindinger, L. M. et al. Relationship between vaginal microbial dysbiosis, inflammation, and pregnancy outcomes in cervical cerclage. Sci. Transl. Med. 8, 350ra102 (2016).

    Article  PubMed  Google Scholar 

  34. Romero, R. et al. The vaginal microbiota of pregnant women who subsequently have spontaneous preterm labor and delivery and those with a normal delivery at term. Microbiome 2, 18 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Nelson, D. B. et al. Early pregnancy changes in bacterial vaginosis-associated bacteria and preterm delivery. Paediatr. Perinat. Epidemiol. 28, 88–96 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  36. McKinnon, L. R. et al. The evolving facets of bacterial vaginosis: implications for HIV transmission. AIDS Res. Hum. Retroviruses 35, 219–228 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Krakowsky, Y. et al. The effect of gender-affirming medical care on the vaginal and neovaginal microbiomes of transgender and gender diverse people. Front. Cell. Infect. Microbiol. 11, 769950 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  38. France, M. T. et al. VALENCIA: a nearest centroid classification method for vaginal microbial communities based on composition. Microbiome 8, 166 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Vancuren, S. J. & Hill, J. E. Update on cpnDB: a reference database of chaperonin sequences. Database 2019, baz033 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Fredricks, D. N., Fiedler, T. L., Thomas, K. K., Oakley, B. B. & Marrazzo, J. M. Targeted PCR for detection of vaginal bacteria associated with bacterial vaginosis. J. Clin. Microbiol 45, 3270–3276 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shi, Y., Chen, L., Tong, J. & Xu, C. Preliminary characterization of vaginal microbiota in healthy Chinese women using cultivation-independent methods. J. Obstet. Gynaecol. Res. 35, 525–532 (2009).

    Article  PubMed  Google Scholar 

  42. McClelland, R. S. et al. Evaluation of the association between the concentrations of key vaginal bacteria and the increased risk of HIV acquisition in African women from five cohorts: a nested case–control study. Lancet Infect. Dis. 18, 554–564 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Balle, C. et al. Hormonal contraception alters vaginal microbiota and cytokines in South African adolescents in a randomized trial. Nat. Commun. 11, 5578 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sabo, M. C. et al. Association between vaginal washing and vaginal bacterial concentrations. PLoS ONE 14, e01210825 (2019).

    Google Scholar 

  45. Lennard, K. et al. Microbial composition predicts genital tract inflammation and persistent bacterial vaginosis in South African adolescent females. Infect. Immun. 86, e00410-17 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Bradshaw, C. S. et al. The association of Atopobium vaginae and Gardnerella vaginalis with bacterial vaginosis and recurrence after oral metronidazole therapy. J. Infect. Dis. 194, 826–836 (2006).

    Article  Google Scholar 

  47. Vargas-Robles, D. et al. Changes in the vaginal microbiota across a gradient of urbanization. Sci. Rep. 10, 12487 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Holm, J. B. et al. Comparative metagenome-assembled genome analysis of “Candidatus Lachnocurva vaginae”, formerly known as bacterial vaginosis-associated bacterium-1 (BVAB1). Front. Cell. Infect. Microbiol. 10, 117 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Srinivasan, S. & Fredricks, D. N. The human vaginal bacterial biota and bacterial vaginosis. Interdiscip. Perspect. Infect. Dis. 2008, 750479 (2008).

    Article  PubMed  CAS  Google Scholar 

  50. Gajer, P. et al. Temporal dynamics of the human vaginal microbiota. Sci. Transl. Med. 4, 132ra52 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Srinivasan, S. et al. Temporal variability of human vaginal bacteria and relationship with bacterial vaginosis. PLoS ONE 5, e10197 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Tevi-Benissan, C. et al. In vivo semen-associated pH neutralization of cervicovaginal secretions. Clin. Diagnostic Lab. Immunol. 4, 367–374 (1997).

    Article  CAS  Google Scholar 

  53. Mehta, S. D. et al. The microbiome composition of a man’s penis predicts incident bacterial vaginosis in his female sex partner with high accuracy. Front. Cell. Infect. Microbiol. 10, 433 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Gilbert, J. A. & Lynch, S. V. Community ecology as a framework for human microbiome research. Nat. Med. 25, 884–889 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wheater, P. R., Burkitt, H. G. & Daniels, V. G. Functional Histology. A Text and Colour Atlas (Churchill Livingstone, 1979).

  56. Anderson, D. J., Marathe, J. & Pudney, J. The structure of the human vaginal stratum corneum and its role in immune defense. Am. J. Reprod. Immunol. 71, 618–623 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pudney, J., Quayle, A. J. & Anderson, D. J. Immunological microenvironments in the human vagina and cervix: mediators of cellular immunity are concentrated in the cervical transformation zone. Biol. Reprod. 73, 1253–1263 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Franklin, R. & Kutteh, W. Characterization of immunoglobulins and cytokines in human cervical mucus: influence of exogenous and endogenous hormones. J. Reprod. Immunol. 42, 93–106 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Dierks, K. Der normale mensuelle zyklus der menschlichen vaginalschleimhaut. Arch. f. Gynäkologie 130, 46–69 (1927).

    Article  Google Scholar 

  60. Han, L., Taub, R. & Jensen, J. T. Cervical mucus and contraception: what we know and what we don’t. Contraception 96, 310–321 (2017).

    Article  PubMed  Google Scholar 

  61. Odeblad, E. The discovery of different types of cervical mucus and the Billings Ovulation Method. Bull. Nat. Fam. Plan. Counc. Vic. 21, 3–34 (1994).

