An updated view on the role of the female reproductive tract microbiome in IVF outcomes
https://doi.org/10.17749/2313-7347/ob.gyn.rep.2023.433
Abstract
Introduction. In the last decade, a high-throughput 16S ribosomal RNA (rRNA) sequencing allowed to markedly extend insights into female reproductive tract microbiome. However, evidence about its role on in vitro fertilization (IVF) outcomes remains scarce and controversial.
Aim: to analyze literature data for assessing an impact of the vaginal, uterine, and ovarian microbiome on IVF outcomes.
Materials and Methods. The review was carried out based on publications from available in PubMed/MEDLINE, EBSCO, ResearchGate, Google Academy and еLibrary databases released over the last 20 years. For this, there was search for keywords and their combinations in Russian- and English-written publications: «vaginal microbiome», «cervical microbiome», «uterine microbiome», «ovarian microbiome», «microbiome of ovarian follicles», «IVF», «miscarriage», «early pregnancy loss», «implantation failure», «ovarian failure», «inflammasome». Only full-text original articles and reviews published in peer-reviewed journals were included in the review. Exclusion criteria were as follows: studies containing less than 10 observations per group, abstracts of conferences, studies on the male reproductive tract microbiome. Duplicate publicationswere excluded. The publications were selected independently by two co-authors, and in case of discrepancy two other co-authors were involved.
Results. Vaginal, uterine, and ovarian microbiomes were characterized by providing relevant classifications and the features related to implantation failures and pregnancy loss after IVF. It was found that a decline in total Lactobacillus level and elevated proportion of L. jensenii, G. vaginalis, and Proteobacteria in the vaginal microbiome were predictors of implantation failure. In addition, IVF failure was also associated with the presence of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Streptococcus, Haemophilus, Staphylococcus, Brevundimonas, and Ralstonia in the uterine cavity as well as Bifidobacterium, Gardnerella, and Klebsiella in the endometrial tissue. On the other hand, Lactobacillus dominance in the uterine microbiome has a favorable effect. The colonization of the follicle by any microorganisms as well as the presence of follicular fluid anaerobic bacteria-derived metabolite trimethylamine-N-oxide (TMAO) associated with bacterial vaginosis additionally alters IVF outcomes. Moreover, the role of infectious cues in lowered ovarian reserve has also been established. Activation of the NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome by microbe-derived ligands stimulates production of pro-inflammatory cytokines and contributes to reduced follicle number. Blocking NLRP3 in mouse experiments can delay depletion of the follicle pool and result in elevated fertility.
Conclusion. Favorable IVF outcomes are associated with Lactobacillus predominance in the vaginal and endometrial microbiome as well as lack of follicular fluid microorganisms. TMAO detected in the follicular fluid as well as activated NLRP3 inflammasome serve as negative predictors of IVF outcomes.
Keywords
About the Authors
N. B. TursunovaRussian Federation
Nafisa B.Tursunova – 6th-year Student
85 Pobedy Str., Belgorod 308015
O. P. Lebedeva
Russian Federation
Olga P. Lebedeva – MD, Dr Med Sci, Associate Professor, Professor, Department of Obstetrics and Gynecology, Belgorod National Research University; Leading Researcher, Laboratory of Metagenomics and Food Biotechnology, Voronezh State University of Engineering Technologies
Scopus Author ID: 55655876400
Researcher ID: E-5969-2015
85 Pobedy Str., Belgorod 308015
19 Prospect Revolutsii, Voronezh 394036
O. B. Altukhova
Russian Federation
Oxana B. Altukhova – MD, Dr Med Sci, Associate Professor, Head of the Department of Obstetrics and Gynecology, Belgorod National Research University; Head of Gynecological Department, Belgorod Regional Clinical Hospital of St. Joasaph
Scopus Author ID: 57216900558
85 Pobedy Str., Belgorod 308015
8/9 Nekrasova Str., Belgorod 308000
A. V. Nagorny
Russian Federation
Andrey V. Nagorny – MD, PhD, Head of the Accreditation and Simulation Center, Associate Professor, Department of Obstetrics and Gynecology, Belgorod National Research University; Obstetrician-Gynecologist, Department of Gynecology, Belgorod Regional Clinical Hospital of St. Joasaph
85 Pobedy Str., Belgorod 308015
8/9 Nekrasova Str., Belgorod 308000
References
1. Morotskaya A.V. Molecular factors of endometrial receptivity. [Molekulyarnye faktory receptivnosti endometriya]. Zhurnal akusherstva i zhenskih boleznej. 2017;66(S):128–9. (In Russ.).
