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The impact of the female genital tract microbiome in women health and reproduction: a review

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Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

The aim of this review is to gather the available research focusing on female genital tract (FGT) microbiome. Research question focuses in decipher which is the role of FGT microbiota in eubiosis, assisted reproduction techniques (ARTs), and gynaecological disorders, and how microbiome could be utilised to improve reproduction outcomes and to treat fertility issues.

Methods

PubMed was searched for articles in English from January 2004 to April 2021 for “genital tract microbiota and reproduction”, “endometrial microbiome”, “microbiome and reproduction” and “microbiota and infertility”. Manual search of the references within the resulting articles was performed.

Results

Current knowledge confirms predominance of Lactobacillus species, both in vagina and endometrium, whereas higher variability of species is both found in fallopian tubes and ovaries. Microbial signature linked to different disorders such endometriosis, bacterial vaginosis, and gynaecological cancers are described. Broadly, low variability of species and Lactobacillus abundance within the FGT is associated with better reproductive and ART outcomes.

Conclusion

Further research regarding FGT microbiome configuration needs to be done in order to establish a more precise link between microbiota and eubiosis or dysbiosis. Detection of bacterial species related with poor reproductive outcomes, infertility or gynaecological diseases could shape new tools for their diagnosis and treatment, as well as resources to assess the pregnancy prognosis based on endometrial microbiota. Data available suggest future research protocols should be standardised, and it needs to include the interplay among microbiome, virome and mycobiome, and the effect of antibiotics or probiotics on the microbiome shifts.

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References

  1. Davies J. In a Map for human life, count the microbes, too. Science (80-). 2001;291:2316b – 2316. https://doi.org/10.1126/science.291.5512.2316b

  2. Franasiak JM, Scott RT. Reproductive tract microbiome in assisted reproductive technologies. Fertil Steril. 2015;104:1364–71. https://doi.org/10.1016/j.fertnstert.2015.10.012.

    Article  PubMed  Google Scholar 

  3. Moreno I, Simon C. Deciphering the effect of reproductive tract microbiota on human reproduction. Reprod Med Biol. 2019;18:40–50. https://doi.org/10.1002/rmb2.12249.

    Article  PubMed  Google Scholar 

  4. Peterson J, Garges S, Giovanni M, McInnes P, Wang L, Schloss JA, et al. The NIH human microbiome project. Genome Res. 2009;19:2317–23. https://doi.org/10.1101/gr.096651.109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Huttenhower C, Gevers D, Knight R, Abubucker S, Badger JH, Chinwalla AT, et al. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486:207–14. https://doi.org/10.1038/nature11234.

    Article  CAS  Google Scholar 

  6. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449:804–10. https://doi.org/10.1038/nature06244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Proctor LM, Creasy HH, Fettweis JM, Lloyd-Price J, Mahurkar A, Zhou W, et al. The Integrative human microbiome project. Nature. 2019;569:641–8. https://doi.org/10.1038/s41586-019-1238-8.

    Article  CAS  Google Scholar 

  8. Tissier H. Recherches sur la flore intestinale des nourrissons : état normal et pathologique. 1st ed. Paris:G. Carre and C. Naud;1900.

  9. Mitchell CM, Haick A, Nkwopara E, Garcia R, Rendi M, Agnew K, et al. Colonization of the upper genital tract by vaginal bacterial species in nonpregnant women. Am J Obstet Gynecol. 2015;212:611.e1–9. https://doi.org/10.1016/j.ajog.2014.11.043.

    Article  Google Scholar 

  10. Franasiak JM, Werner MD, Juneau CR, Tao X, Landis J, Zhan Y, et al. Endometrial microbiome at the time of embryo transfer: next-generation sequencing of the 16S ribosomal subunit. J Assist Reprod Genet. 2016;33:129–36. https://doi.org/10.1007/s10815-015-0614-z.

    Article  CAS  PubMed  Google Scholar 

  11. Moreno I, Codoñer FM, Vilella F, Valbuena D, Martinez-Blanch JF, Jimenez-Almazán J, et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol. 2016;215:684–703. https://doi.org/10.1016/j.ajog.2016.09.075.

    Article  PubMed  Google Scholar 

  12. Tao X, Franasiak JM, Zhan Y, Scott RT, Rajchel J, Bedard J, et al. Characterizing the endometrial microbiome by analyzing the ultra-low bacteria from embryo transfer catheter tips in IVF cycles: next generation sequencing (NGS) analysis of the 16S ribosomal gene. Hum Microbiome J. 2017;3:15–21. https://doi.org/10.1016/j.humic.2017.01.004.

    Article  Google Scholar 

  13. 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. https://doi.org/10.1038/s41467-017-00901-0.

  14. Miles SM, Hardy BL, Merrell DS. Investigation of the microbiota of the reproductive tract in women undergoing a total hysterectomy and bilateral salpingo-oopherectomy. Fertil Steril. 2017;107:813–820.e1. https://doi.org/10.1016/j.fertnstert.2016.11.028.

    Article  PubMed  Google Scholar 

  15. Khan KN, Fujishita A, Masumoto H, Muto H, Kitajima M, Masuzaki H, et al. Molecular detection of intrauterine microbial colonization in women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2016;199:69–75. https://doi.org/10.1016/j.ejogrb.2016.01.040.

    Article  CAS  PubMed  Google Scholar 

  16. Fang RL, Chen LX, Shu WS, Yao SZ, Wang SW, Chen YQ. Barcoded sequencing reveals diverse intrauterine microbiomes in patients suffering with endometrial polyps. Am J Transl Res. 2016;8:1581–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Verstraelen H, Vilchez-Vargas R, Desimpel F, Jauregui R, Vankeirsbilck N, Weyers S, et al. Characterisation of the human uterine microbiome in non-pregnant women through deep sequencing of the V1-2 region of the 16S rRNA gene. PeerJ. 2016;4. https://doi.org/10.7717/peerj.1602.