    Google Scholar 

  62. Lacroix, G., Gouyer, V., Gottrand, F. & Desseyn, J.-L. The cervicovaginal mucus barrier. Int. J. Mol. Sci. 21, 8266 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  63. Voynow, J. A. & Rubin, B. K. Mucins, mucus, and sputum. Chest 135, 505–512 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Voynow, J. A. & Fischer, B. M. in Encyclopedia of Respiratory Medicine (eds Laurent, G. J. & Shapiro, S. D.) 56–62 (Academic, 2006).

  65. Reily, C., Stewart, T. J., Renfrow, M. B. & Novak, J. Glycosylation in health and disease. Nat. Rev. Nephrol. 15, 346–366 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Critchfield, A. S. et al. Cervical mucus properties stratify risk for preterm birth. PLoS ONE 8, e69528 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Domino, S. E. et al. Cervical mucins carry α(1,2)fucosylated glycans that partly protect from experimental vaginal candidiasis. Glycoconj. J. 26, 1125–1134 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cone, R. A. Barrier properties of mucus. Adv. Drug Deliv. Rev. 61, 75–85 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Agarwal, K. & Lewis, A. L. Vaginal sialoglycan foraging by Gardnerella vaginalis: mucus barriers as a meal for unwelcome guests? Glycobiology 31, 667–680 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Vagios, S. & Mitchell, C. M. Mutual preservation: a review of interactions between cervicovaginal mucus and microbiota. Front. Cell. Infect. Microbiol. 11, 676114 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gipson, I. K. et al. The amount of MUC5B mucin in cervical mucus peaks at midcycle. J. Clin. Endocrinol. Metab. 86, 594–600 (2001).

    CAS  PubMed  Google Scholar 

  72. Andersch-Björkman, Y., Thomsson, K. A., Larsson, J. M. H., Ekerhovd, E. & Hansson, G. C. Large scale identification of proteins, mucins, and their O-glycosylation in the endocervical mucus during the menstrual cycle. Mol. Cell. Proteom. 6, 708–716 (2007).

    Article  CAS  Google Scholar 

  73. Tester, R. & Al-Ghazzewi, F. H. Intrinsic and extrinsic carbohydrates in the vagina: a short review on vaginal glycogen. Int. J. Biol. Macromol. 112, 203–206 (2018).

    Article  CAS  PubMed  Google Scholar 

  74. Mirmonsef, P. et al. Free glycogen in vaginal fluids is associated with Lactobacillus colonization and low vaginal pH. PLoS ONE 9, e102467 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Seidman, J. D., Cho, K. R., Ronnett, B. M. & Kurman, R. J. in Blausteins Pathology of the Female Genital Tract (eds Kurman, R. J. et al.) 679–784 (Springer, 2011).

  76. Mirmonsef, P. et al. Glycogen levels in undiluted genital fluid and their relationship to vaginal pH, estrogen, and progesterone. PLoS ONE 11, e0153553 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Farage, M. & Maibach, H. Lifetime changes in the vulva and vagina. Arch. Gynecol. Obstet. 273, 195–202 (2006).

    Article  PubMed  Google Scholar 

  78. Konar, H. DC Duttas Textbook of Gynecology (JP Medical, 2016).

  79. Rousseaux, C. G., Wallig, M. A. & Haschek, W. M. Fundamentals of Toxicologic Pathology (Academic, 2009).

  80. Kingsberg, S. A., Wysocki, S., Magnus, L. & Krychman, M. L. Vulvar and vaginal atrophy in postmenopausal women: findings from the REVIVE (REal women’s VIews of treatment options for menopausal Vaginal changEs) survey. J. Sex. Med. 10, 1790–1799 (2013).

    Article  PubMed  Google Scholar 

  81. Schwenkhagen, A. Hormonal changes in menopause and implications on sexual health. J. Sex. Med. 4, 220–226 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Moncla, B. J., Chappell, C. A., Debo, B. M. & Meyn, L. A. The effects of hormones and vaginal microflora on the glycome of the female genital tract: cervical–vaginal fluid. PLoS ONE 11, e0158687 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Mirmonsef, P. et al. Exploratory comparison of vaginal glycogen and Lactobacillus levels in preand postmenopausal women. Menopause 22, 702–709 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Panda, S., Das, A., Santa Singh, A. & Pala, S. Vaginal pH: a marker for menopause. J. Midlife Health 5, 34–37 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Muhleisen, A. L. & Herbst-Kralovetz, M. M. Menopause and the vaginal microbiome. Maturitas 91, 42–50 (2016).

    Article  PubMed  Google Scholar 

  86. The North Americal Menopause Society. The 2020 genitourinary syndrome of menopause position statement of The North American Menopause Society. Menopause 27, 976–992 (2020).

    Article  Google Scholar 

  87. Ma, B. et al. A comprehensive non-redundant gene catalog reveals extensive within-community intraspecies diversity in the human vagina. Nat. Commun. 11, 940 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Garud, N. R., Good, B. H., Hallatschek, O. & Pollard, K. S. Evolutionary dynamics of bacteria in the gut microbiome within and across hosts. PLoS Biol. 17, e3000102 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Agashe, D. The stabilizing effect of intraspecific genetic variation on population dynamics in novel and ancestral habitats. Am. Nat. 174, 255–267 (2009).

