Recurrent Pregnancy Loss (RPL) affects 1-2% of women, and its triggering factors are unclear. Several studies have shown that the vaginal, endometrial, and gut microbiota may play a role in RPL. A decrease in the quantity of Lactobacillus crispatus in local microbiota has been associated with an increase in local (vaginal and endometrial) inflammatory response and immune cell activation that leads to pregnancy loss. The inflammatory response may be triggered by gram-negative bacteria, lipopolysaccharides (LPS), viral infections, mycosis, or atypia (tumor growth). Bacterial structures and metabolites produced by microbiota could be involved in immune cell modulation and may be responsible for immune cell activation and molecular mimicry. Gut microbiota metabolic products may increase the amount of circulating pro-inflammatory lymphocytes, which, in turn, will migrate into vaginal or endometrial tissues. Local pro-inflammatory Th1 and Th17 subpopulations and a decrease in local Treg and tolerogenic NK cells are accountable for the increase in pregnancy loss. Local microbiota may modulate the local inflammatory response, increasing pregnancy success. Analyzing local and gut microbiota may be necessary to characterize some RPL patients. Although oral supplementation of probiotics has not been shown to modify vaginal or endometrial microbiota, the metabolites produced by it may benefit patients. Lactobacillus crispatus transplantation into the vagina may enhance the required immune tolerogenic response to achieve a normal pregnancy. The effect of hormone stimulation and progesterone to maintain early pregnancy on microbiota has not been adequately studied, and more research is needed in this area. Well-designed clinical trials are required to ascertain the benefit of microbiota modulation in RPL.

Czech Advanced Technology and Research Institute Palacky University 779 00 Olomouc Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Hněvotínská 1333 5 779 00 Olomouc Czech Republic

Laboratory of Experimental Medicine University Hospital Olomouc Faculty of Medicine and Dentistry Palacky University 779 00 Olomouc Czech Republic

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Stephenson M.D. Frequency of factors associated with habitual abortion in 197 couples. Fertil. Steril. 1996;66:24–29. PubMed

Ford H.B., Schust D.J. Recurrent pregnancy loss: Etiology, diagnosis, and therapy. Rev. Obstet. Gynecol. 2009;2:76–83. PubMed PMC

Pillarisetty L.S., Mahdy H. StatPearls. StatPearls Publishing; Treasure Island, FL, USA: 2024. [(accessed on 4 June 2024)]. Recurrent Pregnancy Loss. [Updated 2023 August 28] Available online: https://www.ncbi.nlm.nih.gov/books/NBK554460/ PubMed

Gao H., Liu Q., Wang X., Li T., Li H., Li G., Tan L., Chen Y. Deciphering the role of female reproductive tract microbiome in reproductive health: A review. Front. Cell. Infect. Microbiol. 2024;14:1351540. doi: 10.3389/fcimb.2024.1351540. PubMed DOI PMC

Agostinis C., Mangogna A., Bossi F., Ricci G., Kishore U., Bulla R. Uterine Immunity and Microbiota: A Shifting Paradigm. Front. Immunol. 2019;10:2387. doi: 10.3389/fimmu.2019.02387. PubMed DOI PMC

Gao X., Louwers Y.V., Laven J.S.E., 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;25:622. doi: 10.3390/ijms25010622. PubMed DOI PMC

Lee S.K., Kim C.J., Kim D.J., Kang J.H. Immune cells in the female reproductive tract. Immune Netw. 2015;15:16–26. doi: 10.4110/in.2015.15.1.16. PubMed DOI PMC

Mendz G.L. The Vaginal Microbiome during Pregnancy in Health and Disease. Appl. Microbiol. 2023;3:1302–1338. doi: 10.3390/applmicrobiol3040089. DOI

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

Al-Nasiry S., Ambrosino E., Schlaepfer M., Morré S.A., Wieten L., Voncken J.W., Spinelli M., Mueller M., Kramer B.W. The interplay between reproductive tract microbiota and immunological system in human reproduction. Front. Immunol. 2020;11:378. doi: 10.3389/fimmu.2020.00378. PubMed DOI PMC

Odendaal J., Black N., Bennett P.R., Brosens J., Quenby S., MacIntyre D.A. The endometrial microbiota and early pregnancy loss. Hum. Reprod. 2024;39:638–646. doi: 10.1093/humrep/dead274. PubMed DOI PMC

Lev-Sagie A., De Seta F., Verstraelen H., Ventolini G., Lonnee-Hoffmann R., Vieira-Baptista P. The Vaginal Microbiome: II. Vaginal Dysbiotic Conditions. J. Low. Genit. Tract Dis. 2022;26:79–84. doi: 10.1097/LGT.0000000000000644. PubMed DOI PMC

Elnaggar J.H., Ardizzone C.M., Cerca N., Toh E., Łaniewski P., Lillis R.A., Herbst-Kralovetz M.M., Quayle A.J., Muzny C.A., Taylor C.M. A novel Gardnerella, Prevotella, and Lactobacillus standard that improves accuracy in quantifying bacterial burden in vaginal microbial communities. Front. Cell. Infect. Microbiol. 2023;13:1198113. doi: 10.3389/fcimb.2023.1198113. PubMed DOI PMC

Sola-Leyva A., Andrés-León E., Molina N.M., Terron-Camero L.C., Plaza-Díaz J., Sáez-Lara M.J., Gonzalvo M.C., Sánchez R., Ruíz S., Martínez L., et al. Mapping the entire functionally active endometrial microbiota. Hum. Reprod. 2021;36:1021–1031. doi: 10.1093/humrep/deaa372. PubMed DOI