  18. Baker JM, Chase DM, Herbst-Kralovetz MM. Uterine Microbiota: residents, tourists, or invaders? Front Immunol. 2018;9:1–16. https://doi.org/10.3389/fimmu.2018.00208.

    Article  CAS  Google Scholar 

  19. Moreno I, Franasiak JM. Endometrial microbiota—new player in town. Fertil Steril. 2017;108:32–9. https://doi.org/10.1016/j.fertnstert.2017.05.034.

    Article  PubMed  Google Scholar 

  20. Franasiak JM, Scott RT. Endometrial microbiome. Curr Opin Obstet Gynecol. 2017;29:146–52. https://doi.org/10.1097/GCO.0000000000000357.

    Article  PubMed  Google Scholar 

  21. Bashiardes S, Zilberman-Schapira G, Elinav E. Use of metatranscriptomics in microbiome research. Bioinform Biol Insights. 2016;10:19–25. https://doi.org/10.4137/BBI.S34610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Knight R, Vrbanac A, Taylor BC, Aksenov A, Callewaert C, Debelius J, et al. Best practices for analysing microbiomes. Nat Rev Microbiol. 2018;16:410–22. https://doi.org/10.1038/s41579-018-0029-9.

    Article  CAS  PubMed  Google Scholar 

  23. Sola-Leyva A, Andrés-León E, Molina NM, Terron-Camero LC, Plaza-Díaz J, S-L MJ, et al. Mapping the entire functionally active endometrial microbiota. Hum Reprod. 2021;00:1–11. https://doi.org/10.1093/humrep/deaa372.

    Article  Google Scholar 

  24. Ravel J, Brotman RM. Translating the vaginal microbiome: gaps and challenges. Genome Med. 2016;8:2–4. https://doi.org/10.1186/s13073-016-0291-2.

    Article  CAS  Google Scholar 

  25. García-Velasco JA, Budding D, Campe H, Malfertheiner SF, Hamamah S, Santjohanser C, et al. The reproductive microbiome – clinical practice recommendations for fertility specialists. Reprod BioMed Online. 2020;41:443–53. https://doi.org/10.1016/j.rbmo.2020.06.014.

    Article  CAS  PubMed  Google Scholar 

  26. Molina NM, Sola-Leyva A, Jose Saez-Lara M, Plaza-Diaz J, Tubic-Pavlovic A, Romero B, et al. New opportunities for endometrial health by modifying uterine microbial composition: present or future? Biomolecules. 2020;10. https://doi.org/10.3390/biom10040593.

  27. Hyman RW, Fukushima M, Diamond L, Kumm J, Giudice LC, Davis RW. Microbes on the human vaginal epithelium. Proc Natl Acad Sci U S A. 2005;102:7952–7. https://doi.org/10.1073/pnas.0503236102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhou X, Bent SJ, Schneider MG, Davis CC, Islam MR, Forney LJ, et al. Characterization of vaginal microbial communities in adult healthy women using cultivation-independent methods. Microbiology. 2004;150:2565–73. https://doi.org/10.1099/mic.0.26905-0.

    Article  CAS  PubMed  Google Scholar 

  29. Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SSK, Mcculle SL, et al. Vaginal microbiome of reproductive-age women. PNAS. 2011;108:4680–7. https://doi.org/10.1073/pnas.1002611107.

    Article  PubMed  Google Scholar 

  30. Gajer P, Brotman RM, Bai G, Sakamoto J, Schütte UME, Zhong X, et al. Temporal dynamics of the human vaginal microbiota. Sci Transl Med. 2012;4. https://doi.org/10.1126/scitranslmed.3003605.

  31. Wee BA, Thomas M, Sweeney EL, Frentiu FD, Samios M, Ravel J, et al. A retrospective pilot study to determine whether the reproductive tract microbiota differs between women with a history of infertility and fertile women. Aust New Zeal J Obstet Gynaecol. 2018;58:341–8. https://doi.org/10.1111/ajo.12754.

    Article  Google Scholar 

  32. Liu Z, Kong Y, Gao Y, Ren Y, Zheng C, Deng X, et al. Revealing the interaction between intrauterine adhesion and vaginal microbiota using high-throughput sequencing. Mol Med Rep. 2019;49:4167–74. https://doi.org/10.3892/mmr.2019.10092.

    Article  CAS  Google Scholar 

  33. Riganelli L, Iebba V, Piccioni M, Illuminati I, Bonfiglio G, Neroni B, et al. Structural variations of vaginal and endometrial microbiota: hints on female infertility. Front Cell Infect Microbiol. 2020;10:350. https://doi.org/10.3389/fcimb.2020.00350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Carosso A, Revelli A, Gennarelli G, Canosa S, Cosma S, Borella F, et al. Controlled ovarian stimulation and progesterone supplementation affect vaginal and endometrial microbiota in IVF cycles: a pilot study. J Assist Reprod Genet. 2020;37:2315–26. https://doi.org/10.1007/s10815-020-01878-4.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kyono K, Hashimoto T, Nagai Y, Sakuraba Y. Analysis of endometrial microbiota by 16S ribosomal RNA gene sequencing among infertile patients: a single-center pilot study. Reprod Med Biol. 2018;17:297–306. https://doi.org/10.1002/rmb2.12105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Winters AD, Romero R, Gervasi MT, Gomez-Lopez N, Tran MR, Garcia-Flores V, et al. Does the endometrial cavity have a molecular microbial signature? Sci Rep. 2019;9:1–17. https://doi.org/10.1038/s41598-019-46173-0.