    Article  PubMed  Google Scholar 

  90. Mendes-Soares, H., Suzuki, H., Hickey, R. J., Forney, L. J. & Forneya, L. J. Comparative functional genomics of Lactobacillus spp. reveals possible mechanisms for specialization of vaginal lactobacilli to their environment. J. Bacteriol. 196, 1458–1470 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Gupta, S., Kakkar, V. & Bhushan, I. Crosstalk between vaginal microbiome and female health: a review. Micro. Pathog. 136, 103696 (2019).

    Article  CAS  Google Scholar 

  92. Smith, S. B. & Ravel, J. The vaginal microbiota, host defence and reproductive physiology. J. Physiol. 595, 451–463 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Vos, P. et al. Bergeys Manual of Systematic Bcteriology. Volume Three: The Firmicutes (Springer, 2011).

  94. Stewart-Bull, D. E. S. Evidence that vaginal lactobacilli do not ferment glycogen. Am. J. Obstet. Gynecol. 88, 676–679 (1964).

    Article  Google Scholar 

  95. Spear, G. T. et al. Human alpha-amylase present in lower-genital-tract mucosal fluid processes glycogen to support vaginal colonization by Lactobacillus. J. Infect. Dis. 210, 1019–1028 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. van der Veer, C. et al. Comparative genomics of human Lactobacillus crispatus isolates reveals genes for glycosylation and glycogen degradation: implications for in vivo dominance of the vaginal microbiota. Microbiome 7, 49 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Nunn, K. L. et al. Amylases in the human vagina. mSphere 5, e00943-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Woolston, B. M., Jenkins, D. J., Hood-Pishchany, M. I., Nahoum, S. R. & Balskus, E. P. Characterization of vaginal microbial enzymes identifies amylopullulanases that support growth of Lactobacillus crispatus on glycogen. Preprint at bioRxiv https://doi.org/10.1101/2021.07.19.452977 (2021).

  99. Cruickshank, R. & Sharman, A. The biology of the vagina in the human subject. BJOG 41, 190–207 (1934).

    Article  Google Scholar 

  100. Skarin, A. & Sylwan, J. Vaginal lactobacilli inhibiting the growth of Gardnerella vaginalis, Mobiluncus, and other bacterial species cultured from vaginal content of women with bacterial vaginosis. Acta Pathol. Microbiol. Immunol. Scan. B 94, 399–403 (1986).

    CAS  Google Scholar 

  101. Atassi, F., Brassart, D., Grob, P., Graf, F. & Servin, A. L. Lactobacillus strains isolated from the vaginal microbiota of healthy women inhibit Prevotella bivia and Gardnerella vaginalis in coculture and cell culture. FEMS Immunol. Med. Microbiol. 48, 424–432 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Nunn, K. L. et al. Changes in the vaginal microbiome during the pregnancy to postpartum transition. Reprod. Sci. 28, 1996–2005 (2021).

    Article  CAS  PubMed  Google Scholar 

  103. France, M. T., Mendes-Soares, H. & Forney, L. J. Genomic comparisons of Lactobacillus crispatus and Lactobacillus iners reveal potential ecological drivers of community composition in the vagina. Appl. Environ. Microbiol. 82, 7063–7073 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Witkin, S. S. 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 4, e00460-13 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Manhanzva, M. T. et al. Inflammatory and antimicrobial properties differ between vaginal Lactobacillus isolates from South African women with non-optimal versus optimal microbiota. Sci. Rep. 10, 6196 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Schmitt, M. G. Jr, Soergel, K. H., Wood, C. M. & Steff, J. J. Absorption of short-chain fatty acids from the human ileum. Am. J. Dig. Dis. 22, 340–347 (1977).

    Article  CAS  PubMed  Google Scholar 

  107. Wylie, J. G. & Henderson, A. Hydrogen-peroxide formation and catalase activity in the lactic acid bacteria. J. Gen. Microbiol. 35, 13–26 (1964).

    Article  Google Scholar 

  108. Eschenbach, D. A. et al. Prevalence of hydrogen peroxide-producing Lactobacillus species in normal women and women with bacterial vaginosis. J. Clin. Microbiol. 27, 251–256 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Klebanoff, S. J., Hillier, S. L. & Eschenbach, D. A. Control of microbial flora of the vagina by H2O2-generating lactobacilli. J. Infect. Dis. 194, 94–100 (1991).

    Article  Google Scholar 

  110. Hawes, S. E. et al. Hydrogen peroxide-producing lactobacilli and acquisition of vaginal infections. J. Infect. Dis. 174, 1058–1063 (1996).

    Article  CAS  PubMed  Google Scholar 

  111. Macklaim, J. M., Gloor, G. B., Anukam, K. C., Cribby, S. & Reid, G. At the crossroads of vaginal health and disease, the genome sequence of Lactobacillus iners AB-1. Proc. Natl Acad. Sci. USA 108, 4688–4695 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Strus, M., Brzychczy-Wloch, M., Gosiewski, T., Kochan, P. & Heczko, P. B. The in vitro effect of hydrogen peroxide on vaginal microbial communities. FEMS Immunol. Med. Microbiol. 48, 56–63 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Patterson, J. L., Girerd, P. H., Karjane, N. W. & Jefferson, K. K. Effect of biofilm phenotype on resistance of Gardnerella vaginalis to hydrogen peroxide and lactic acid. Am. J. Obstet. Gynecol. 197, 170.e1–170.e7 (2007).

    Article  CAS  Google Scholar 

  114. Hill, D. R. et al. In vivo assessment of human vaginal oxygen and carbon dioxide levels during and post menses. J. Appl. Physiol. 99, 1582–1591 (2005).