Blazheva S., Pachkova S., Bodurska T., Ivanov P., Blazhev A., Lukanov T., Konova E. Unlocking the Uterine Code: Microbiota, Immune Cells, and Therapy for Recurrent Reproductive Failure. Microorganisms. 2024;12:547. doi: 10.3390/microorganisms12030547. PubMed DOI PMC

Brown R.G., Al-Memar M., Marchesi J.R., Lee Y.S., Smith A., Chan D., Lewis H., Kindinger L., Terzidou V., Bourne T., 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. doi: 10.1016/j.trsl.2018.12.005. PubMed DOI PMC

Song S.D., Acharya K.D., Zhu J.E., Deveney C.M., Walther-Antonio M.R.S., Tetel M.J., Chia N. Daily Vaginal Microbiota Fluctuations Associated with Natural Hormonal Cycle, Contraceptives, Diet, and Exercise. mSphere. 2020;5:e00593-20. doi: 10.1128/msphere.00593-20. PubMed DOI PMC

Toson B., Simon C., Moreno I. The Endometrial Microbiome and Its Impact on Human Conception. Int. J. Mol. Sci. 2022;23:485. doi: 10.3390/ijms23010485. PubMed DOI PMC

Lewis F.M.T., Bernstein K.T., Aral S.O. Vaginal Microbiome and Its Relationship to Behavior, Sexual Health, and Sexually Transmitted Diseases. Obstet. Gynecol. 2017;129:643–654. doi: 10.1097/AOG.0000000000001932. PubMed DOI PMC

Conlon M.A., Bird A.R. The impact of diet and lifestyle on gut microbiota and human health. Nutrients. 2014;7:17–44. doi: 10.3390/nu7010017. PubMed DOI PMC

Holdcroft A.M., Ireland D.J., Payne M.S. The Vaginal Microbiome in Health and Disease—What Role Do Common Intimate Hygiene Practices Play? Microorganisms. 2023;11:298. doi: 10.3390/microorganisms11020298. PubMed DOI PMC

Ma Z.S. Microbiome Transmission During Sexual Intercourse Appears Stochastic and Supports the Red Queen Hypothesis. Front. Microbiol. 2022;12:789983. doi: 10.3389/fmicb.2021.789983. PubMed DOI PMC

McClelland R.S., Lingappa J.R., Srinivasan S., Kinuthia J., John-Stewart G.C., Jaoko W., Richardson B.A., Yuhas K., Fiedler T.L., Mandaliya K.N., 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. 2018;18:554–564. doi: 10.1016/S1473-3099(18)30058-6. PubMed DOI PMC

Chacra L.A., Ly C., Hammoud A., Iwaza R., Mediannikov O., Bretelle F., Fenollar F. Relationship between Bacterial Vaginosis and Sexually Transmitted Infections: Coincidence, Consequence or Co-Transmission? Microorganisms. 2023;11:2470. doi: 10.3390/microorganisms11102470. PubMed DOI PMC

Wang Y., Thakur R., Shen Q., He Y., Chen C. Influences of vaginal microbiota on human papillomavirus infection and host immune regulation: What we have learned? Decod. Infect. Transm. 2023;1:100002. doi: 10.1016/j.dcit.2023.07.001. DOI

Zeng M., Li X., Jiao X., Cai X., Yao F., Xu S., Huang X., Zhang Q., Chen J. Roles of vaginal flora in human papillomavirus infection, virus persistence and clearance. Front. Cell. Infect. Microbiol. 2023;12:1036869. doi: 10.3389/fcimb.2022.1036869. PubMed DOI PMC

Lebeau A., Bruyere D., Roncarati P., Peixoto P., Hervouet E., Cobraiville G., Taminiau B., Masson M., Gallego C., Mazzucchelli G., et al. HPV infection alters vaginal microbiome through down-regulating host mucosal innate peptides used by Lactobacilli as amino acid sources. Nat. Commun. 2022;13:1076. doi: 10.1038/s41467-022-28724-8. PubMed DOI PMC

Mehta S.D., Nandi D., Agingu W., Green S.J., Bhaumik D.K., Bailey R.C., Otieno F. Vaginal and Penile Microbiome Associations With Herpes Simplex Virus Type 2 in Women and Their Male Sex Partners. J. Infect. Dis. 2022;226:644–654. doi: 10.1093/infdis/jiaa529. PubMed DOI PMC

Brotman R.M., Klebanoff M.A., Nansel T.R., Yu K.F., Andrews W.W., Zhang J., Schwebke J.R. Bacterial vaginosis assessed by gram stain and diminished colonization resistance to incident gonococcal, chlamydial, and trichomonal genital infection. J. Infect. Dis. 2010;202:1907–1915. doi: 10.1086/657320. PubMed DOI PMC

Van Gerwen O.T., Muzny C.A., Marrazzo J.M. Sexually transmitted infections and female reproductive health. Nat. Microbiol. 2022;7:1116–1126. doi: 10.1038/s41564-022-01177-x. PubMed DOI PMC

Haggerty C.L., Ness R.B., Totten P.A., Farooq F., Tang G., Ko D.B., Hou X., Fiedler T.L.B., Srinivasan S., Astete S.G., et al. Presence and Concentrations of Select Bacterial Vaginosis-Associated Bacteria Are Associated With Increased Risk of Pelvic Inflammatory Disease. Sex. Transm. Dis. 2020;47:344–346. doi: 10.1097/OLQ.0000000000001164. PubMed DOI PMC