    Article  CAS  Google Scholar 

  37. Xu J, Bian G, Zheng M, Lu G, Chan WY, Li W, et al. Fertility factors affect the vaginal microbiome in women of reproductive age. Am J Reprod Immunol. 2020;83:1–10. https://doi.org/10.1111/aji.13220.

    Article  CAS  Google Scholar 

  38. Li F, Chen C, Wei W, Wang Z, Dai J, Hao L, et al. The metagenome of the female upper reproductive tract. Gigascience. 2018;7:1–8. https://doi.org/10.1093/gigascience/giy107.

    Article  CAS  PubMed  Google Scholar 

  39. Pelzer ES, Willner D, Buttini M, Huygens F. A role for the endometrial microbiome in dysfunctional menstrual bleeding. Antonie van Leeuwenhoek, Int. J. Gen. Mol. Microbiol. 2018;111:933–43. https://doi.org/10.1007/s10482-017-0992-6.

    Article  Google Scholar 

  40. Chen S, Gu Z, Zhang W, Jia S, Wu Y, Zheng P, et al. Microbiome of the lower genital tract in Chinese women with endometriosis by 16s-rRNA sequencing technique: a pilot study. Ann Transl Med. 2020; 8:1440. https://doi.org/10.21037/atm-20-1309.

  41. Usyk M, Zolnik CP, Castle PE, Porras C, Herrero R, Gradissimo A, et al. Cervicovaginal microbiome and natural history of HPV in a longitudinal study. PLoS Pathog. 2020;16:1–20. https://doi.org/10.1371/journal.ppat.1008376.

    Article  CAS  Google Scholar 

  42. 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. https://doi.org/10.1186/s12879-020-05324-9.

  43. Kyono K, Hashimoto T, Kikuchi S, Nagai Y, Sakuraba Y. A pilot study and case reports on endometrial microbiota and pregnancy outcome: an analysis using 16S rRNA gene sequencing among IVF patients, and trial therapeutic intervention for dysbiotic endometrium. Reprod Med Biol. 2019;18:72–82. https://doi.org/10.1002/rmb2.12250.

    Article  CAS  PubMed  Google Scholar 

  44. Leoni C, Ceci O, Manzari C, Fosso B, Volpicella M, Ferrari A, et al. Human Endometrial microbiota at term of normal pregnancies. Genes (Basel). 2019;10:1–11. https://doi.org/10.3390/genes10120971.

    Article  CAS  Google Scholar 

  45. Younge N, McCann JR, Ballard J, Plunkett C, Akhtar S, Araújo-Pérez F, et al. Fetal exposure to the maternal microbiota in humans and mice. JCI Insight. 2019;4. https://doi.org/10.1172/jci.insight.127806.

  46. Svenstrup HF, Fedder J, Abraham-Peskir J, Birkelund S, Christiansen G. Mycoplasma genitalium attaches to human spermatozoa. Hum Reprod. 2003;18:2103–9. https://doi.org/10.1093/humrep/deg392.

    Article  PubMed  Google Scholar 

  47. Hansen LK. Becher N, Bastholm S, Glavind J, Ramsing M, J. Kim C, et al. The cervical mucus plug inhibits, but does not block, the passage of ascending bacteria from the vagina during pregnancy. Acta Obs. Gynecol Scand. 2014;93:102–8. https://doi.org/10.1038/s41598-019-39414-9.

    Article  CAS  Google Scholar 

  48. Swidsinski A, Verstraelen H, Loening-Baucke V, Swidsinski S, Mendling W, Halwani Z. Presence of a polymicrobial endometrial biofilm in patients with bacterial vaginosis. PLoS One. 2013;8:1–6. https://doi.org/10.1371/journal.pone.0053997.

    Article  CAS  Google Scholar 

  49. Garcia-Grau I, Simon C, Moreno I. Uterine microbiome-low biomass and high expectations. Biol Reprod. 2019;101:1102–14. https://doi.org/10.1093/biolre/ioy257.

    Article  PubMed  Google Scholar 

  50. Solt I. The human microbiome and the great obstetrical syndromes: a new frontier in maternal-fetal medicine. Best Pract Res Clin Obstet Gynaecol. 2015;29:165–75. https://doi.org/10.1016/j.bpobgyn.2014.04.024.

    Article  PubMed  Google Scholar 

  51. Pelzer ES, Willner D, Buttini M, Hafner LM, Theodoropoulos C, Huygens F. The fallopian tube microbiome: implications for reproductive health. Oncotarget. 2018; 9:21541–51. https://doi.org/10.18632/oncotarget.25059.

  52. Pelzer ES, Allan JA, Cunningham K, Mengersen K, Allan JM, Launchbury T, et al. Microbial colonization of follicular fluid: alterations in cytokine expression and adverse assisted reproduction technology outcomes. Hum Reprod. 2011;26:1799–812. https://doi.org/10.1093/humrep/der108.

    Article  CAS  PubMed  Google Scholar 

  53. Iebba V, Totino V, Gagliardi A, Santangelo F, Cacciotti F, Trancassini M, et al. Eubiosis and dysbiosis: the two sides of the microbiota. New Microbiol. 2016;39:1–12.

    CAS  PubMed  Google Scholar 

  54. Fischbach MA. Microbiome: Focus on Causation and Mechanism. Cell. 2018;174:785–90. https://doi.org/10.1016/j.cell.2018.07.038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Green KA, Zarek SM, Catherino WH. Gynecologic health and disease in relation to the microbiome of the female reproductive tract. Fertil Steril. 2015;104:1351–7. https://doi.org/10.1016/j.fertnstert.2015.10.010.

