Indexes of nonspecific immune protection of the vagina before and after treatment of bacterial vaginosis

Bacterial vaginosis is a serious public health problem due to the increased risk of sexually transmitted infections and development of various obstetric and gynecological disorders. The local production of cytokines and antimicrobial peptides in the vagina plays an important role in regulation of genital tract immunity. The aim of the present study was to compare microflora and factors of nonspecific protection in vaginal environment in women with bacterial vaginosis before and after treatment. Our study included 110 patients with bacterial vaginosis (main group) and 26 conditionally healthy women with vaginal normocenosis (control group). The Amsel clinical criteria were determined, the vaginal microbiocenosis was studied using a molecular biology method using the Femoflor-16 test system. The contents of IL-6, IL-8, TNFa, IL-10 cytokines and acute phase proteins of C-reactive protein, C3-complement component and lactoferrin in vaginal secretions were studied by ELISA test systems. Methods of variation parametric and nonparametric statistics were used for statistical analysis. Statistically significant differences were taken at a confidence level of p < 0.05. Bacterial vaginosis was found to be accompanied by increased levels of IL-6, IL-8, TNFa and IL-10 (by 5.6, 5.5, 6.8, 4.1 times, respectively), and C-reactive protein by > 10 times, along with decrease in the C3 component of complement, and lactoferrin by 2.2 and 1.4 times, respectively, in the vaginal discharge (p < 0.001). After treatment of vaginosis, the patient groups with initial local dominance of obligate anaerobes (Sneathia spp. / Leptotrichia spp. / Fusobacterium spp., Megasphaera spp. / Veillonella spp. / Dialister spp., Atopobium vaginae and Mycoplasma hominis) exhibited increased levels of IL-6, TNFa and IL-10, along with low content of the C3 component of complement and lactoferrin. Thus, post-treatment preservation of low C3 component and lactoferrin levels may serve as a marker of recurrent bacterial vaginosis.

1. Budilovskaya O.V., Shipitsyna E.V., Gerasimova E.N., Safronova M.M., Savicheva A.M. Species diversity of vaginal lactobacilli in norm and in dysbiotic states. Zhurnal akusherstva i zhenskikh bolezney = Journal of Obstetrics and Women’s Diseases, 2017, Vol. 66, no. 2, pp. 24-32. (In Russ.)

2. Nazarova V.V., Shipitsyna E.V., Gerasimova E.N., Savicheva A.M. Criteria for diagnosis of bacterial vaginosis using the test Femoflor-16. Zhurnal akusherstva i zhenskikh bolezney = Journal of Obstetrics and Women’s Diseases, 2017, Vol. 66, no. 4, pp. 57-67. (In Russ.)

3. Sinyakova A.A., Shipitsyna E.V., Budilovskaya O.V., Bolotskikh V.M., Savicheva A.M. Anamnestic and microbiological predictors of miscarriage. Zhurnal akusherstva i zhenskikh bolezney = Journal of Obstetrics and Women’s Diseases, 2019, Vol. 68, no. 2, pp. 59-70. (In Russ.)

4. Amabebe E., Anumba D.O.C. The vaginal microenvironment: the physiologic role of lactobacilli. Front. Med. (Lausanne), 2018, Vol. 5, 181. doi: 10.3389/fmed.2018.00181.

5. Anahtar M.N., Byrne E.H., Doherty K.E., Bowman B.A., Yamamoto H.S., Soumillon M., Padavattan N., Ismail N., Moodley A., Sabatini M.E., Ghebremichael M.S., Nusbaum C., Huttenhower C., Virgin H.W., Ndung’u T., Dong K.L., Walker B.D., Fichorova R.N., Kwon D.S. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity, 2015, Vol. 42, no. 5, pp. 965-976. doi: 10.1016/j.immuni.2015.04.019.

6. Bautista C.T., Wurapa E., Sateren W.B., Morris S., Hollingsworth B., Sanchez J.L. Bacterial vaginosis: a synthesis of the literature on etiology, prevalence, risk factors, and relationship with chlamydia and gonorrhea infections. Mil. Med. Res., 2016, Vol. 3, 4. doi: 10.1186/s40779-016-0074-5.