Brown S.E., Schwartz J.A., Robinson C.K., O’Hanlon D.E., Bradford L.L., He X., Mark K.S., Bruno V.M., Ravel J., Brotman R.M. The Vaginal Microbiota and Behavioral Factors Associated With Genital Candida albicans Detection in Reproductive-Age Women. Sex. Transm. Dis. 2019;46:753–758. doi: 10.1097/OLQ.0000000000001066. PubMed DOI PMC

Sobstyl A., Chałupnik A., Mertowska P., Grywalska E. How Do Microorganisms Influence the Development of Endometriosis? Participation of Genital, Intestinal and Oral Microbiota in Metabolic Regulation and Immunopathogenesis of Endometriosis. Int. J. Mol. Sci. 2023;24:10920. doi: 10.3390/ijms241310920. PubMed DOI PMC

Gao Q., Fan T., Luo S., Zheng J., Zhang L., Cao L., Zhang Z., Li L., Huang Z., Zhang H., et al. Lactobacillus gasseri LGV03 isolated from the cervico-vagina of HPV-cleared women modulates epithelial innate immune responses and suppresses the growth of HPV-positive human cervical cancer cells. Transl. Oncol. 2023;35:101714. doi: 10.1016/j.tranon.2023.101714. PubMed DOI PMC

Krog M.C., Hugerth L.W., Fransson E., Bashir Z., Andersen A.N., Edfeldt G., Engstrand L., Schuppe-Koistinen I., Nielsen H.S. The healthy female microbiome across body sites: Effect of hormonal contraceptives and the menstrual cycle. Hum. Reprod. 2022;37:1525–1543. doi: 10.1093/humrep/deac094. PubMed DOI PMC

van den Tweel M.M., van den Munckhof E.H.A., van der Zanden M., Molijn A.C., van Lith J.M.M., Le Cessie S., Boers K.E. Bacterial vaginosis in a subfertile population undergoing fertility treatments: A prospective cohort study. J. Assist. Reprod. Genet. 2024;41:441–450. doi: 10.1007/s10815-023-03000-w. PubMed DOI PMC

Wang T., Li P., Bai X., Tian S., Yang M., Leng D., Kui H., Zhang S., Yan X., Zheng Q., et al. Vaginal microbiota are associated with in vitro fertilization during female infertility. iMeta. 2024;3:e185. doi: 10.1002/imt2.185. PubMed DOI PMC

Elnashar A.M. Impact of endometrial microbiome on fertility. Middle East Fertil. Soc. J. 2021;26:4. doi: 10.1186/s43043-020-00050-3. DOI

Hugon A.M., Golos T.G. Non-human primate models for understanding the impact of the microbiome on pregnancy and the female reproductive tract†. Biol. Reprod. 2023;109:1–16. doi: 10.1093/biolre/ioad042. PubMed DOI PMC

Schuster H.J., Bos A.M., Himschoot L., van Eekelen R., Matamoros S.P., de Boer M.A., Oudijk M.A., Ris-Stalpers C., Cools P., Savelkoul P.H., et al. Vaginal microbiota and spontaneous preterm birth in pregnant women at high risk of recurrence. Heliyon. 2024;10:e30685. doi: 10.1016/j.heliyon.2024.e30685. PubMed DOI PMC

Sun S., Serrano M.G., Fettweis J.M., Basta P., Rosen E., Ludwig K., Sorgen A.A., Blakley I.C., Wu M.C., Dole N., et al. Race, the Vaginal Microbiome, and Spontaneous Preterm Birth. mSystems. 2022;7:e0001722. doi: 10.1128/msystems.00017-22. PubMed DOI PMC

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

Nelson D.B., Bellamy S., Nachamkin I., Ness R.B., Macones G.A., Allen-Taylor L. First trimester bacterial vaginosis, individual microorganism levels, and risk of second trimester pregnancy loss among urban women. Fertil. Steril. 2007;88:1396–1403. doi: 10.1016/j.fertnstert.2007.01.035. PubMed DOI PMC

Nelson D.B., Hanlon A., Nachamkin I., Haggerty C., Mastrogiannis D.S., Liu C., Fredricks D.N. Early Pregnancy Changes in Bacterial Vaginosis-Associated Bacteria and Preterm Delivery. Paediatr. Perinat. Epidemiology. 2014;28:88–96. doi: 10.1111/ppe.12106. PubMed DOI PMC

Nelson D.B., Hanlon A.L., Wu G., Liu C., Fredricks D.N. First Trimester Levels of BV-Associated Bacteria and Risk of Miscarriage Among Women Early in Pregnancy. Matern. Child Health J. 2015;19:2682–2687. doi: 10.1007/s10995-015-1790-2. PubMed DOI

DiGiulio D.B., Callahan B.J., McMurdie P.J., Costello E.K., Lyell D.J., Robaczewska A., Sun C.L., Goltsman D.S.A., Wong R.J., Shaw G., et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc. Natl. Acad. Sci. USA. 2015;112:11060–11065. doi: 10.1073/pnas.1502875112. PubMed DOI PMC

Ahmadi A., Khodabandehloo M., Ramazanzadeh R., Farhadifar F., Nikkhoo B., Soofizade N., Rezaii M. Association between Ureaplasma urealyticum endocervical infection and spontaneous abortion. Iran. J. Microbiol. 2014;6:392–397. PubMed PMC

McPherson E. Recurrence of stillbirth and second trimester pregnancy loss. Am. J. Med Genet. A. 2016;170:1174–1180. doi: 10.1002/ajmg.a.37606. PubMed DOI