    Article  PubMed  Google Scholar 

  56. Diop K, Dufour JC, Levasseur A, Fenollar F. Exhaustive repertoire of human vaginal microbiota. Hum Microbiome J. 2019;11. https://doi.org/10.1016/j.humic.2018.11.002.

  57. Ata B, Yildiz S, Turkgeldi E, Brocal VP, Dinleyici EC, Moya A, et al. The endobiota study: comparison of vaginal, cervical and gut microbiota between women with stage 3/4 endometriosis and healthy controls. Sci Rep. 2019;9:1–9. https://doi.org/10.1038/s41598-019-39700-6.

    Article  CAS  Google Scholar 

  58. Lloyd-Price J, Abu-Ali G, Huttenhower C. The healthy human microbiome. Genome Med. 2016;8:1–11. https://doi.org/10.1186/s13073-016-0307-y.

    Article  Google Scholar 

  59. Skafte-holm A, Humaidan P, Bernabeu A, Lledo B, Jensen JS, Haahr T. The association between vaginal dysbiosis and reproductive outcomes in sub-fertile women undergoing ivf-treatment: a systematic prisma review and meta-analysis. Pathogens. 2021;10:1–17. https://doi.org/10.3390/pathogens10030295.

    Article  Google Scholar 

  60. Einenkel R, Zygmunt M, Muzzio DO. Microorganisms in the healthy upper reproductive tract: from denial to beneficial assignments for reproductive biology. Reprod Biol. 2019;19:113–8. https://doi.org/10.1016/j.repbio.2019.04.001.

    Article  PubMed  Google Scholar 

  61. Greenbaum S, Greenbaum G, Moran-Gilad J, Weintruab AY. Ecological dynamics of the vaginal microbiome in relation to health and disease. Am J Obstet Gynecol. 2019;220:324–35. https://doi.org/10.1016/j.ajog.2018.11.1089.

    Article  PubMed  Google Scholar 

  62. Leyva-Gómez G, Del Prado-Audelo ML, Ortega-Peña S, Mendoza-Muñoz N, Urbán-Morlán Z, González-Torres M, et al. Modifications in vaginal microbiota and their influence on drug release: challenges and opportunities. Pharmaceutics. 2019;11:1–18. https://doi.org/10.3390/pharmaceutics11050217.

    Article  CAS  Google Scholar 

  63. Huang B, Fettweis JM, Brooks JP, Jefferson KK, Buck GA. The Changing landscape of the vaginal microbiome. Clin Lab Med. 2014;34:747–61. https://doi.org/10.1016/j.cll.2014.08.006.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Stoyancheva G, Marzotto M, Dellaglio F, Torriani S. Bacteriocin production and gene sequencing analysis from vaginal Lactobacillus strains. Arch Microbiol. 2014;196:645–53. https://doi.org/10.1007/s00203-014-1003-1.

    Article  CAS  PubMed  Google Scholar 

  65. 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. https://doi.org/10.1186/s40168-018-0418-3.

  66. Witkin SS, Mendes-Soares M. LI, Jayaram Aswathi, J LW, Forney Larry J. Influence of vaginal bacteria and d- and l-lactic acid isomers on vaginal extracellular matrix metal.pdf. MBio. 2013;4:1–7. https://doi.org/10.1128/mBio.00460-13.Editor.

    Article  Google Scholar 

  67. Gupta S, Kumar N, Singhal N, Kaur R, Manektala U. Vaginal microflora in postmenopausal women on hormone replacement therapy. Indian J Pathol Microbiol. 2006;49:457–61.

    PubMed  Google Scholar 

  68. Al-Baghdadi O, Ewies AAA. Topical estrogen therapy in the management of postmenopausal vaginal atrophy: an up-to-date overview. Climacteric. 2009;12:91–105. https://doi.org/10.1080/13697130802585576.

    Article  CAS  PubMed  Google Scholar 

  69. Kadogami D, Nakaoka Y, Morimoto Y. Use of a vaginal probiotic suppository and antibiotics to influence the composition of the endometrial microbiota. Reprod Biol. 2020;20:307–14. https://doi.org/10.1016/j.repbio.2020.07.001.

    Article  PubMed  Google Scholar 

  70. Muhleisen AL, Herbst-Kralovetz MM. Menopause and the vaginal microbiome. Maturitas. 2016;91:42–50. https://doi.org/10.1016/j.maturitas.2016.05.015.

    Article  PubMed  Google Scholar 

  71. Power ML, Quaglieri C, Schulkin J. Reproductive microbiomes: a new thread in the microbial network. Reprod Sci. 2017;24:1482–92. https://doi.org/10.1177/1933719117698577.

    Article  PubMed  Google Scholar 

  72. Romero R, Hassan SS, Gajer P, Tarca AL, Fadrosh DW, Nikita L, et al. The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women. Microbiome. 2014;2:1–19. https://doi.org/10.1186/2049-2618-2-4.

    Article  Google Scholar 

  73. Digiulio DB, Callahan BJ, Mcmurdie PJ, Costello EK, Lyell DJ, Robaczewska A, et al. Temporal and spatial variation of the human microbiota during pregnancy. PNAS. 2015;112:11060–5. https://doi.org/10.1073/pnas.1502875112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Aagaard K, Riehle K, Ma J, Segata N, Mistretta TA, Coarfa C, et al. A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy. PLoS One. 2012;7:1–13. https://doi.org/10.1371/journal.pone.0036466.

