ENDOMETRIAL MICROBIOTA COMPOSITION, Α-DEFENSIN AND TRANSFORMING GROWTH FACTOR Β1 LEVELS IN WOMEN WITH VIRAL INFECTION-DRIVEN INFERTILITY
- Authors: Budilovskaya O.1, Kopylova A.1, Krysanova A.1, Khusnutdinova T.1, Shalepo K.1, Ryzhov J.1, Obedkova K.1, Khalenko V.1, Tapilskaya N.1, Storozheva K.1, Savicheva A.1, Kogan I.1
-
Affiliations:
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
- Section: ORIGINAL ARTICLES
- Submitted: 13.06.2025
- Accepted: 20.08.2025
- URL: https://iimmun.ru/iimm/article/view/17944
- DOI: https://doi.org/10.15789/2220-7619-EMC-17944
- ID: 17944
Cite item
Full Text
Abstract
Abstract
A viral infection can interfere with implantation processes, affecting angiogenesis and endometrial receptivity, invasive trophoblast activity, and disrupting the balance of immune factors.
The aim of the study was to assess endometrial microbiota composition, to measure the levels of α-defensin, growth factors in infertile women with viral infection.
Materials and methods. 80 female infertile patients aged 26-46 years were examined divided into two groups: main group – women with endometrium-bearing viruses found in their (25 patients), and comparison group – 55 women without endometrium-bearing viruses. The endometrial microbiota was studied using molecular biological tests. α-Defensin (DEFa1), fibroblast growth factor 2 (FGF2), and transforming growth factor beta 1 (TGF-β1) in the endometrium were determined by ELISA.
Results. Viruses were detected in endometrium 31.3% of the examined women. Herpesviridae viruses accounted for 34%, while Human Papillomavirus – 66%. Lactobacillus spp. most often dominated in endometrial microbiota in both groups (group 1 – 68% (17/25), group 2 – 78% (43/55)). The second most common microbial community types were Gardnerella vaginalis and Atopobium vaginae (Fannyhessea vaginae), which accounted for 20% and 15% in groups 1 and 2, respectively. In group 1, the highest viral load was found in endometrial samples with a high concentration of L. iners, as well as upon a decline or absence of Lactobacillus spp. (p<0.05). The concentration of L. crispatus and L. jensenii was significantly higher in group 2 (p<0.05). Patients with endometrium-bearing viruses had increased DEFα levels comprising 4.32 ng/ml (0.497; 16.1) compared with patients without endometrium-bearing viruses (0.7 ng/ml (0.7; 20)), as well as decreased levels of TGFb – 2 ng/ml (0.2; 9.8) and 4.54 ng/ml (0;16), respectively (p<0.05).
Conclusions. Viral damage to the endometrium is associated with an increased concentration of L. iners, or with a deficiency or absence of Lactobacillus spp., as well as with an increased level of DEFα, active against viruses, and a decrease in TGF β1, indicating a violation of endometrial tissue homeostasis.
About the authors
Olga Budilovskaya
D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
Email: o.budilovskaya@gmail.com
ORCID iD: 0000-0001-7673-6274
SPIN-code: 7603-6982
PhD Senior Researcher of the Experimental Microbiology Group
Россия, 199034,Russia, St. Petersburg, Mendeleevskaya Line, 3Anastasia Kopylova
D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
Email: khripushina_a_a@mail.ru
ORCID iD: 0000-0002-6387-4878
postgraduate student of the Department of Assisted Reproductive Technologies
Россия, 199034, Russia, St. Petersburg, Mendeleevskaya Line, 3Anna Krysanova
D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
Email: krusanova.anna@mail.ru
ORCID iD: 0000-0003-4798-1881
SPIN-code: 2438-0230
ResearcherId: K-3678-2018
PhD Senior Researcher Department of Medical Microbiology
Россия, 199034, Russia, St. Petersburg, Mendeleevskaya Line, 3Tatiana Khusnutdinova
D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
Email: husnutdinovat@yandex.ru
ORCID iD: 0000-0002-2742-2655
SPIN-code: 9533-9754
ResearcherId: K-1852-2018
PhD Senior Researcher of the Experimental Microbiology Group
Россия, 199034, Russia, St. Petersburg, Mendeleevskaya Line, 3Kira Shalepo
D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
Email: 2474151@mail.ru
ORCID iD: 0000-0002-3002-3874
SPIN-code: 2527-7198
PhD, Senior Researcher of the Experimental Microbiology Group
Россия, 199034, Russia, St. Petersburg, Mendeleevskaya Line, 3Julian Ryzhov
D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
Email: julian.ryzhov@gmail.com
ORCID iD: 0000-0002-5073-8279
SPIN-code: 8320-1234
PhD, junior research scientist of the Department of Assisted Reproductive Technologies
Россия, 199034, Russia, St. Petersburg, Mendeleevskaya Line, 3Ksenia Obedkova
D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
Email: obedkova_ks@mail.ru
ORCID iD: 0000-0002-2056-7907
SPIN-code: 2709-2890
PhD, Senior Researcher of the Department of Assisted Reproductive Technologies
Россия, 199034, Russia, St. Petersburg, Mendeleevskaya Line, 3Vladislava Khalenko
D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
Email: vkhalenko@gmail.com
ORCID iD: 0000-0001-5313-2259
SPIN-code: 9694-3758
junior research scientist of the Department of Assisted Reproductive Technologies
Россия, 199034, Russia, St. Petersburg, Mendeleevskaya Line, 3Natalya Tapilskaya
D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
Email: tapnatalia@yandex.ru
ORCID iD: 0000-0001-5309-0087
SPIN-code: 3605-0413
MD, professor; Head of the Department of Assisted Reproductive Technologies
Россия, 199034, Russia, St. Petersburg, Mendeleevskaya Line, 3Ksenia Storozheva
D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
Email: kvstorozheva@mail.ru
ORCID iD: 0009-0005-8954-0234
SPIN-code: 9392-1886
postgraduate student of the Department of Assisted Reproductive Technologies
Россия, 199034, Russia, St. Petersburg, Mendeleevskaya Line, 3Alevtina Savicheva
D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
Email: savitcheva@mail.ru
ORCID iD: 0000-0003-3870-5930
SPIN-code: 8007-2630
MD, Professor, Head of the Department of Medical Microbiology
Россия, 199034, Russia, St. Petersburg, Mendeleevskaya Line, 3Igor Kogan
D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology
Author for correspondence.