7. Bilardi J.E., Walker S., Temple-Smith M., McNair R., Mooney-Somers J., Bellhouse C., Fairley C.K., Chen M.Y., Bradshaw C. The burden of bacterial vaginosis: women’s experience of the physical, emotional, sexual and social impact of living with recurrent bacterial vaginosis. PLoS One, 2013, Vol. 8, no. 9, e74378. doi: 10.1371/journal.pone.0074378.

8. Brown R.G., Al-Memar M., Marchesi J.R., Lee Y.S., Smith A., Chan D., Lewis H., Kindinger L., Terzidou V., Bourne T., Bennett P.R., MacIntyre D.A. Establishment of vaginal microbiota composition in early pregnancy and its association with subsequent preterm prelabor rupture of the fetal membranes. Transl. Res., 2019, Vol. 207, pp. 30-43. doi: 10.1016/j.trsl.2018.12.005.

9. Bradshaw C.S., Sobel J.D. Current treatment of bacterial vaginosis-limitations and need for innovation. J. Infect. Dis., 2016, Vol. 214, no. 1, pp. 14-20.

10. Campisciano G., Zanotta N., Licastro D., De Seta F., Comar M. In vivo microbiome and associated immune markers: new insights into the pathogenesis of vaginal dysbiosis. Sci. Rep., 2018, no. 8, no. 1, 2307. doi: 10.1038/s41598-018-20649-x.

11. Deng Y., Zhang Y., Wu T., Niu K., Jiao X., Ma W., Peng C., Wu W. Complement C3 deposition restricts the proliferation of internalized Staphylococcus aureus by promoting autophagy. Front. Cell. Infect. Microbiol., 2024, Vol. 14, 1400068. doi: 10.3389/fcimb.2024.1400068.

12. Doerflinger S.Y., Throop A.L., Herbst-Kralovetz M.M. Bacteria in the vaginal microbiome alter the innate immune response and barrier properties of the human vaginal epithelia in a species-specific manner. J. Infect. Dis., 2014, Vol. 209, no. 12, pp. 1989-1999.

13. Gilbert N.M., Lewis W.G., Li G. Sojka D.K., Lubin J.B., Lewis A.L. Gardnerella vaginalis and Prevotella bivia trigger distinct and overlapping phenotypes in a mouse model of bacterial vaginosis. J. Infect. Dis., 2019, Vol. 220, no. 7, pp. 1099-1108.

14. Gondwe T., Ness R., Totten P.A., Astete S., Tang G., Gold M.A., Martin D., Haggerty C.L. Novel bacterial vaginosis-associated organisms mediate the relationship between vaginal douching and pelvic inflammatory disease. Sex. Transm. Infect., 2020, Vol. 96, no. 6, pp. 439-444.

15. Łaniewski P., Herbst-Kralovetz M.M. Bacterial vaginosis and health-associated bacteria modulate the immunometabolic landscape in 3D model of human cervix. NPJ Biofilms Microbiomes, 2021, Vol. 7, no. 1, 88. doi: 10.1038/s41522-021-00259-8.

16. Lepanto M.S., Rosa L., Paesano R., Valenti P., Cutone A. Lactoferrin in aseptic and septic inflammation. Molecules, 2019, Vol. 24, no. 7, 1323. doi: 10.3390/molecules24071323.

17. Lokken E.M., Mandaliya K., Srinivasan S., Richardson B.A., Kinuthia J., Lannon S., Jaoko W., Alumera H., Kemoli A., Fay E., John-Stewart G., Fredricks D.N., McClelland R.S. Impact of preconception vaginal microbiota on women’s risk of spontaneous preterm birth: protocol for a prospective case-cohort study. BMJ Open, 2020, Vol. 10, no. 2, e035186. doi: 10.1136/bmjopen-2019-035186.