    Article  CAS  Google Scholar 

  75. Zheng N, Guo R, Yao Y, Jin M, Cheng Y, Ling Z. Lactobacillus iners is associated with vaginal dysbiosis in healthy pregnant women: a preliminary study. Biomed Res Int. 2019;2019. https://doi.org/10.1155/2019/6079734.

  76. Freitas AC, Chaban B, Bocking A, Rocco M, Yang S, Hill JE, et al. The vaginal microbiome of pregnant women is less rich and diverse, with lower prevalence of Mollicutes, compared to non-pregnant women. Sci Rep. 2017;7:1–16. https://doi.org/10.1038/s41598-017-07790-9.

    Article  CAS  Google Scholar 

  77. Moreno I, Garcia-Grau I, Bau D, Perez-Villaroya D, Gonzalez-Monfort M, Vilella F, et al. The first glimpse of the endometrial microbiota in early pregnancy. Am J Obstet Gynecol. 2020;222:296–305. https://doi.org/10.1016/j.ajog.2020.01.031.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J. The placenta harbors a unique microbiome. Sci Transl Med. 2014;6:1–11. https://doi.org/10.1126/scitranslmed.3008599.

    Article  CAS  Google Scholar 

  79. Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: The role of the immune system at the implantation site. Ann N Y Acad Sci. 2011;1221:80–7. https://doi.org/10.1111/j.1749-6632.2010.05938.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wylie KM, Wylie T, Cahill AG, Macones GA, Tuuli MG, Stout MJ. The Vaginal Eukaryotic DNA Virome and Preterm Birth. Am J Obstet Gynecol. 2018;219:189.e1–189.e12. https://doi.org/10.1016/j.physbeh.2017.03.040.

    Article  CAS  Google Scholar 

  81. Brown RG, Al-Memar M, Marchesi JR, Lee YS, Smith A, Chan D, et al. Establishment of vaginal microbiota composition in early pregnancy and its association with subsequent preterm prelabor rupture of the fetal membranes. Transl Res. 2019;207:30–43. https://doi.org/10.1016/j.trsl.2018.12.005.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Fettweis JM, Serrano MG, Brooks JP, Edwards DJ, Girerd PH, Parikh HI, et al. The vaginal microbiome and preterm birth. Nat Med. 2019;25:1012–21. https://doi.org/10.1038/s41591-019-0450-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Tabatabaei N, Eren AM, Barreiro LB, Yotova V, Dumaine A, Allard C, et al. Vaginal microbiome in early pregnancy and subsequent risk of spontaneous preterm birth: a case–control study. BJOG An Int J Obstet Gynaecol. 2019;126:349–58. https://doi.org/10.1111/1471-0528.15299.

    Article  CAS  Google Scholar 

  84. Fredricks DN, Fiedler TL, Marrazzo JM. Molecular identification of bacteria associated with bacterial vaginosis. N Engl J Med. 2005;353:1899–911. https://doi.org/10.1056/NEJMoa043802.

    Article  CAS  PubMed  Google Scholar 

  85. Smith SB, Ravel J. The vaginal microbiota, host defence and reproductive physiology. J Physiol. 2017;595:451–63. https://doi.org/10.1113/JP271694.

    Article  CAS  PubMed  Google Scholar 

  86. Ceccarani C, Foschi C, Parolin C, D’Antuono A, Gaspari V, Consolandi C, et al. Diversity of vaginal microbiome and metabolome during genital infections. Sci Rep. 2019;9. https://doi.org/10.1038/s41598-019-50410-x.

  87. Vazquez F, Fernández-Blázquez A, García B. Vaginosis Vaginal microbiota. Enferm Infecc Microbiol Clin. 2019;37:592–601. https://doi.org/10.1016/j.eimc.2018.11.009.

    Article  Google Scholar 

  88. Coudray MS, Madhivanan P. Bacterial vaginosis—a brief synopsis of the literature. Eur J Obstet Gynecol Reprod Biol. 2020;245:143–8. https://doi.org/10.1016/j.ejogrb.2019.12.035.

    Article  CAS  PubMed  Google Scholar 

  89. Lev-Sagie A, Goldman-Wohl D, Cohen Y, Dori-Bachash M, Leshem A, Mor U, et al. Vaginal microbiome transplantation in women with intractable bacterial vaginosis. Nat Med. 2019;25:1500–4. https://doi.org/10.1038/s41591-019-0600-6.

    Article  CAS  PubMed  Google Scholar 

  90. Haahr T, Zacho J, Bräuner M, Shathmigha K, Skov Jensen J, Humaidan P. Reproductive outcome of patients undergoing in vitro fertilisation treatment and diagnosed with bacterial vaginosis or abnormal vaginal microbiota: a systematic PRISMA review and meta-analysis. BJOG An Int J Obstet Gynaecol. 2019;126:200–7. https://doi.org/10.1111/1471-0528.15178.

    Article  CAS  Google Scholar 

  91. Cicinelli E, De Ziegler D, Nicoletti R, Colafiglio G, Saliani N, Resta L, et al. Chronic endometritis: correlation among hysteroscopic, histologic, and bacteriologic findings in a prospective trial with 2190 consecutive office hysteroscopies. Fertil Steril. 2008;89:677–84. https://doi.org/10.1016/j.fertnstert.2007.03.074.

    Article  PubMed  Google Scholar 

  92. Liu Y, Ko EY-L, Wong KK-W, Chen X, Cheung W-C, Law TS-M, et al. Endometrial microbiota in infertile women with and without chronic endometritis as diagnosed using a quantitative and reference range-based method. Fertil Steril. 2019;112:707–717.e1. https://doi.org/10.1016/j.fertnstert.2019.05.015.