Email: ikogan@mail.ru
ORCID iD: 0000-0002-7351-6900
SPIN-code: 6572-6450
Corresponding Member of the RAS, Dr. Med. Sci., Professor, Director of the Institute
Россия, 199034, Russia, St. Petersburg, Mendeleevskaya Line, 3References
- Кущ А.А., Кистенёва Л.Б., Климова Р.Р., Чешик С.Г. Роль герпесвирусов в развитии заболеваний урогенитального тракта и бесплодия у женщин // Вопросы вирусологии. - 2020. - Т. 65. - №6. - C. 317-325. doi: 10.36233/0507-4088-2020-65-6-2
- Agostinis C, Mangogna A, Bossi F, Ricci G, Kishore U, Bulla R. Uterine Immunity and Microbiota: A Shifting Paradigm. Front Immunol. 2019;10:2387. Published 2019 Oct 17. doi: 10.3389/fimmu.2019.02387
- Alazzam MB, Al-Radaideh AT, Binsaif N, AlGhamdi AS, Rahman MA. Advanced Deep Learning Human Herpes Virus 6 (HHV-6) Molecular Detection in Understanding Human Infertility. Comput Intell Neurosci. 2022 Jan 7;2022:1422963. doi: 10.1155/2022/1422963. Retraction in: Comput Intell Neurosci. 2023 Jul 26;2023:9892510. doi: 10.1155/2023/9892510.
- Balla B, Illés A, Tobiás B, Pikó H, Beke A, Sipos M, Lakatos P, Kósa JP. The Role of the Vaginal and Endometrial Microbiomes in Infertility and Their Impact on Pregnancy Outcomes in Light of Recent Literature. Int J Mol Sci. 2024 Dec 9;25(23):13227. doi: 10.3390/ijms252313227.
- Bardos J, Fiorentino D, Longman RE, Paidas M. Immunological Role of the Maternal Uterine Microbiome in Pregnancy: Pregnancies Pathologies and Alterated Microbiota. Front Immunol. 2020 Jan 8;10:2823. doi: 10.3389/fimmu.2019.02823
- Chee WJY, Chew SY, Than LTL. Vaginal microbiota and the potential of Lactobacillus derivatives in maintaining vaginal health. Microb Cell Fact. 2020 Nov 7;19(1):203. doi: 10.1186/s12934-020-01464-4
- Chen C, Song X, Wei W, Zhong H, Dai J, Lan Z, Li F, Yu X, Feng Q, Wang Z, Xie H, Chen X, Zeng C, Wen B, Zeng L, Du H, Tang H, Xu C, Xia Y, Xia H, Yang H, Wang J, Wang J, Madsen L, Brix S, Kristiansen K, Xu X, Li J, Wu R, Jia H. The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases. Nat Commun. 2017 Oct 17;8(1):875. doi: 10.1038/s41467-017-00901-0
- Elovitz, M.A., Gajer, P., Riis, V. et al. Cervicovaginal microbiota and local immune response modulate the risk of spontaneous preterm delivery. Nat Commun 10, 1305 (2019). doi: 10.1038/s41467-019-09285-9.
- Franasiak J.M., Alecsandru D., Forman E.J., Gemmell L.C., Goldberg J.M., Llarena N., Margolis C., Laven J., Schoenmakers S., Seli E. A review of the pathophysiology of recurrent implantation failure. Fertil. Steril. 2021;116:1436–1448. doi: 10.1016/j.fertnstert.2021.09.014.