    Article  PubMed  Google Scholar 

  115. O’Hanlon, D. E., Lanier, B. R., Moench, T. R. & Cone, R. A. Cervicovaginal fluid and semen block the microbicidal activity of hydrogen peroxide produced by vaginal lactobacilli. BMC Infect. Dis. 10, 120 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Abdelmaksoud, A. A. et al. Comparison of Lactobacillus crispatus isolates from Lactobacillus-dominated vaginal microbiomes with isolates from microbiomes containing bacterial vaginosis-associated bacteria. Microbiology 162, 466–475 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Stoyancheva, G., Marzotto, M., Dellaglio, F. & Torriani, S. Bacteriocin production and gene sequencing analysis from vaginal Lactobacillus strains. Arch. Microbiol. 196, 645–653 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Sillanpaa, J. et al. Characterization of the collagen-binding S-layer protein CbsA of Lactobacillus crispatus. J. Bacteriol. 182, 6440–6450 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Toba, T. et al. A collagen-binding S-layer protein in Lactobacillus crispatus. Appl. Environ. Microbiol. 61, 2467–2471 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kobatake, E. & Kabuki, T. S-layer protein of Lactobacillus helveticus SBT2171 promotes human β-defensin 2 expression via TLR2–JNK signaling. Front. Microbiol. 10, 2414 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Abramov, V. M. et al. S-layer protein 2 of Lactobacillus crispatus 2029, its structural and immunomodulatory characteristics and roles in protective potential of the whole bacteria against foodborne pathogens. Int. J. Biol. Macromol. 150, 400–412 (2020).

    Article  CAS  PubMed  Google Scholar 

  122. Kwok, L. et al. Adherence of Lactobacillus crispatus to vaginal epithelial cells from women with or without a history of recurrent urinary tract infection. J. Urol. 176, 2050–2054 (2006).

    Article  PubMed  Google Scholar 

  123. Osset, J., Bartolome, R. M., Garcia, E. & Andreu, A. Assessment of the capacity of Lactobacillus to inhibit the growth of uropathogens and block their adhesion to vaginal epithelial cells. J. Infect. Dis. 183, 485–491 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Anahtar, M. N. et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity 42, 965–976 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. McLaren, M. R. & Callahan, B. J. Pathogen resistance may be the principal evolutionary advantage provided by the microbiome. Philos. Trans. R. Soc. Lond. B Biol. Sci. 375, 20190592 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Grace, J. B. et al. Integrative modelling reveals mechanisms linking productivity and plant species richness. Nature 529, 390–393 (2016).

    Article  CAS  PubMed  Google Scholar 

  127. Howe, L. et al. Mucinase and sialidase activity of the vaginal microflora: implications for the pathogensis of preterm labour. Int. J. STD AIDS 10, 442–447 (1999).

    Article  CAS  PubMed  Google Scholar 

  128. Briselden, A. M., Moncla, B. J., Stevens, C. E. & Hillier, S. L. Sialidases (neuraminidases) in bacterial vaginosis and bacterial vaginosis-associated microflora. J. Clin. Microbiol. 30, 663–666 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Robinson, L. S., Schwebke, J., Lewis, W. G. & Lewis, A. L. Identification and characterization of NanH2 and NanH3, enzymes responsible for sialidase activity in the vaginal bacterium Gardnerella vaginalis. J. Biol. Chem. 294, 5230–5245 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hardy, L. et al. The presence of the putative Gardnerella vaginalis sialidase A gene in vaginal specimens is associated with bacterial vaginosis biofilm. PLoS ONE 12, e0172522 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Lewis, W. G., Robinson, L. S., Gilbert, N. M., Perry, J. C. & Lewis, A. L. Degradation, foraging, and depletion of mucus sialoglycans by the vagina-adapted Actinobacterium Gardnerella vaginalis. J. Biol. Chem. 288, 12067–12079 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Smayevsky, J., Canigia, L. F., Lanza, A. & Bianchini, H. Vaginal microflora associated with bacterial vaginosis in nonpregnant women: reliability of sialidase detection. Infect. Dis. Obstet. Gynecol. 9, 17–22 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Rampersaud, R. et al. Inerolysin, a cholesterol-dependent cytolysin produced by Lactobacillus iners. J. Bacteriol. 193, 1034–1041 (2011).

    Article  CAS  PubMed  Google Scholar 

  134. Gelber, S. E., Aguilar, J. L., Lewis, K. L. & Ratner, A. J. Functional and phylogenetic characterization of Vaginolysin, the human-specific cytolysin from Gardnerella vaginalis. J. Bacteriol. 190, 3896–3903 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Nelson, T. M. et al. Vaginal biogenic amines: biomarkers of bacterial vaginosis or precursors to vaginal dysbiosis? Front. Physiol. 6, 253 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Petrova, M. I., Reid, G., Vaneechoutte, M. & Lebeer, S. Lactobacillus iners: friend or foe? Trends Microbiol. 25, 182–191 (2017).

    Article  CAS  PubMed  Google Scholar 

  137. Munoz, A. et al. Modeling the temporal dynamics of cervicovaginal microbiota identifies targets that may promote reproductive health. Microbiome 9, 163 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Macklaim, J. M. et al. Comparative meta-RNA-seq of the vaginal microbiota and differential expression by Lactobacillus iners in health and dysbiosis. Microbiome 1, 12 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  139. France, M. T. et al. Insight into the ecology of vaginal bacteria through integrative analyses of metagenomic and metatranscriptomic data. Genome Biol. https://doi.org/10.1186/s13059-022-02635-9 (2022).