    Article  PubMed  Google Scholar 

  93. Moreno I, Garcia-Grau I, Perez-Villaroya D, Gonzalez-Monfort M, Bahçeci M, Barrionuevo MJ, et al. Endometrial microbiota composition is associated with reproductive outcome in infertile patients medRxiv. 2021. https://doi.org/10.1101/2021.02.05.21251207.

  94. Johnston-MacAnanny EB, Hartnett J, Engmann LL, Nulsen JC, Sanders MM, Benadiva CA. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization. Fertil Steril. 2010;93:437–41. https://doi.org/10.1016/j.fertnstert.2008.12.131.

    Article  PubMed  Google Scholar 

  95. Kitaya K, Nagai Y, Arai W, Sakuraba Y, Ishikawa T. Characterization of microbiota in endometrial fluid and vaginal secretions in infertile women with repeated implantation failure. Mediat Inflamm. 2019;2019:1–10. https://doi.org/10.1155/2019/4893437.

    Article  CAS  Google Scholar 

  96. Cicinelli E, Matteo M, Tinelli R, Pinto V, Marinaccio M, Indraccolo U, et al. Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment. Reprod Sci. 2014;21:640–7. https://doi.org/10.1177/1933719113508817.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Cicinelli E, Matteo M, Trojano G, Mitola PC, Tinelli R, Vitagliano A, et al. Chronic endometritis in patients with unexplained infertility: prevalence and effects of antibiotic treatment on spontaneous conception. Am J Reprod Immunol. 2018:79. https://doi.org/10.1111/aji.12782.

  98. Moreno I, Cicinelli E, Garcia-Grau I, Gonzalez-Monfort M, Bau D, Vilella F, et al. The diagnosis of chronic endometritis in infertile asymptomatic women: a comparative study of histology, microbial cultures, hysteroscopy, and molecular microbiology. Am J Obstet Gynecol. 2018;218:602.e1–602.e16. https://doi.org/10.1016/j.ajog.2018.02.012.

    Article  Google Scholar 

  99. Kitaya K, Takeuchi T, Mizuta S, Matsubayashi H, Ishikawa T. Endometritis: new time, new concepts. Fertil Steril. 2018;110:344–50. https://doi.org/10.1016/j.fertnstert.2018.04.012.

    Article  PubMed  Google Scholar 

  100. American Cancer Society | Information and Resources about for Cancer[Internet; available at https://www.cancer.org/]. (accessed 2021 Jan 9).

  101. Banerjee S, Tian T, Wei Z, Shih N, Feldman MD, Coukos G, et al. The ovarian cancer oncobiome. Oncotarget. 2017;8:36225–45. https://doi.org/10.18632/oncotarget.16717.

    Article  PubMed  PubMed Central  Google Scholar 

  102. 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;9:1–11. https://doi.org/10.1038/s41598-018-38031-2.

    Article  CAS  Google Scholar 

  103. Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science (80-). 2020;368:973–80. https://doi.org/10.1126/science.aay9189.

    Article  CAS  Google Scholar 

  104. Giudice LC. Endometriosis. N Engl J Med. 2010;362:2389–98. https://doi.org/10.1056/NEJMcp1000274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Vargas E, Aghajanova L, Gemzell-Danielsson K, Altmäe S, Esteban FJ. Cross-disorder analysis of endometriosis and its comorbid diseases reveals shared genes and molecular pathways and proposes putative biomarkers of endometriosis. Reprod BioMed Online. 2020;40:305–18. https://doi.org/10.1016/j.rbmo.2019.11.003.

    Article  CAS  PubMed  Google Scholar 

  106. Khan KN, Fujishita A, Kitajima M, Hiraki K, Nakashima M, Masuzaki H. Intra-uterine microbial colonization and occurrence of endometritis in women with endometriosis. Hum Reprod. 2014;29:2446–56. https://doi.org/10.1093/humrep/deu222.

    Article  CAS  PubMed  Google Scholar 

  107. Cregger MA, Lenz K, Leary E, Leach R, Fazleabas A, White B, et al. Reproductive microbiomes: using the microbiome as a novel diagnostic tool for endometriosis. Reprod. Immunol Open Access. 2017;02. https://doi.org/10.21767/2476-1974.100036.

  108. Akiyama K, Nishioka K, Khan KN, Tanaka Y, Mori T, Nakaya T, et al. Molecular detection of microbial colonization in cervical mucus of women with and without endometriosis. Am J Reprod Immunol. 2019;82:1–9. https://doi.org/10.1111/aji.13147.

    Article  CAS  Google Scholar 

  109. Hernandes C, Silveira P, Rodrigues Sereia AF, Christoff AP, Mendes H, Valter de Oliveira LF, et al. Microbiome profile of deep endometriosis patients: comparison of vaginal fluid, endometrium and lesion. Diagnostics. 2020:10–163. https://doi.org/10.3390/diagnostics10030163.

  110. Takebayashi A, Kimura F, Kishi Y, Ishida M, Takahashi A, Yamanaka A, et al. The association between endometriosis and chronic endometritis. PLoS One. 2014;9. https://doi.org/10.1371/journal.pone.0088354.

  111. Pinto V, Matteo M, Tinelli R, Mitola PC, De Ziegler D, Cicinelli E. Altered uterine contractility in women with chronic endometritis. Fertil Steril. 2015;103:1049–52. https://doi.org/10.1016/j.fertnstert.2015.01.007.