2. Ombelet W. WHO fact sheet on infertility gives hope to millions of infertile couples worldwide. Facts Views Vis Obgyn. 2020;12(4):249–51.
3. Guerri G., Maniscalchi T., Barati S. et al. Non-syndromic monogenic female infertility. Acta Biomed. 2019;90(10–S):68–74. https://doi.org/10.23750/abm.v90i10-S.8763.
4. Korsak V.S., Smirnova A.A., Shurygina O.V. ART Register of RAHR, 2017. [Registr VRT Rossijskoj associacii reprodukcii cheloveka. Otchet za 2017 god]. Russian Journal of Human Reproduction. 2019;25(6):9-21. (In Russ.). https://doi.org/10.17116/repro2019250619.
5. Kozlova A.A., Nikolaeva A.V., Priputnevich T.V. et al. Vaginal microbiome in woman during pregnancy and postpartum period: dynamics, its link with the intestinal microflora and its influence microbiota formation in newborns. [Mikrobiom vlagalishcha zhenshchiny vo vremya beremennosti i v poslerodovom periode: dinamika, vzaimosvyaz' s kishechnoj mikrofloroj, vliyanie na stanovlenie mikrobioty novorozhdennogo]. Akusherstvo i ginekologiya. Novosti. Mneniya. Obuchenie. 2021;9(4):71–8. (In Russ.). https://doi.org/10.33029/2303-9698-2021-9-4-71-78.
6. Lebedeva O.P., Gryaznova M.V., Kozarenko O.N. Vaginal microbiome in patients with menstrual cycle disorders (review). [Mikrobiom vlagalishcha pri narusheniyah menstrual'nogo cikla (obzor)]. Research Results in Biomedicine. 2021;7(4):433–50. (In Russ.). https://doi.org/10.18413/2658-6533-2021-7-4-0-9.
7. Franasiak J.M., Scott R.T. Reproductive tract microbiome in assisted reproductive technologies. Fertil Steril. 2015;104(6):1364–71. https://doi.org/10.1016/j.fertnstert.2015.10.012.
8. Cason C., D’Accolti M., Soffritti I. et al. Next-generation sequencing and PCR technologies in monitoring the hospital microbiome and its drug resistance. Front Microbiol. 2022;13:969863. https://doi.org/10.3389/fmicb.2022.969863.
9. Boyarsky K.Yu., Kahiani E.I. Microbiome of the human reproductive system. [Mikrobiom reproduktivnoj sistemy cheloveka]. Russian Journal of Human Reproduction. 2019;25(4):27–34. (In Russ.). https://doi.org/10.17116/repro20192504127.
10. Moher D., Liberati A., Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. PLoS Med. 2009;6(6):e1000097. https://doi.org/10.1371/journal.pmed1000097.
11. Ravel J., Gajer P., Abdo Z. et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A. 2011;108 Suppl 1(Suppl 1):4680–7. https://doi.org/10.1073/pnas.1002611107.
12. Moosa Y., Kwon D., de Oliveira T., Wong E.B. Determinants of vaginal microbiota composition. Front Cell Infect Microbiol. 2020;10:467. https://doi.org/10.3389/fcimb.2020.00467.
13. Gupta P., Singh M.P., Goyal K. Diversity of vaginal microbiome in pregnancy: deciphering the obscurity. Front Public Health. 2020;8:326. https://doi.org/10.3389/fpubh.2020.00326.
14. Brotman R.M., Bradford L.L., Conrad M. et al. Association between Trichomonas vaginalis and vaginal bacterial community composition among reproductive-age women. Sex Transm Dis. 2012;39(10):807–12. https://doi.org/10.1097/OLQ.0b013e3182631c79.
15. Anahtar M.N., Byrne E.H., Doherty K.E. et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity. 2015;42(5):965–76. https://doi.org/10.1016/j.immuni.2015.04.019.
16. Gosmann C., Anahtar M.N., Handley S.A. et al. Lactobacillus-deficient cervicovaginal bacterial communities are associated with increased HIV acquisition in young South African women. Immunity. 2017;46(1):29–37. https://doi.org/10.1016/j.immuni.2016.12.013.
17. Moreno I., Simon C. Deciphering the effect of reproductive tract microbiota on human reproduction. Reprod Med Biol. 2018;18(1):40–50. https://doi.org/10.1002/rmb2.12249.