Işik G., Demirezen Ş., Dönmez H.G., Beksaç M.S. Bacterial vaginosis in association with spontaneous abortion and recurrent pregnancy losses. J. Cytol. 2016;33:135–140. PubMed PMC

Kuon R.J., Togawa R., Vomstein K., Weber M., Goeggl T., Strowitzki T., Markert U.R., Zimmermann S., Daniel V., Dalpke A.H., et al. Higher prevalence of colonization with Gardnerella vaginalis and gram-negative anaerobes in patients with recurrent miscarriage and elevated peripheral natural killer cells. J. Reprod. Immunol. 2017;120:15–19. doi: 10.1016/j.jri.2017.03.001. PubMed DOI

Al-Memar M., Bobdiwala S., Fourie H., Mannino R., Lee Y., Smith A., Marchesi J., Timmerman D., Bourne T., Bennett P., et al. The association between vaginal bacterial composition and miscarriage: A nested case-control study. BJOG. 2020;127:264–274. doi: 10.1111/1471-0528.15972. PubMed DOI PMC

Chang D.H., Shin J., Rhee M.S., Park K.R., Cho B.K., Lee S.K., Kim B.C. Vaginal Microbiota Profiles of Native Korean Women and Associations with High-Risk Pregnancy. J. Microbiol. Biotechnol. 2020;30:248–258. doi: 10.4014/jmb.1908.08016. PubMed DOI PMC

Xu L., Huang L., Lian C., Xue H., Lu Y., Chen X., Xia Y. Vaginal Microbiota Diversity of Patients with Embryonic Miscarriage by Using 16S rDNA High-Throughput Sequencing. Int. J. Genom. 2020;2020:1764959. doi: 10.1155/2020/1764959. PubMed DOI PMC

Shi Y., Yamada H., Sasagawa Y., Tanimura K., Deguchi M. Uterine endometrium microbiota and pregnancy outcome in women with recurrent pregnancy loss. J. Reprod. Immunol. 2022;152:103653. doi: 10.1016/j.jri.2022.103653. PubMed DOI

Shahid M., Quinlivan J.A., Peek M., Castaño-Rodríguez N., Mendz G.L. Is there an association between the vaginal microbiome and first-trimester miscarriage? A prospective observational study. J. Obstet. Gynaecol. Res. 2022;48:119–128. doi: 10.1111/jog.15086. PubMed DOI

Ncib K., Bahia W., Leban N., Mahdhi A., Trifa F., Mzoughi R., Haddad A., Jabeur C., Donders G. Microbial Diversity and Pathogenic Properties of Microbiota Associated with Aerobic Vaginitis in Women with Recurrent Pregnancy Loss. Diagnostics. 2022;12:2444. doi: 10.3390/diagnostics12102444. PubMed DOI PMC

Vomstein K., Reider S., Böttcher B., Watschinger C., Kyvelidou C., Tilg H., Moschen A.R., Toth B. 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. doi: 10.1016/j.jri.2022.103634. PubMed DOI

Moreno I., Garcia-Grau I., Perez-Villaroya D., Gonzalez-Monfort M., Bahçeci M., Barrionuevo M.J., Taguchi S., Puente E., Dimattina M., Lim M.W., et al. Endometrial microbiota composition is associated with reproductive outcome in infertile patients. Microbiome. 2022;10:1. doi: 10.1186/s40168-021-01184-w. PubMed DOI PMC

Severgnini M., Morselli S., Camboni T., Ceccarani C., Laghi L., Zagonari S., Patuelli G., Pedna M.F., Sambri V., Foschi C., et al. A Deep Look at the Vaginal Environment During Pregnancy and Puerperium. Front. Cell. Infect. Microbiol. 2022;12:838405. doi: 10.3389/fcimb.2022.838405. PubMed DOI PMC

Peuranpää P., Holster T., Saqib S., Kalliala I., Tiitinen A., Salonen A., Hautamäki H. Female reproductive tract microbiota and recurrent pregnancy loss: A nested case-control study. Reprod. Biomed. Online. 2022;45:1021–1031. doi: 10.1016/j.rbmo.2022.06.008. PubMed DOI

Shu J., Lin S., Wu Y., Zhu J., Gong D., Zou X., Zhu H., Gao J. A potential role for the uterine microbiome in missed abortions. J. Biol. Regul. Homeost. Agents. 2022;36:1055–1063.

Tanaka S.E., Sakuraba Y., Kitaya K., Ishikawa T. Differential Vaginal Microbiota Profiling in Lactic-Acid-Producing Bacteria between Infertile Women with and without Chronic Endometritis. Diagnostics. 2022;12:878. doi: 10.3390/diagnostics12040878. PubMed DOI PMC

Dong M., Dong Y., Bai J., Li H., Ma X., Li B., Wang C., Li H., Qi W., Wang Y., et al. Interactions between microbiota and cervical epithelial, immune, and mucus barrier. Front. Cell. Infect. Microbiol. 2023;13:1124591. doi: 10.3389/fcimb.2023.1124591. PubMed DOI PMC

Mori R., Hayakawa T., Hirayama M., Ozawa F., Yoshihara H., Goto S., Kitaori T., Ozaki Y., Sugiura-Ogasawara M. Cervicovaginal microbiome in patients with recurrent pregnancy loss. J. Reprod. Immunol. 2023;157:103944. doi: 10.1016/j.jri.2023.103944. PubMed DOI