  140. Bloom, S. M. et al. Cysteine dependence in Lactobacillus iners constitutes a novel therapeutic target to modify the vaginal microbiota. Nat. Microbiol. https://doi.org/10.1038/s41564-022-01070-7 (2022).

  141. Amsel, R. et al. Nonspecific vaginitis: diagnostic criteria and microbial and epidemiological associations. Am. J. Med. 74, 14–22 (1983).

    Article  CAS  PubMed  Google Scholar 

  142. Nugent, R. P., Krohn, M. A. & Hillier, S. L. Reliability of diagnosing bacterial vaginosis is improved by standardized method of Gram stain Interpretation. J. Clin. Microbiol. 29, 297–301 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Workowski, K. et al. Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm. Rep. 70, 1–187 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Verwijs, M. C., Agaba, S. K., Darby, A. C. & van de Wijgert, J. Impact of oral metronidazole treatment on the vaginal microbiota and correlates of treatment failure. Am. J. Obstet. Gynecol. 222, 157.e1–157.e13 (2020).

    Article  CAS  Google Scholar 

  145. Ferris, D. G., Litaker, M. S., Woodward, L., Mathis, D. & Hendrich, J. Treatment of bacterial vaginosis: a comparison of oral metronidazole, metronidazole vaginal gel, and clindamycin vaginal cream. J. Fam. Pract. 41, 443–450 (1995).

    CAS  PubMed  Google Scholar 

  146. Muzny, C. A. & Schwebke, J. R. Asymptomatic bacterial vaginosis: to treat or not to treat?. Curr. Infect. Dis. Rep. 22, 32 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Bhandari, P., Tingley, J. P., Palmer, D. R. J., Abbott, D. W. & Hill, J. E. Characterization of an α-glucosidase enzyme conserved in Gardnerella spp. isolated from the human vaginal microbiome. J. Bacteriol. 203, e0021321 (2021).

    Article  PubMed  Google Scholar 

  148. Nunn, K. L. et al. Vaginal glycogen, not estradiol, is associated with vaginal bacterial community composition in black adolescent women. J. Adolesc. Health 65, 130–138 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Ragaliauskas, T. et al. Inerolysin and vaginolysin, the cytolysins implicated in vaginal dysbiosis, differently impair molecular integrity of phospholipid membranes. Sci. Rep. 9, 10606 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Randis, T. M. et al. Vaginolysin drives epithelial ultrastructural responses to Gardnerella vaginalis. Infect. Immun. 81, 4544–4550 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Thapa, R., Ray, S. & Ketel, P. A. Interaction of macrophages and cholesterol-dependent cytolysins: the impact on immune response and cellular survival. Toxins 12, 531 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  152. O’Hanlon, D. E., Gajer, P., Brotman, R. M. & Ravel, J. Asymptomatic bacterial vaginosis is associated with depletion of mature superficial cells shed from the vaginal epithelium. Front. Cell. Infect. Microbiol. 10, 106 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Srinivasan, S. et al. Metabolic signatures of bacterial vaginosis. mBio 6, e00204-15 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Chattopadhyay, M. K., Tabor, C. W. & Tabor, H. Polyamines protect Escherichia coli cells from the toxic effect of oxygen. Proc. Natl Acad. Sci. USA 100, 2261–2265 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Borgogna, J. L. et al. Biogenic amines increase the odds of bacterial vaginosis and affect the growth of and lactic acid production by vaginal Lactobacillus spp. Appl. Environ. Microbiol. 87, e03068-20 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Cruden, D. L. & Galask, R. P. Reduction of trimethylamine oxide to trimethylamine by Mobiluncus strains isolated from patients with bacterial vaginosis. Microb. Ecol. Health Dis. 1, 95–100 (2009).

    Google Scholar 

  157. Fredricks, D. N., Fiedler, T. L. & Marrazzo, J. M. Molecular identification of bacteria associated with bacterial vaginosis. in. N. Engl. J. Med. 353, 1899–1911 (2005).

    Article  CAS  PubMed  Google Scholar 

  158. Piot, P. et al. Biotypes of Gardnerella vaginalis. J. Clin. Microbiol. 20, 677–679 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Vaneechoutte, M. et al. Emended description of Gardnerella vaginalis and description of Gardnerella leopoldii sp. nov., Gardnerella piotii sp. nov. and Gardnerella swidsinskii sp. nov., with delineation of 13 genomic species within the genus Gardnerella. Int. J. Syst. Evol. Microbiol. 69, 679–687 (2019).

    Article  CAS  PubMed  Google Scholar 

  160. Castro, J., Jefferson, K. K. & Cerca, N. Genetic heterogeneity and taxonomic diversity among Gardnerella species. Trends Microbiol. 28, 202–211 (2020).

    Article  CAS  PubMed  Google Scholar 

  161. Janulaitiene, M. et al. Phenotypic characterization of Gardnerella vaginalis subgroups suggests differences in their virulence potential. PLoS ONE 13, e0200625 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Ahmed, A. et al. Comparative genomic analyses of 17 clinical isolates of Gardnerella vaginalis provide evidence of multiple genetically isolated clades consistent with subspeciation into genovars. J. Bacteriol. 194, 3922–3937 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Serrano, M. G. et al. Racioethnic diversity in the dynamics of the vaginal microbiome during pregnancy. Nat. Med. 25, 1001–1011 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Marconi, C. et al. Characterization of the vaginal microbiome in women of reproductive age from 5 regions in Brazil. Sex. Transm. Dis. 47, 562–569 (2020).