18. France M.T., Ma B., Gajer P. et al. VALENCIA: a nearest centroid classification method for vaginal microbial communities based on composition. Microbiome. 2020;8(1):166. https://doi.org/10.1186/s40168-020-00934-6.
19. Gryaznova M., Lebedeva O., Kozarenko O. et al. Lower genital tract microbiome in early pregnancy in the Eastern European population. Microorganisms. 2022;10(12):2368. https://doi.org/10.3390/microorganisms10122368.
20. Lebedeva O.P., Popov V.N., Syromyatnikov M.Y. et al. Female reproductive tract microbiome and early miscarriages. APMIS. 2023;131(2):61–76. https://doi.org/10.1111/apm.13288.
21. Ricci S., De Giorgi S., Lazzeri E. et al. Impact of asymptomatic genital tract infections on in vitro Fertilization (IVF) outcome. PLoS One. 2018;13(11):e0207684. https://doi.org/10.1371/journal.pone.0207684.
22. Schoenmakers S., Laven J. The vaginal microbiome as a tool to predict IVF success. Curr Opin Obstet Gynecol. 2020;32(3):169–78. https://doi.org/10.1097/GCO.0000000000000626.
23. Koedooder R., Singer M., Schoenmakers S. 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(6):1042–54. https://doi.org/10.1093/humrep/dez065.
24. Fu M., Zhang X., Liang Y. et al. Alterations in vaginal microbiota and associated metabolome in women with recurrent implantation failure. mBio. 2020;11(3):e03242–19. https://doi.org/10.1128/mBio.03242-19.
25. Diaz-Martínez M.D.C., Bernabeu A., Lledó B. et al. Impact of the vaginal and endometrial microbiome pattern on assisted reproduction outcomes. J Clin Med. 2021;10(18):4063. https://doi.org/10.3390/jcm10184063.
26. Mitchell C.M., Haick A., Nkwopara E. et al. Colonization of the upper genital tract by vaginal bacterial species in nonpregnant women. Am J Obstet Gynecol. 2015;212(5):611.e1–9. https://doi.org/10.1016/j.ajog.2014.11.043.
27. Miles S.M., Hardy B.L., Merrell D.S. Investigation of the microbiota of the reproductive tract in women undergoing a total hysterectomy and bilateral salpingo-oopherectomy. Fertil Steril. 2017;107(3):813–820.e1. https://doi.org/10.1016/j.fertnstert.2016.11.028.
28. Chen C., Song X., Wei W. et al. The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases. Nat Commun. 2017;8(1):875. https://doi.org/10.1038/s41467-017-00901-0.
29. Li F., Chen C., Wei W. et al. The metagenome of the female upper reproductive tract. Gigascience. 2018;7(10):giy107. https://doi.org/10.1093/gigascience/giy107.
30. Wee B. A., Thomas M., Sweeney E. L. 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 N Z J Obstet Gynaecol. 2018;58(3):341–8. https://doi.org/10.1111/ajo.12754.
31. Winters A.D., Romero R., Gervasi M. T. et al. Does the endometrial cavity have a molecular microbial signature? Sci Rep. 2019;9(1):9905. https://doi.org/10.1038/s41598-019-46173-0.
32. Pelzer E.S., Willner D., Buttini M.et al. A role for the endometrial microbiome in dysfunctional menstrual bleeding. Antonie Van Leeuwenhoek. 2018;111(6):933–43. https://doi.org/10.1007/s10482-017-0992-6.
33. Verstraelen H., Vilchez-Vargas R., Desimpel F. 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:e1602. https://doi.org/10.7717/peerj.1602.
34. Baker J.M., Chase D.M., Herbst-Kralovetz M.M. Uterine microbiota: residents, tourists, or invaders? Front Immunol. 2018;9:208. https://doi.org/10.3389/fimmu.2018.00208.
35. Moreno I., Codoñer F. M., Vilella F. et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol. 2016;215(6):684–703. https://doi.org/10.1016/j.ajog.2016.09.075.
36. Kyono K., Hashimoto T., Nagai Y. et al. Analysis of endometrial microbiota by 16S ribosomal RNA gene sequencing among infertile patients: a single-center pilot study. Reprod Med Biol. 2018;17(3):297–306. https://doi.org/10.1002/rmb2.12105.
37. Franasiak J.M., Werner M.D., Juneau C.R. et al. Endometrial microbiome at the time of embryo transfer: next-generation sequencing of the 16S ribosomal subunit. J Assist Reprod Genet. 2016;33(1):129–36. https://doi.org/10.1007/s10815-015-0614-z.