Masucci L., D’Ippolito S., De Maio F., Quaranta G., Mazzarella R., Bianco D.M., Castellani R., Inversetti A., Sanguinetti M., Gasbarrini A., et al. Celiac Disease Predisposition and Genital Tract Microbiota in Women Affected by Recurrent Pregnancy Loss. Nutrients. 2023;15:221. doi: 10.3390/nu15010221. PubMed DOI PMC

Wang Y., Wang X., Zhu M., Ge L., Liu X., Su K., Chen Z., Zhao W. The Interplay Between Cervicovaginal Microbial Dysbiosis and Cervicovaginal Immunity. Front. Immunol. 2022;13:857299. doi: 10.3389/fimmu.2022.857299. PubMed DOI PMC

Celicanin M.M., Haahr T., Humaidan P., Skafte-Holm A. Vaginal dysbiosis—The association with reproductive outcomes in IVF patients: A systematic review and meta-analysis. Curr. Opin. Obstet. Gynecol. 2024;36:155–164. doi: 10.1097/GCO.0000000000000953. PubMed DOI PMC

Grewal K., Lee Y.S., Smith A., Brosens J.J., Bourne T., Al-Memar M., Kundu S., MacIntyre D.A., Bennett P.R. Chromosomally normal miscarriage is associated with vaginal dysbiosis and local inflammation. BMC Med. 2022;20:38. doi: 10.1186/s12916-021-02227-7. PubMed DOI PMC

Liu Y., Chen H., Feng L., Zhang J. Interactions between gut microbiota and metabolites modulate cytokine network imbalances in women with unexplained miscarriage. NPJ Biofilms Microbiomes. 2021;7:24. doi: 10.1038/s41522-021-00199-3. PubMed DOI PMC

Vomstein K., Krog M.C., Wrønding T., Nielsen H.S. The microbiome in recurrent pregnancy loss—A scoping review. J. Reprod. Immunol. 2024;163:104251. doi: 10.1016/j.jri.2024.104251. PubMed DOI

Liu F.T., Yang S., Yang Z., Zhou P., Peng T., Yin J., Ye Z., Shan H., Yu Y., Li R. An Altered Microbiota in the Lower and Upper Female Reproductive Tract of Women with Recurrent Spontaneous Abortion. Microbiol. Spectr. 2022;10:e0046222. PubMed PMC

Wang L., Chen J., He L., Liu H., Liu Y., Luan Z., Li H., Liu W., Luo M. Association between the vaginal and uterine microbiota and the risk of early embryonic arrest. Front. Microbiol. 2023;14:1137869. doi: 10.3389/fmicb.2023.1137869. PubMed DOI PMC

Takimoto K., Yamada H., Shimada S., Fukushi Y., Wada S. Chronic Endometritis and Uterine Endometrium Microbiota in Recurrent Implantation Failure and Recurrent Pregnancy Loss. Biomedicines. 2023;11:2391. doi: 10.3390/biomedicines11092391. PubMed DOI PMC

Palomino M.M., Allievi M.C., Gordillo T.B., Bockor S.S., Fina Martin J., Ruzal S.M. Surface layer proteins in species of the family Lactobacillaceae. Microb. Biotechnol. 2023;16:1232–1249. doi: 10.1111/1751-7915.14230. PubMed DOI PMC

France M., Alizadeh M., Brown S., Ma B., Ravel J. Towards a deeper understanding of the vaginal microbiota. Nat. Microbiol. 2022;7:367–378. doi: 10.1038/s41564-022-01083-2. PubMed DOI PMC

Mendes-Soares H., Suzuki H., Hickey R.J., Forney L.J. Comparative functional genomics of Lactobacillus spp. reveals possible mechanisms for specialization of vaginal lactobacilli to their environment. J. Bacteriol. 2014;196:1458–1470. doi: 10.1128/JB.01439-13. PubMed DOI PMC

Smith S.B., Ravel J. The vaginal microbiota, host defence and reproductive physiology. J. Physiol. 2017;595:451–463. doi: 10.1113/JP271694. PubMed DOI PMC

Zheng N., Guo R., Wang J., Zhou W., Ling Z. Contribution of Lactobacillus iners to Vaginal Health and Diseases: A Systematic Review. Front. Cell. Infect. Microbiol. 2021;11:792787. doi: 10.3389/fcimb.2021.792787. PubMed DOI PMC

Cela V., Daniele S., Obino M.E.R., Ruggiero M., Zappelli E., Ceccarelli L., Papini F., Marzi I., Scarfò G., Tosi F., et al. Endometrial Dysbiosis Is Related to Inflammatory Factors in Women with Repeated Implantation Failure: A Pilot Study. J. Clin. Med. 2022;11:2481. doi: 10.3390/jcm11092481. PubMed DOI PMC

Santoro A., Travaglino A., Inzani F., Angelico G., Raffone A., Maruotti G.M., Straccia P., Arciuolo D., Castri F., D’Alessandris N., et al. The Role of Plasma Cells as a Marker of Chronic Endometritis: A Systematic Review and Meta-Analysis. Biomedicines. 2023;11:1714. doi: 10.3390/biomedicines11061714. PubMed DOI PMC

Ma N., Li J., Zhang J., Jin Y., Wang J., Qin W., Hang F., Qin A. Combined oral antibiotics and intrauterine perfusion can improve in vitro fertilization and embryo transfer pregnancy outcomes in patients with chronic endometritis and repeated embryo implantation failure. BMC Women’s Health. 2023;23:344. doi: 10.1186/s12905-023-02443-8. PubMed DOI PMC