- Gao X, Louwers YV, Laven JSE, Schoenmakers S. Clinical Relevance of Vaginal and Endometrial Microbiome Investigation in Women with Repeated Implantation Failure and Recurrent Pregnancy Loss. Int J Mol Sci. 2024 Jan 3;25(1):622. doi: 10.3390/ijms25010622
- Guo F, Si C, Zhou M, Wang J, Zhang D, Leung PCK, Xu B, Zhang A. Decreased PECAM1-mediated expression in the mid-secretory endometrium in women with recurrent implantation failure. Hum Reprod. 2018 May 1;33(5):832-843. doi: 10.1093/humrep/dey022. Erratum in: Hum Reprod. 2020 Jan 1;35(1):253. doi: 10.1093/humrep/dez236
- Ae Ra Han, Endometrial microbiome in reproductive failure: The possibility of metagenomic analysis Clinical and Experimental Reproductive Medicine 2024;cerm.2024.07171. doi: 10.5653/cerm.2024.07171
- Jiang P, Tang X, Wang H, Dai C, Su J, Zhu H, Song M, Liu J, Nan Z, Ru T, Li Y, Wang J, Yang J, Chen B, Dai J, Hu Y. Collagen-binding basic fibroblast growth factor improves functional remodeling of scarred endometrium in uterine infertile women: a pilot study. Sci China Life Sci. 2019 Dec;62(12):1617-1629. doi: 10.1007/s11427-018-9520-2
- Lindsay CV, Potter JA, Grimshaw AA, Abrahams VM, Tong M. Endometrial responses to bacterial and viral infection: a scoping review. Hum Reprod Update. 2023 Sep 5;29(5):675-693. doi: 10.1093/humupd/dmad013
- Lingasamy P, Modhukur V, Mändar R, Salumets A. Exploring Immunome and Microbiome Interplay in Reproductive Health: Current Knowledge, Challenges, and Novel Diagnostic Tools. Semin Reprod Med. 2023 Sep;41(5):172-189. doi: 10.1055/s-0043-1778017. Epub 2024 Jan 23
- McBride, A.A. Human papillomaviruses: diversity, infection and host interactions. Nat Rev Microbiol 20, 95–108 (2022). doi: 10.1038/s41579-021-00617-5
- Emre Okyay, Hakan Kula, Onur Yavuz, Asli Akdoner, Erkan Cagliyan. The Human Papillomavirus and Its Relationship to Infertility and Endometriosis. Clin. Exp. Obstet. Gynecol. 2023, 50(8), 170. doi: 10.31083/j.ceog5008170
- Ostanin AA, Aizikovich BI, Aizikovich IV, Kozhin AY, Chernykh ER. Role of cytokines in the regulation of reproductive function. Bull Exp Biol Med. 2007 Jan;143(1):75-9. doi: 10.1007/s10517-007-0021-2
- Pantos K, Grigoriadis S, Maziotis E, Pistola K, Xystra P, Pantou A, Kokkali G, Pappas A, Lambropoulou M, Sfakianoudis K, et al. The Role of Interleukins in Recurrent Implantation Failure: A Comprehensive Review of the Literature. International Journal of Molecular Sciences. 2022; 23(4):2198. doi: 10.3390/ijms23042198
- Rezaei, M., Moghoofei, M. The role of viral infection in implantation failure: direct and indirect effects. Reprod Biol Endocrinol 22, 142 (2024). doi: 10.1186/s12958-024-01303-w
- Rokhsartalab Azar P, Karimi S, Haghtalab A, et al. The role of the endometrial microbiome in embryo implantation and recurrent implantation failure. J Reprod Immunol. 2024;162:104192. doi: 10.1016/j.jri.2024.104192
- Tantengco OAG, Menon R. Breaking Down the Barrier: The Role of Cervical Infection and Inflammation in Preterm Birth. Front Glob Womens Health. 2022 Jan 18;2:777643. doi: 10.3389/fgwh.2021.777643
- Tapilskaya NI, Savicheva AM, Shalepo KV, Budilovskaya OV, Gzgzyan AM, Bespalova ON, Khusnutdinova TA, Krysanova AA, Obedkova KV, Safarian GK. Local Immune Biomarker Expression Depending on the Uterine Microbiota in Patients with Idiopathic Infertility. International Journal of Molecular Sciences. 2023; 24(8):7572 doi: 10.3390/ijms24087572
- Wang WJ, Zhang H, Chen ZQ, Zhang W, Liu XM, Fang JY, Liu FJ, Kwak-Kim J. Endometrial TGF-β, IL-10, IL-17 and autophagy are dysregulated in women with recurrent implantation failure with chronic endometritis. Reprod Biol Endocrinol. 2019 Jan 3;17(1):2. doi: 10.1186/s12958-018-0444-9
- Wylie KM, Mihindukulasuriya KA, Zhou Y, Sodergren E, Storch GA, Weinstock GM. Metagenomic analysis of double-stranded DNA viruses in healthy adults. BMC Biol. 2014 Sep 10;12:71. doi: 10.1186/s12915-014-0071-7
- Xiao B., Wu C., Song W. et al. Association Analysis on Recurrence of Bacterial Vaginosis Revealed Microbes and Clinical Variables Important for Treatment Outcome. Front Cell Infect Microbiol. 2019;9:189. doi: 10.3389/fcimb.2019.00189
Supplementary files