38. Moreno I., Garcia-Grau I., Perez-Villaroya D. et al. Endometrial microbiota composition is associated with reproductive outcome in infertile patients. Microbiome. 2022;10(1):1. https://doi.org/10.1186/s40168-021-01184-w.
39. Barinova V.V., Kuznetsova N.B., Bushtyreva I.O. et al. Endometrial microbiome in women with multiple failed in vitro fertilization cycles. [Mikrobiom endometriya u zhenshchin s mnogokratnymi neudachami ekstrakorporal'nogo oplodotvoreniya]. Voprosy ginekologii, akusherstva i perinatologii. 2021;20(3):5–11. (In Russ.). https://doi.org/10.20953/1726-1678-20213-5-11.
40. Barinova V.V., Kuznetsova N.B., Bushtyreva I.O. et al. Endometrial microbiome in women with and without a history of repeated failures of assisted reproductive technology: what are norm and pathology? [Mikrobiom endometriya pri mnogokratnyh neudachah vspomogatel'nyh reproduktivnyh tekhnologij i u zdorovyh zhenshchin: gde norma i gde patologiya?]. Akusherstvo i ginekologiya. 2021;(6):105–14. (In Russ.). https://doi.org/10.18565/aig.2021.6.105-114.
41. Vomstein K., Reider S., Böttcher B. et al. Uterine microbiota plasticity during the menstrual cycle: Differences between healthy controls and patients with recurrent miscarriage or implantation failure. J Reprod Immunol. 2022;151:103634. https://doi.org/10.1016/j.jri.2022.103634.
42. Pelzer E.S., Allan J.A., Cunningham K. et al. Microbial colonization of follicular fluid: alterations in cytokine expression and adverse assisted reproduction technology outcomes. Hum Reprod. 2011;26(7):1799–812. https://doi.org/10.1093/humrep/der108.
43. Pelzer E.S., Allan J.A., Waterhouse M.A. et al. Microorganisms within human follicular fluid: effects on IVF. PLoS One. 2013;8(3):e59062. https://doi.org/10.1371/journal.pone.0059062.
44. Borges E.D., Berteli T.S., Reis T.F. et al. Microbial contamination in assisted reproductive technology: source, prevalence, and cost. J Assist Reprod Genet. 2020;37(1):53–61. https://doi.org/10.1007/s10815-019-01640-5.
45. Peymani R., DeCherney A. Microbiome, infection and inflammation in infertility. In: Genital Infections and Infertility. Ed. A. Darwich. Intech Open, 2016. 99–133. https://doi.org/10.5772/63090.
46. Pelzer E.S., Allan J.A., Theodoropoulos C. et al. Hormone-dependent bacterial growth, persistence and biofilm formation – a pilot study investigating human follicular fluid collected during IVF cycles. PLoS One. 2012;7(12):e49965. https://doi.org/10.1371/journal.pone.0049965.
47. Swain J.E. Optimal human embryo culture. Semin Reprod Med. 2015;33(2):103–17. https://doi.org/10.1055/s-0035-1546423.
48. Maduka R., Osaikhuwuomwan J., Aziken M. The effect of bacterial colonization of the embryo transfer catheter on Outcome of In vitro Fertilization–Embryo transfer treatment. Afr J Med Health Sci. 2018;17(1):7–13. https://doi.org/10.5897/AJMHS.9000011.
49. Poletto K.Q., de Lima Y.A.R., Approbato M.S. Effect of the air filtration system replacement on embryo quality in the assisted reproduction laboratory. Rev Bras Ginecol Obstet. 2018;40(10):625–30. https://doi.org/10.1055/s-0038-1670715.
50. Ceccarani C., Foschi C., Parolin C. et al. Diversity of vaginal microbiome and metabolome during genital infections. Sci Rep. 2019;9(1):14095. https://doi.org/10.1038/s41598-019-50410-x.
51. Chen M.L., Zhu X.H., Ran L. et al. Trimethylamine-N-oxide induces vascular inflammation by activating the NLRP3 inflammasome through the SIRT3-SOD2-mtROS signaling pathway. J Am Heart Assoc. 2017;6(9):e006347. https://doi.org/10.1161/JAHA.117.006347.
52. Lebedeva O.P. The role of NOD1 and NOD2 receptors in recognazing pathogens in the female reproductive tract. [Rol' receptorov NOD1 i NOD2 v raspoznavanii patogenov v zhenskom reproduktivnom trakte]. Akusherstvo i ginekologiya. 2019;(5):25–9. (In Russ.). https://doi.org/10.18565/aig.2019.5.25-29.