Kitaya K., Yasuo T. Commonalities and Disparities between Endometriosis and Chronic Endometritis: Therapeutic Potential of Novel Antibiotic Treatment Strategy against Ectopic Endometrium. Int. J. Mol. Sci. 2023;24:2059. doi: 10.3390/ijms24032059. PubMed DOI PMC

Christiansen O.B., Steffensen R., Nielsen H.S., Varming K. Multifactorial etiology of recurrent miscarriage and its scientific and clinical implications. Gynecol. Obstet. Investig. 2008;66:257–267. doi: 10.1159/000149575. PubMed DOI

Ishimwe J.A. Maternal microbiome in preeclampsia pathophysiology and implications on offspring health. Physiol. Rep. 2021;9:e14875. doi: 10.14814/phy2.14875. PubMed DOI PMC

Rafat D., Singh S., Nawab T., Khan F., Khan A.U., Khalid S. Association of vaginal dysbiosis and gestational diabetes mellitus with adverse perinatal outcomes. Int. J. Gynecol. Obstet. 2022;158:70–78. doi: 10.1002/ijgo.13945. PubMed DOI

Kan H., He Y., Li Q., Mu Y., Dong Y., Fan W., Zhang M., Wang T., Li Y., Liu H., et al. Differential Effect of Vaginal Microbiota on Spontaneous Preterm Birth among Chinese Pregnant Women. BioMed Res. Int. 2022;2022:3536108. doi: 10.1155/2022/3536108. PubMed DOI PMC

Esmaeili S.A., Mahmoudi M., Rezaieyazdi Z., Sahebari M., Tabasi N., Sahebkar A., Rastin M. Generation of tolerogenic dendritic cells using Lactobacillus rhamnosus and Lactobacillus delbrueckii as tolerogenic probiotics. J. Cell. Biochem. 2018;119:7865–7872. doi: 10.1002/jcb.27203. PubMed DOI

Qi X., Yun C., Pang Y., Qiao J. The impact of the gut microbiota on the reproductive and metabolic endocrine system. Gut Microbes. 2021;13:1894070. doi: 10.1080/19490976.2021.1894070. PubMed DOI PMC

Sun Y., Gao S., Ye C., Zhao W. Gut microbiota dysbiosis in polycystic ovary syndrome: Mechanisms of progression and clinical applications. Front. Cell. Infect. Microbiol. 2023;13:1142041. doi: 10.3389/fcimb.2023.1142041. PubMed DOI PMC

Corrie L., Awasthi A., Kaur J., Vishwas S., Gulati M., Kaur I.P., Gupta G., Kommineni N., Dua K., Singh S.K. Interplay of Gut Microbiota in Polycystic Ovarian Syndrome: Role of Gut Microbiota, Mechanistic Pathways and Potential Treatment Strategies. Pharmaceuticals. 2023;16:197. doi: 10.3390/ph16020197. PubMed DOI PMC

Fettweis J.M., Serrano M.G., Brooks J.P., Edwards D.J., Girerd P.H., Parikh H.I., Huang B., Arodz T.J., Edupuganti L., Glascock A.L., et al. The vaginal microbiome and preterm birth. Nat. Med. 2019;25:1012–1021. doi: 10.1038/s41591-019-0450-2. PubMed DOI PMC

Zhu J., Jin J., Qi Q., Li L., Zhou J., Cao L., Wang L. The association of gut microbiome with recurrent pregnancy loss: A comprehensive review. Drug Discov. Ther. 2023;17:157–169. doi: 10.5582/ddt.2023.01010. PubMed DOI

Soyer Caliskan C., Yurtcu N., Celik S., Sezer O., Kilic S.S., Cetin A. Derangements of vaginal and cervical canal microbiota determined with real-time PCR in women with recurrent miscarriages. J. Obstet. Gynaecol. 2022;42:2105–2114. doi: 10.1080/01443615.2022.2033183. PubMed DOI

Song D., He Y., Wang Y., Liu Z., Xia E., Huang X., Xiao Y., Li T.-C. Impact of antibiotic therapy on the rate of negative test results for chronic endometritis: A prospective randomized control trial. Fertil. Steril. 2021;115:1549–1556. doi: 10.1016/j.fertnstert.2020.12.019. PubMed DOI

Salmeri N., Sinagra E., Dolci C., Buzzaccarini G., Sozzi G., Sutera M., Candiani M., Ungaro F., Massimino L., Danese S., et al. Microbiota in Irritable Bowel Syndrome and Endometriosis: Birds of a Feather Flock Together—A Review. Microorganisms. 2023;11:2089. doi: 10.3390/microorganisms11082089. PubMed DOI PMC

Peelen M.J., Luef B.M., Lamont R.F., de Milliano I., Jensen J.S., Limpens J., Hajenius P.J., Jørgensen J.S., Menon R., PREBIC Biomarker Working Group 2014–2018 The influence of the vaginal microbiota on preterm birth: A systematic review and recommendations for a minimum dataset for future research. Placenta. 2019;79:30–39. doi: 10.1016/j.placenta.2019.03.011. PubMed DOI

Ghosh S.S., Wang J., Yannie P.J., Ghosh S. Intestinal Barrier Dysfunction, LPS Translocation, and Disease Development. J. Endocr. Soc. 2020;4:bvz039. doi: 10.1210/jendso/bvz039. PubMed DOI PMC

den Besten G., van Eunen K., Groen A.K., Venema K., Reijngoud D.-J., Bakker B.M. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 2013;54:2325–2340. doi: 10.1194/jlr.R036012. PubMed DOI PMC