    Article  CAS  PubMed  Google Scholar 

  165. Borgdorff, H. et al. The association between ethnicity and vaginal microbiota composition in Amsterdam, the Netherlands. PLoS ONE 12, e0181135 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Yildirim, S. et al. Primate vaginal microbiomes exhibit species specificity without universal Lactobacillus dominance. ISME J. 8, 2431–2444 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Rhoades, N. S. et al. Longitudinal profiling of the macaque vaginal microbiome reveals similarities to diverse human vaginal communities. mSystems 6, e01322-20 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Curley, T. & Forster, C. S. Recurrent UTIs in girls: what is the role of the microbiome? Urology 151, 94–97 (2021).

    Article  PubMed  Google Scholar 

  169. Marild, S. & Jodal, U. Incidence rate of first-time symptomatic urinary tract infection in children under 6 years of age. Acta Pædiatr. 87, 549–552 (1998).

    Article  CAS  PubMed  Google Scholar 

  170. Brotman, R. M. et al. Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy. Menopause 21, 450–458 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Shen, J. et al. Effects of low dose estrogen therapy on the vaginal microbiomes of women with atrophic vaginitis. Sci. Rep. 6, 24380 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Hammerschlag, M. R. et al. Anaerobic microflora of the vagina in children. Am. J. Obstet. Gynecol. 131, 853–856 (1978).

    Article  CAS  PubMed  Google Scholar 

  173. Mitchell, C. M. et al. Association between postmenopausal vulvovaginal discomfort, vaginal microbiota, and mucosal inflammation. Am. J. Obstet. Gynecol. 225, 159.E1–159.E15 (2021).

    Article  CAS  Google Scholar 

  174. Gliniewicz, K. et al. Comparison of the vaginal microbiomes of premenopausal and postmenopausal women. Front. Microbiol. 10, 193 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Łaniewski, P. & Herbst-Kralovetz, M. M. Investigating microbiome and menopause for healthy aging in women. Nat. Microbiol. https://doi.org/10.1038/s41564-022-01071-6 (2022).

  176. Bidlingmaier, F., Wagner-Barnack, M., Butenandt, O. & Knorr, D. Plasma estrogens in childhood and puberty under physiologic and pathologic conditions. Pedia. Res. 7, 901–907 (1973).

    Article  CAS  Google Scholar 

  177. Xiaoming, W. et al. Characteristics of the vaginal microbiomes in prepubertal girls with and without vulvovaginitis. Eur. J. Clin. Microbiol. Infect. Dis. 40, 1253–1261 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Hickey, R. J. et al. Vaginal microbiota of adolescent girls prior to the onset of menarche resemble those of reproductive-age women. mBio 6, e00097-15 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Cohen, C. R. et al. Bacterial vaginosis associated with increased risk of female-to-male HIV-1 transmission: a prospective cohort analysis among African couples. PLoS Med. 9, e1001251 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Borgdorff, H. et al. Lactobacillus-dominated cervicovaginal microbiota associated with reduced HIV/STI prevalence and genital HIV viral load in African women. ISME J. 8, 1781–1793 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Brotman, R. M. Vaginal microbiome and sexually transmitted infections: an epidemiologic perspective. J. Clin. Invest. 121, 4610–4617 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Cherpes, T. L., Meyn, L. A., Krohn, M. A., Lurie, J. G. & Hillier, S. L. Association between acquisition of herpes simplex virus type 2 in women and bacterial vaginosis. Clin. Infect. Dis. 37, 319–325 (2003).

    Article  PubMed  Google Scholar 

  183. Balkus, J. E. et al. Bacterial vaginosis and the risk of Trichomonas vaginalis acquisition among HIV-1-negative women. Sex. Transm. Dis. 41, 123–128 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  184. van Houdt, R. et al. Lactobacillus iners-dominated vaginal microbiota is associated with increased susceptibility to Chlamydia trachomatis infection in Dutch women: a case–control study. Sex. Transm. Infect. 94, 117–123 (2018).

    Article  PubMed  Google Scholar 

  185. Lee, J. E. et al. Association of the vaginal microbiota with human papillomavirus infection in a Korean twin cohort. PLoS ONE 8, e63514 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Norenhag, J. et al. The vaginal microbiota, human papillomavirus and cervical dysplasia: a systematic review and network meta-analysis. BJOG 127, 171–180 (2020).

    Article  CAS  PubMed  Google Scholar 

  187. 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. 221, 9–18.e8 (2019).

    Article  PubMed  Google Scholar 

  188. Oh, H. Y. et al. The association of uterine cervical microbiota with an increased risk for cervical intraepithelial neoplasia in Korea. Clin. Microbiol. Infect. 21, 674.e1–674.e9 (2015).

    Article  CAS  Google Scholar 

  189. Mitra, A. et al. Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity. Sci. Rep. 5, 16865 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Shannon, B. et al. Association of HPV infection and clearance with cervicovaginal immunology and the vaginal microbiota. Mucosal Immunol. 10, 1310–1319 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. King, C. C. et al. Bacterial vaginosis and the natural history of human papillomavirus. Infect. Dis. Obstet. Gynecol. 2011, 319460 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Watts, D. H. et al. Effects of bacterial vaginosis and other genital infections on the natural history of human papillomavirus infection in HIV-1-infected and high-risk HIV-1-uninfected women. J. Infect. Dis. 191, 1129–1139 (2005).