    Article  PubMed  Google Scholar 

  112. Khan KN, Fujishita A, Hiraki K, Kitajima M, Nakashima M, Fushiki S, et al. Bacterial contamination hypothesis: a new concept in endometriosis. Reprod Med Biol. 2018;17:125–33. https://doi.org/10.1002/rmb2.12083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Leonardi M, Hicks C, El-Assaad F, El-Omar E, Condous G. Endometriosis and the microbiome: a systematic review. BJOG An Int J Obstet Gynaecol. 2019:1–11. https://doi.org/10.1111/1471-0528.15916.

  114. Wei W, Zhang X, Tang H, Zeng L, Wu R. Microbiota composition and distribution along the female reproductive tract of women with endometriosis. Ann Clin Microbiol Antimicrob. 2020;19. https://doi.org/10.1186/s12941-020-00356-0.

  115. Shahanavaj K, Gil-Bazo I, Castiglia M, Bronte G, Passiglia F, Carreca AP, et al. Cancer and the microbiome: potential applications as new tumor biomarker. Expert Rev Anticancer Ther. 2015;15:317–30. https://doi.org/10.1586/14737140.2015.992785.

    Article  CAS  PubMed  Google Scholar 

  116. Walther-António 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. https://doi.org/10.1186/s13073-016-0368-y.

  117. 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;9:1–16. https://doi.org/10.1038/s41598-019-55720-8.

    Article  CAS  Google Scholar 

  118. Lu W, He F, Lin Z, Liu S, Tang L, Huang Y, et al. Dysbiosis of the endometrial microbiota and its association with inflammatory cytokines in endometrial cancer. Int J Cancer. 2021;148:1708–16. https://doi.org/10.1002/ijc.33428.

    Article  CAS  PubMed  Google Scholar 

  119. Azziz R, Carmina E, Chen Z, Dunaif A, Laven JSE, Legro RS, et al. Polycystic ovary syndrome. Nat Rev Dis Prim. 2016;2. https://doi.org/10.1038/nrdp.2016.57.

  120. Giampaolino P, Foreste V, Di Filippo C, Gallo A, Mercorio A, Serafino P, et al. Microbiome and PCOS: state-of-art and future aspects. Int J Mol Sci. 2021;22:1–16. https://doi.org/10.3390/ijms22042048.

    Article  CAS  Google Scholar 

  121. Pelzer ES, Allan JA, Waterhouse MA, Ross T, Beagley KW, Knox CL. Microorganisms within human follicular fluid: effects on IVF. PLoS One. 2013;8:e59062. https://doi.org/10.1371/journal.pone.0059062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tu Y, Zheng G, Ding G, Wu Y, Xi J, Ge Y, et al. Comparative analysis of lower genital tract microbiome between PCOS and Healthy women. Front Physiol. 2020;11:1–10. https://doi.org/10.3389/fphys.2020.01108.

    Article  Google Scholar 

  123. Hong X, Qin P, Huang K, Ding X, Ma J, Xuan Y, et al. Association between polycystic ovary syndrome and the vaginal microbiome: a case-control study. Clin Endocrinol. 2020;93:52–60. https://doi.org/10.1111/cen.14198.

    Article  CAS  Google Scholar 

  124. Moreno I, Simon C. Relevance of assessing the uterine microbiota in infertility. Fertil Steril. 2018;110:337–43. https://doi.org/10.1016/j.fertnstert.2018.04.041.

    Article  PubMed  Google Scholar 

  125. Gnainsky Y, Granot I, Aldo P, Barash A, Or Y, Mor G, et al. Biopsy-induced inflammatory conditions improve endometrial receptivity: the mechanism of action. Reproduction. 2015;149:75–85. https://doi.org/10.1530/REP-14-0395.

    Article  CAS  PubMed  Google Scholar 

  126. Maier E, Anderson RC, Roy NC. Understanding how commensal obligate anaerobic bacteria regulate immune functions in the large intestine. Nutrients. 2015;7:45–73. https://doi.org/10.3390/nu7010045.

    Article  CAS  Google Scholar 

  127. Schoenmakers S, Laven J. The vaginal microbiome as a tool to predict IVF success. Curr Opin Obstet Gynecol. 2020;32:169–78. https://doi.org/10.1097/GCO.0000000000000626.

    Article  PubMed  Google Scholar 

  128. Hyman RW, Herndon CN, Jiang H, Palm C, Fukushima M, Bernstein D, et al. The dynamics of the vaginal microbiome during infertility therapy with in vitro fertilization-embryo transfer. J Assist Reprod Genet. 2012;29:105–15. https://doi.org/10.1007/s10815-011-9694-6.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Koedooder R, Singer M, Schoenmakers S, Savelkoul PHM, Morré SA, De Jonge JD, et al. The vaginal microbiome as a predictor for outcome of in vitro fertilization with or without intracytoplasmic sperm injection: a prospective study. Hum Reprod. 2019;34:1042–54. https://doi.org/10.1093/humrep/dez065.

    Article  CAS  PubMed  Google Scholar 

  130. Bernabeu A, Lledo B, Díaz MC, Lozano FM, Ruiz V, Fuentes A, et al. Effect of the vaginal microbiome on the pregnancy rate in women receiving assisted reproductive treatment. J Assist Reprod Genet. 2019;36:2111–9. https://doi.org/10.1007/s10815-019-01564-0.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Singer M, Borg M, Ouburg S, Morré SA. The relation of the vaginal microbiota to early pregnancy development during in vitro fertilization treatment—a meta-analysis. J Gynecol Obstet Hum Reprod. 2019;48:223–9. https://doi.org/10.1016/j.jogoh.2019.01.007.