53. Navarro-Pando J.M., Alcocer-Gómez E., Castejón-Vega B. et al. Inhibition of the NLRP3 inflammasome prevents ovarian aging. Sci Adv. 2021;7(1):eabc7409. https://doi.org/10.1126/sciadv.abc7409.
54. Lliberos C., Liew S. H., Mansell A. et al. The inflammasome contributes to depletion of the ovarian reserve during aging in mice. Front Cell Dev Biol. 2021;8:628473. https://doi.org/10.3389/fcell.2020.628473.
55. Nagy R.A., Homminga I., Jia C. et al. Trimethylamine-N-oxide is present in human follicular fluid and is a negative predictor of. embryo quality. Hum Reprod. 2020;35(1):81–8. https://doi.org/10.1093/humrep/dez224.
56. Adamyan L.V., Pivazyan L.G. Interdisciplinary approach and the current state of the issue of premature ovarian aging (literature review). [Mezhdisciplinarnyj podhod i sovremennoe sostoyanie voprosa o prezhdevremennom starenii yaichnikov (obzor literatury)]. Russian Journal of Human Reproduction. 2023;29(1):94–103. (In Russ.). https://doi.org/10.17116/repro20232901194.
57. Wu J., Ning Y., Tan L. et al. Characteristics of the vaginal microbiome in women with premature ovarian insufficiency. J Ovarian Res. 2021;14(1):172. https://doi.org/10.1186/s13048021-00923-9.
58. Wang J., Xu J., Han Q., et al. Changes in the vaginal microbiota associated with primary ovarian failure. BMC Microbiol. 2020;20(1):230. https://doi.org/10.1186/s12866-020-01918-0.
59. Lebedeva O.P., Qirko R. Expression of toll-like receptors in the female reproductive tract and its hormonal regulation (review). [Ekspressiya toll-podobnyh receptorov v zhenskom reproduktivnom trakte i ee gormonal'naya regulyaciya (obzor)]. Research Results in Biomedicine. 2018;4(3):3–17. (In Russ.). https://doi.org/10.18413/2313-8955-2018-4-3-0-1.
60. Lebedeva O.P., Zhukova I.O., Ivashova O.N. et al. The role of RIG-I, AIM2 and IFI16 receptors for viral DNA and RNA in the pathogenesis of spontaneous and early missed miscarriages. [Rol' receptorov RIG-I, AIM2 i IFI16, raspoznayushchih virusnuyu DNK i RNK, v patogeneze samoproizvol'nyh vykidyshej i nerazvivayushchejsya beremennosti rannih srokov]. Akusherstvo i ginekologiya. 2018;(7):579–61. (In Russ.). https://doi.org/10.18565/aig.2018.7.57-61.
61. Chernikov O.V., Moon J.S., Chen A. et al. Editorial: NLRP3 Inflammasome: regulatory mechanisms, role in health and disease and therapeutic potential. Front Immunol. 2021;12:765199. https://doi.org/10.3389/fimmu.2021.765199.
62. Zhang Z., Wang F., Zhang Y. Expression and contribution of NLRP3 inflammasome during the follicular development induced by PMSG. Front Cell Dev Biol. 2019;7:256. https://doi.org/10.3389/fcell.2019.00256.
63. Lliberos C., Liew S. H., Zareie P. et al. Evaluation of inflammation and follicle depletion during ovarian ageing in mice. Sci Rep. 2021;11(1):278. https://doi.org/10.1038/s41598-020-79488-4.
64. de Zoete M. R., Palm N. W., Zhu S. et al. Inflammasomes. Cold Spring Harb Perspect Biol. 2014;6(12):a016287. https://doi.org/10.1101/cshperspect.a016287.
65. Dou X., Sun Y., Li J. et al. Short-term rapamycin treatment increases ovarian lifespan in young and middle-aged female mice. Aging Cell. 2017;16(4):825–6. https://doi.org/10.1111/acel.12617.
Review
For citations:
Tursunova N.B., Lebedeva O.P., Altukhova O.B., Nagorny A.V. An updated view on the role of the female reproductive tract microbiome in IVF outcomes. Obstetrics, Gynecology and Reproduction. 2023;17(4):512-525. (In Russ.) https://doi.org/10.17749/2313-7347/ob.gyn.rep.2023.433

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