    Article  PubMed  Google Scholar 

  193. Brotman, R. M. et al. Interplay between the temporal dynamics of the vaginal microbiota and human papillomavirus detection. J. Infect. Dis. 210, 1723–1733 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Di Paola, M. et al. Characterization of cervico-vaginal microbiota in women developing persistent high-risk human papillomavirus infection. Sci. Rep. 7, 10200 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Gupta, K. et al. Inverse association of H2O2-producing lactobacilli and vaginal Escherichia coli colonization in women with recurrent urinary tract infections. J. Infect. Dis. 178, 446–450 (1998).

    Article  CAS  PubMed  Google Scholar 

  196. Kirjavainen, P. V. et al. Abnormal immunological profile and vaginal microbiota in women prone to urinary tract infections. Clin. Vaccine Immunol. 16, 29–36 (2009).

    Article  CAS  PubMed  Google Scholar 

  197. McClelland, R. S. et al. Prospective study of vaginal bacterial flora and other risk factors for vulvovaginal candidiasis. J. Infect. Dis. 199, 1883–1890 (2009).

    Article  PubMed  Google Scholar 

  198. Zhou, X. et al. Vaginal microbiota of women with frequent vulvovaginal candidiasis. Infect. Immun. 77, 4130–4135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Brown, S. E. et al. The vaginal microbiota and behavioral factors associated with genital Candida albicans detection in reproductive-age women. Sex. Transm. Dis. 46, 753–758 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Ness, R. B. et al. A cluster analysis of bacterial vaginosis-associated microflora and pelvic inflammatory disease. Am. J. Epidemiol. 162, 585–590 (2005).

    Article  PubMed  Google Scholar 

  201. Haggerty, C. L. et al. Presence and concentrations of select bacterial vaginosis-associated bacteria are associated with increased risk of pelvic inflammatory disease. Sex. Transm. Dis. 47, 344–346 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Haggerty, C. L. et al. Identification of novel microbes associated with pelvic inflammatory disease and infertility. Sex. Transm. Infect. 92, 441–446 (2016).

    Article  PubMed  Google Scholar 

  203. Hillier, S. L. et al. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. The Vaginal Infections and Prematurity Study Group. N. Engl. J. Med. 333, 1737–1742 (1995).

    Article  CAS  PubMed  Google Scholar 

  204. Leitich, H. et al. Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am. J. Obstet. Gynecol. 189, 139–147 (2003).

    Article  PubMed  Google Scholar 

  205. Fettweis, J. M. et al. The vaginal microbiome and preterm birth. Nat. Med. 25, 1012–1021 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Petricevic, L. et al. Characterisation of the vaginal Lactobacillus microbiota associated with preterm delivery. Sci. Rep. 4, 5136 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Peelen, M. J. et al. The influence of the vaginal microbiota on preterm birth: a systematic review and recommendations for a minimum dataset for future research. Placenta 79, 30–39 (2019).

    Article  PubMed  Google Scholar 

  208. Gustin, A. T. et al. Recurrent bacterial vaginosis following metronidazole treatment is associated with microbiota richness at diagnosis. Am. J. Obstet. Gynecol. https://doi.org/10.1016/j.ajog.2021.09.018 (2021).

  209. Deng, Z.-L. et al. Metatranscriptome analysis of the vaginal microbiota reveals potential mechanisms for recurrence and protection against metronidazole in bacterial vaginosis. mSphere 3, e00262-18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Larsson, P. G. & Forsum, U. Bacterial vaginosis—a disturbed bacterial flora and treatment enigma. APMIS 113, 305–316 (2005).

    Article  CAS  PubMed  Google Scholar 

  211. Plummer, E. L. et al. Lactic acid-containing products for bacterial vaginosis and their impact on the vaginal microbiota: a systematic review. PLoS ONE 16, e0246953 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Reichman, O., Akins, R. & Sobel, J. D. Boric acid addition to suppressive antimicrobial therapy for recurrent bacterial vaginosis. Sex. Transm. Dis. 36, 732–734 (2009).

    Article  CAS  PubMed  Google Scholar 

  213. Macklaim, J. M., Clemente, J. C., Knight, R., Gloor, G. B. & Reid, G. Changes in vaginal microbiota following antimicrobial and probiotic therapy. Microb. Ecol. Health Dis. 26, 27799 (2015).

    PubMed  Google Scholar 

  214. Husain, S. et al. Effects of oral probiotic supplements on vaginal microbiota during pregnancy: a randomised, double-blind, placebo-controlled trial with microbiome analysis. BJOG 127, 275–284 (2020).

    Article  CAS  PubMed  Google Scholar 

  215. Oerlemans, E. F. M. et al. Impact of a lactobacilli-containing gel on vulvovaginal candidosis and the vaginal microbiome. Sci. Rep. 10, 7976 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Marcotte, H. et al. An exploratory pilot study evaluating the supplementation of standard antibiotic therapy with probiotic lactobacilli in South African women with bacterial vaginosis. BMC Infect. Dis. 19, 824 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Bohbot, J. M. et al. Efficacy and safety of vaginally administered lyophilized Lactobacillus crispatus IP 174178 in the prevention of bacterial vaginosis recurrence. J. Gynecol. Obstet. Hum. Reprod. 47, 81–86 (2018).

    Article  CAS  PubMed  Google Scholar 

  218. Mastromarino, P., Vitali, B. & Mosca, L. Bacterial vaginosis: a review on clinical trials with probiotics. Nat. Microbiol. 36, 229–238 (2013).