18. Mao X., Chen H., Peng X., Zhao X., Yu Z., Xu D. Dysbiosis of vaginal and cervical microbiome is associated with uterine fibroids. Front. Cell. Infect. Microbiol., 2023, Vol. 13, 1196823. doi: 10.3389/fcimb.2023.1196823.

19. Mondal A.С., Sharma R., Trivedi N. Bacterial vaginosis: A state of microbial dysbiosis. Med. Microecol., 2023, Vol. 16, 100082. doi: 10.1016/j.medmic.2023.10008.

20. Mouliou D.S. C-Reactive protein: pathophysiology, diagnosis, false test results and a novel diagnostic algorithm for clinicians. Diseases, 2023, Vol. 11, no. 4, 132. doi: 10.3390/diseases11040132.

21. Muzny C.A, Łaniewski P., Schwebke J.R., Herbst-Kralovetz M.M. Host-vaginal microbiota interactions in the pathogenesis of bacterial vaginosis. Curr. Opin. Infect. Dis., 2020, Vol. 33, no. 1, pp. 59-65. doi: 10.1097/QCO.0000000000000620.

22. Ng B.K., Chuah J.N., Cheah F.C., Mohamed Ismail N.A., Tan G.C., Wong K.K., Lim P.S. Maternal and fetal outcomes of pregnant women with bacterial vaginosis. Front. Surg., 2023, Vol. 10, 1084867. doi: 10.3389/fsurg.2023.1084867.

23. Ostrycharz E., Hukowska-Szematowicz B. New insights into the role of the complement system in human viral diseases. Biomolecules, 2022, Vol. 12, no. 2, 226. doi: 10.3390/biom12020226.

24. 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., 2019, Vol. 46, no. 5, pp. 304-311.

25. Saadaoui M., Singh P., Ortashi O., Al Khodor S. Role of the vaginal microbiome in miscarriage: exploring the relationship. Front. Cell. Infect. Microbiol., 2023, Vol. 13, 1232825. doi: 10.3389/fcimb.2023.1232825.

26. Sanchez-Garcia E.K., Contreras-Paredes A., Martinez-Abundis E., Garcia-Chan D., Lizano M., de la CruzHernandez E. Molecular epidemiology of bacterial vaginosis and its association with genital micro-organisms in asymptomatic women. J. Med. Microbiol., 2019, Vol. 68, no. 9, pp. 1373-1382.

27. Tian Z., Zhao M., Sui X., Li X., Qin L., Chen Z.J., Zhao S., Zhao H. Associations between vaginal microbiota and endometrial polypoid lesions in women of reproductive age: a cross-sectional study. Reprod. Biomed, Online, 2024, Vol. 48, no. 2, 103602. doi: 10.1016/j.rbmo.2023.103602.

28. van Teijlingen N.H., van Smoorenburg M.Y., Sarrami-Forooshani R., Zijlstra-Willems E.M., van Hamme J.L., Borgdorff H., van de Wijgert J.HHM, van Leeuwen E., van der Post J.AM, Strijbis K., Ribeiro C.MS, Geijtenbeek T.BH. Prevotella timonensis bacteria associated with vaginal dysbiosis enhance human immunodeficiency virus type 1 susceptibility of vaginal CD4+ T сells. J. Infect. Dis., 2024, Vol. 230, no. 1, pp. e43-e47.

29. Valenti P., Rosa L., Capobianco D., Lepanto M.S., Schiavi E., Cutone A., Paesano R., Mastromarino P. Role of lactobacilli and lactoferrin in the mucosal cervicovaginal defense. Front. Immunol., 2018, Vol. 9, 376. doi: 10.3389/fimmu.2018.00376.

30. Zhang Z., Ma Q., Zhang L., Ma L., Wang D., Yang Y., Jia P., Wu Y., Wang F. Human papillomavirus and cervical cancer in the microbial world: exploring the vaginal microecology. Front. Cell. Infect. Microbiol., 2024, no. 14, 1325500. doi: 10.3389/fcimb.2024.1325500.