Tersigni C., D’Ippolito S., Di Nicuolo F., Marana R., Valenza V., Masciullo V., Scaldaferri F., Malatacca F., de Waure C., Gasbarrini A., et al. Recurrent pregnancy loss is associated to leaky gut: A novel pathogenic model of endometrium inflammation? J. Transl. Med. 2018;16:102. doi: 10.1186/s12967-018-1482-y. PubMed DOI PMC

Charoensappakit A., Sae-Khow K., Leelahavanichkul A. Gut Barrier Damage and Gut Translocation of Pathogen Molecules in Lupus, an Impact of Innate Immunity (Macrophages and Neutrophils) in Autoimmune Disease. Int. J. Mol. Sci. 2022;23:8223. doi: 10.3390/ijms23158223. PubMed DOI PMC

Poggi A., Benelli R., Venè R., Costa D., Ferrari N., Tosetti F., Zocchi M.R. Human Gut-Associated Natural Killer Cells in Health and Disease. Front. Immunol. 2019;10:961. doi: 10.3389/fimmu.2019.00961. PubMed DOI PMC

Pelzer E.S., Willner D., Buttini M., Huygens F. A role for the endometrial microbiome in dysfunctional menstrual bleeding. Antonie Leeuwenhoek. 2018;111:933–943. doi: 10.1007/s10482-017-0992-6. PubMed DOI

Tersigni C., Barbaro G., Castellani R., Onori M., Granieri C., Scambia G., Di Simone N. Oral administration of Bifidobacterium longum ES1 reduces endometrial inflammation in women with recurrent pregnancy loss. Am. J. Reprod. Immunol. 2024;91:e13804. doi: 10.1111/aji.13804. PubMed DOI

Huang L., Thonusin C., Chattipakorn N., Chattipakorn S.C. Impacts of gut microbiota on gestational diabetes mellitus: A comprehensive review. Eur. J. Nutr. 2021;60:2343–2360. doi: 10.1007/s00394-021-02483-6. PubMed DOI

Belizário J.E., Faintuch J., Garay-Malpartida M. Gut Microbiome Dysbiosis and Immunometabolism: New Frontiers for Treatment of Metabolic Diseases. Mediat. Inflamm. 2018;2018:2037838. doi: 10.1155/2018/2037838. PubMed DOI PMC

Larsen J.M. The immune response to Prevotella bacteria in chronic inflammatory disease. Immunology. 2017;151:363–374. doi: 10.1111/imm.12760. PubMed DOI PMC

Russell J.T., Roesch L.F.W., Ördberg M., Ilonen J., Atkinson M.A., Schatz D.A., Triplett E.W., Ludvigsson J. Genetic risk for autoimmunity is associated with distinct changes in the human gut microbiome. Nat. Commun. 2019;10:3621. doi: 10.1038/s41467-019-11460-x. PubMed DOI PMC

Yang P., Lu T., Liang X., Huang T., Wu L., He Z., Xiao X., Fan S. The influence of placenta microbiota of normal term pregnant women on immune regulation during pregnancy. BMC Pregnancy Childbirth. 2024;24:171. doi: 10.1186/s12884-024-06353-x. PubMed DOI PMC

Yang S., Wang H., Li D., Li M. An Estrogen-NK Cells Regulatory Axis in Endometriosis, Related Infertility, and Miscarriage. Int. J. Mol. Sci. 2024;25:3362. doi: 10.3390/ijms25063362. PubMed DOI PMC

López-Moreno A., Aguilera M. Probiotics Dietary Supplementation for Modulating Endocrine and Fertility Microbiota Dysbiosis. Nutrients. 2020;12:757. doi: 10.3390/nu12030757. PubMed DOI PMC

Murphy K., Gromisch M., Srinivasan S., Wang T., Wood L., Proll S., Liu C., Fiedler T., Valint D.J., Fredricks D.N., et al. IgA coating of vaginal bacteria is reduced in the setting of bacterial vaginosis (BV) and preferentially targets BV-associated species. Infect. Immun. 2023;92:e0037323. doi: 10.1128/iai.00373-23. PubMed DOI PMC

Azkargorta M., Bregón-Villahoz M., Escobes I., Ibáñez-Pérez J., Iloro I. In-depth proteomics and natural peptidomics analyses reveal antibacterial peptides in human endometrial fluid. J. Proteom. 2020;216:103652. doi: 10.1016/j.jprot.2020.103652. PubMed DOI

Garmendia J.V., De Sanctis J.B. A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation. Immuno. 2021;1:174–193. doi: 10.3390/immuno1030011. DOI

Dai M., Xu Y., Gong G., Zhang Y. Roles of immune microenvironment in the female reproductive maintenance and regulation: Novel insights into the crosstalk of immune cells. Front. Immunol. 2023;14:1109122. doi: 10.3389/fimmu.2023.1109122. PubMed DOI PMC

Hedger M.P. Knobil and Neill’s Physiology of Reproduction. Academic Press; Cambridge, MA, USA: 2015. The Immunophysiology of Male Reproduction; pp. 805–892. DOI

Solders M., Gorchs L., Erkers T., Lundell A.C., Nava S., Gidlöf S., Tiblad E., Magalhaes I., Kaipe H. MAIT cells accumulate in placental intervillous space and display a highly cytotoxic phenotype upon bacterial stimulation. Sci. Rep. 2017;7:6123. doi: 10.1038/s41598-017-06430-6. PubMed DOI PMC