    Google Scholar 

  219. Stapleton, A. E. et al. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. in. Clin. Infect. Dis. 52, 1212–1217 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Reid, G., Beuerman, D., Heinemann, C. & Bruce, A. W. Probiotic Lactobacillus dose required to restore and maintain a normal vaginal flora. FEMS Immunol. Med. Microbiol. 32, 37–41 (2001).

    Article  CAS  PubMed  Google Scholar 

  221. Cohen, C. R. et al. Randomized trial of Lactin-V to prevent recurrence of bacterial vaginosis. N. Engl. J. Med. 382, 1906–1915 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Rohlke, F. & Stollman, N. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Therap. Adv. Gastroenterol. 5, 403–420 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Liwinski, T. & Elinav, E. Harnessing the microbiota for therapeutic purposes. Am. J. Transpl. 20, 1482–1488 (2020).

    Article  Google Scholar 

  224. Lev-Sagie, A. et al. Vaginal microbiome transplantation in women with intractable bacterial vaginosis. Nat. Med. 25, 1500–1504 (2019).

    Article  CAS  PubMed  Google Scholar 

  225. DeLong, K. et al. Conceptual design of a universal donor screening approach for vaginal microbiota transplant. Front. Cell. Infect. Microbiol. 9, 306 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. DiGiulio, D. B. et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc. Natl Acad. Sci. USA 112, 11060–11065 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Park, J. C. & Im, S. H. Of men in mice: the development and application of a humanized gnotobiotic mouse model for microbiome therapeutics. Exp. Mol. Med. 52, 1383–1396 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Kennedy, E. A., King, K. Y. & Baldridge, M. T. Mouse microbiota models: comparing germ-free mice and antibiotics treatment as tools for modifying gut bacteria. Front. Physiol. 9, 1534 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Sierra, L. J. et al. Colonization of the cervicovaginal space with Gardnerella vaginalis leads to local inflammation and cervical remodeling in pregnant mice. PLoS ONE 13, e0191524 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  230. Gilbert, N. M., Lewis, W. G. & Lewis, A. L. Clinical features of bacterial vaginosis in a murine model of vaginal infection with Gardnerella vaginalis. PLoS ONE 8, e59539 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Gilbert, N. M. et al. Gardnerella vaginalis and Prevotella bivia trigger distinct and overlapping phenotypes in a mouse model of bacterial vaginosis. J. Infect. Dis. 220, 1099–1108 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  232. Raterman, E. L. & Jerse, A. E. Female mouse model of Neisseria gonorrhoeae Infection. Methods Mol. Biol. 1997, 413–429 (2019).

    Article  CAS  PubMed  Google Scholar 

  233. Kaser, T. et al. Chlamydia suis and Chlamydia trachomatis induce multifunctional CD4 T cells in pigs. Vaccine 35, 91–100 (2017).

    Article  CAS  PubMed  Google Scholar 

  234. Policicchio, B. B., Pandrea, I. & Apetrei, C. Animal models for HIV cure research. Front. Immunol. 7, 12 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  235. De Clercq, E., Kalmar, I. & Vanrompay, D. Animal models for studying female genital tract infection with Chlamydia trachomatis. Infect. Immun. 81, 3060–3067 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  236. Ogawa-Tominaga, M., Umezu, T., Nakajima, T. & Tomooka, Y. Stratification of mouse vaginal epithelium. 1. Development of three-dimensional models in vitro with clonal cell lines. Biol. Reprod. 99, 718–726 (2018).

    PubMed  Google Scholar 

  237. Pyles, R. B. et al. Cultivated vaginal microbiomes alter HIV-1 infection and antiretroviral efficacy in colonized epithelial multilayer cultures. PLoS ONE 9, e93419 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  238. Barrila, J. et al. Organotypic 3D cell culture models: using the rotating wall vessel to study host–pathogen interactions. Nat. Rev. Microbiol 8, 791–801 (2010).

    Article  CAS  PubMed  Google Scholar 

  239. Hjelm, B. E., Berta, A. N., Nickerson, C. A., Arntzen, C. J. & Herbst-Kralovetz, M. M. Development and characterization of a three-dimensional organotypic human vaginal epithelial cell model. Biol. Reprod. 82, 617–627 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Xiao, S. et al. A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nat. Commun. 8, 14584 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Rothbauer, M., Zirath, H. & Ertl, P. Recent advances in microfluidic technologies for cell-to-cell interaction studies. Lab Chip 18, 249–270 (2018).

    Article  CAS  PubMed  Google Scholar 

  242. Stahl, P. L. et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science 353, 78–82 (2016).

    Article  CAS  PubMed  Google Scholar 

  243. Rodriques, S. G. et al. Slide-seq: a scalable technology for measuring genome-wide expression at high spatial resolution. Science 363, 1463–1467 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This Review was supported by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Nursing Research (NINR) of the National Institutes of Health (NIH) under awards number U19AI158930, R21AI162006 and R01NR01549. M.A. acknowledges support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH under award number T32DK067872.

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Correspondence to Jacques Ravel.

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J.R. is co-founder of LUCA Biologics, a biotechnology company focusing on translating microbiome research into live biotherapeutics drugs for women’s health. All other authors declare that they have no competing interests.

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Nature Microbiology thanks Heather Jaspan and the other, anonymous, reviewers for their contribution to the peer review of this work.

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France, M., Alizadeh, M., Brown, S. et al. Towards a deeper understanding of the vaginal microbiota. Nat Microbiol 7, 367–378 (2022). https://doi.org/10.1038/s41564-022-01083-2

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