    Article  CAS  PubMed  Google Scholar 

  132. Hashimoto T, Kyono K. Does dysbiotic endometrium affect blastocyst implantation in IVF patients? J Assist Reprod Genet. 2019;36:2471–8. https://doi.org/10.1007/s10815-019-01630-7.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Díaz-Gimeno P, Horcajadas JA, Martínez-Conejero JA, Esteban FJ, Alamá P, Pellicer A, et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril. 2011;95 https://doi.org/10.1016/j.fertnstert.2010.04.063.

  134. Benner M, Ferwerda G, Joosten I, van der Molen RG. How uterine microbiota might be responsible for a receptive, fertile endometrium. Hum Reprod Update. 2018;24:393–415. https://doi.org/10.1093/humupd/dmy012.

    Article  CAS  PubMed  Google Scholar 

  135. Liu Y, Wong KKW, Ko EYL, Chen X, Huang J, Tsui SKW, et al. Systematic comparison of bacterial colonization of endometrial tissue and fluid samples in recurrent miscarriage patients: implications for future endometrial microbiome studies. Clin Chem. 2018;64:1743–52. https://doi.org/10.1373/clinchem.2018.289306.

    Article  CAS  PubMed  Google Scholar 

  136. Garcia-Grau I, Perez-Villaroya D, Bau D, Gonzalez-Monfort M, Vilella F, Moreno I, et al. Taxonomical and functional assessment of the endometrial microbiota in a context of recurrent reproductive failure: A case report. Pathogens. 2019;8:4–6. https://doi.org/10.3390/pathogens8040205.

    Article  CAS  Google Scholar 

  137. Chenoll E, Moreno I, Sánchez M, Garcia-Grau I, Silva Á, González-Monfort M, et al. Selection of new probiotics for endometrial health. Front Cell Infect Microbiol. 2019;9. https://doi.org/10.3389/fcimb.2019.00114.

  138. DeLong K, Zulfiqar F, Hoffmann DE, Tarzian AJ, Ensign LM. Vaginal Microbiota transplantation: the next frontier. J. Law, Med. Ethics. 2019;47:555–67. https://doi.org/10.1177/1073110519897731.

    Article  Google Scholar 

  139. Koedooder R, Mackens S, Budding A, Fares D, Blockeel C, Laven J, et al. Identification and evaluation of the microbiome in the female and male reproductive tracts. Hum Reprod Update. 2019;25:298–325. https://doi.org/10.1093/humupd/dmy048.

    Article  PubMed  Google Scholar 

  140. Shafquat A, Joice R, Simmons SL, Huttenhower C. Functional and phylogenetic assembly of microbial communities in the human microbiome. Trends Microbiol. 2014;22:261–6. https://doi.org/10.1016/j.tim.2014.01.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Peric A, Weiss J, Vulliemoz N, Baud D, Stojanov M. Bacterial colonization of the female upper genital tract. Int J Mol Sci. 2019;20:3405. https://doi.org/10.3390/ijms20143405.

    Article  CAS  PubMed Central  Google Scholar 

  142. O’Callaghan JL, Turner R, Dekker Nitert M, Barrett HL, Clifton V, Pelzer ES. Re-assessing microbiomes in the low-biomass reproductive niche. BJOG An Int J Obstet Gynaecol. 2020;127:147–58. https://doi.org/10.1111/1471-0528.15974.

    Article  Google Scholar 

  143. Weyrich LS, Farrer AG, Eisenhofer R, Arriola LA, Young J, Selway CA, et al. Laboratory contamination over time during low-biomass sample analysis. Mol Ecol Resour. 2019;19:982–96. https://doi.org/10.1111/1755-0998.13011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Molina NM, Sola-Leyva A, Haahr T, Aghajanova L, Laudanski P, Castilla JA, et al. Analysing endometrial microbiome: methodological considerations and recommendations for good practice. Hum Reprod. 2021;00:1–21. https://doi.org/10.1093/humrep/deab009.

    Article  Google Scholar 

  145. Leigh Greathouse K, Sinha R, Vogtmann E. DNA extraction for human microbiome studies: the issue of standardization. Genome Biol. 2019;20:212. https://doi.org/10.1186/s13059-019-1843-8.

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors are very grateful to Irene Bosch for the original drawing on Figure 1 and Figure 2.

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Authors and Affiliations

  1. IVI Global Education, Edificio Bipolo, Hospital Universitario La Fe, Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Spain

    Paula Punzón-Jiménez

  2. Department of Pediatrics, Obstetrics and Gynaecology, Universitat de València, Av. Blasco Ibáñez, 15, 46010, Valencia, Spain

    Paula Punzón-Jiménez

  3. IVIRMA Valencia, Plaza de la Policía Local, 3, 46015, Valencia, Spain

    Elena Labarta

  4. IVI Foundation – IIS La Fe, Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Spain

    Elena Labarta

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P.P. contributed to the data collection and interpretation, E.L. revised the article and approved the final version. The first and last authors significantly contributed to the study conception and design, performed statistical analyses, and data interpretation and drafted the article.

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Correspondence to Paula Punzón-Jiménez.

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P.P declares no conflicts of interest. E.L. received a grant from Ferring in 2020, has provided consultancy services for MSD and Ferring Pharmaceuticals, and is part of the Ferring Pharmaceuticals LIFE program and Merck Global program for Fertility Innovation Leaders. During the past 12 months, she has received honoraria from Angelini/IBSA, Merck, MSD, and Ferring Pharmaceuticals for lecturing.

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Punzón-Jiménez, P., Labarta, E. The impact of the female genital tract microbiome in women health and reproduction: a review. J Assist Reprod Genet 38, 2519–2541 (2021). https://doi.org/10.1007/s10815-021-02247-5

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