Favaro R.R., Phillips K., Delaunay-Danguy R., Ujčič K., Markert U.R. Emerging Concepts in Innate Lymphoid Cells, Memory, and Reproduction. Front. Immunol. 2022;13:824263. doi: 10.3389/fimmu.2022.824263. PubMed DOI PMC

Gibbs A., Leeansyah E., Introini A., Paquin-Proulx D., Hasselrot K., Andersson E., Broliden K., Sandberg J.K., Tjernlund A. MAIT cells reside in the female genital mucosa and are biased towards IL-17 and IL-22 production in response to bacterial stimulation. Mucosal Immunol. 2017;10:35–45. doi: 10.1038/mi.2016.30. PubMed DOI PMC

Lund J.M., Hladik F., Prlic M. Advances and challenges in studying the tissue-resident T cell compartment in the human female reproductive tract. Immunol. Rev. 2023;316:52–62. doi: 10.1111/imr.13212. PubMed DOI PMC

Prašnikar E., Kunej T., Gorenjak M., Potočnik U., Kovačič B., Knez J. Transcriptomics of receptive endometrium in women with sonographic features of adenomyosis. Reprod. Biol. Endocrinol. 2022;20:2. doi: 10.1186/s12958-021-00871-5. PubMed DOI PMC

Jewanraj J., Ngcapu S., Osman F., Mtshali A., Singh R., Mansoor L.E., Abdool Karim S.S., Abdool Karim Q., Passmore J.S., Liebenberg L.J.P. The Impact of Semen Exposure on the Immune and Microbial Environments of the Female Genital Tract. Front. Reprod. Health. 2020;2:566559. doi: 10.3389/frph.2020.566559. PubMed DOI PMC

Koga K., Izumi G., Mor G., Fujii T., Osuga Y. Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy complications. Am. J. Reprod. Immunol. 2014;72:192–205. doi: 10.1111/aji.12258. PubMed DOI

Benjelloun F., Quillay H., Cannou C., Marlin R., Madec Y., Fernandez H., Chrétien F., Le Grand R., Barré-Sinoussi F., Nugeyre M.T., et al. Activation of Toll-Like Receptors Differentially Modulates Inflammation in the Human Reproductive Tract: Preliminary Findings. Front. Immunol. 2020;11:1655. doi: 10.3389/fimmu.2020.01655. PubMed DOI PMC

Cuadrado-Torroglosa I., García-Velasco J.A., Alecsandru D. The Impacts of Inflammatory and Autoimmune Conditions on the Endometrium and Reproductive Outcomes. J. Clin. Med. 2024;13:3724. doi: 10.3390/jcm13133724. PubMed DOI PMC

Gholiof M., Adamson-De Luca E., Wessels J.M. The female reproductive tract microbiotas, inflammation, and gynecological conditions. Front. Reprod. Health. 2022;4:963752. doi: 10.3389/frph.2022.963752. PubMed DOI PMC

Berryman M.A., Ilonen J., Triplett E.W., Ludvigsson J. Important denominator between autoimmune comorbidities: A review of class II HLA, autoimmune disease, and the gut. Front. Immunol. 2023;14:1270488. doi: 10.3389/fimmu.2023.1270488. PubMed DOI PMC

Ludgate M.E., Masetti G., Soares P. The relationship between the gut microbiota and thyroid disorders. Nat. Rev. Endocrinol. 2024;20:1–15. doi: 10.1038/s41574-024-01003-w. PubMed DOI

Godines-Enriquez M.S., Miranda-Velásquez S., Enríquez-Pérez M.M., Arce-Sánchez L., Martínez-Cruz N., Flores-Robles C.M., Aguayo-González P., Morales-Hernández F.V., Villarreal-Barranca A., Suárez-Rico B.V., et al. Prevalence of Thyroid Autoimmunity in Women with Recurrent Pregnancy Loss. Medicina. 2021;57:96. doi: 10.3390/medicina57020096. PubMed DOI PMC

Turesheva A., Aimagambetova G., Ukybassova T., Marat A., Kanabekova P., Kaldygulova L., Amanzholkyzy A., Ryzhkova S., Nogay A., Khamidullina Z., et al. Recurrent Pregnancy Loss Etiology, Risk Factors, Diagnosis, and Management. Fresh Look into a Full Box. J. Clin. Med. 2023;12:4074. doi: 10.3390/jcm12124074. PubMed DOI PMC

Buendia-Roldan I., Ponce-Gallegos M.A., Lara-Beltrán D., Del Ángel-Pablo A.D., Pérez-Rubio G., Mejía M., Selman M., Falfán-Valencia R. The HLA-DRB1*07 Allele Is Associated with Interstitial Lung Abnormalities (ILA) and Subpleural Location in a Mexican Mestizo Population. Biomolecules. 2022;12:1662. doi: 10.3390/biom12111662. PubMed DOI PMC

Miko E., Barakonyi A. The Role of Hydrogen-Peroxide (H2O2) Produced by Vaginal Microbiota in Female Reproductive Health. Antioxidants. 2023;12:1055. doi: 10.3390/antiox12051055. PubMed DOI PMC

Vanstokstraeten R., Callewaert E., Blotwijk S., Rombauts E., Crombé F., Emmerechts K., Soetens O., Vandoorslaer K., De Geyter D., Allonsius C., et al. Comparing Vaginal and Endometrial Microbiota Using Culturomics: Proof of Concept. Int. J. Mol. Sci. 2023;24:5947. doi: 10.3390/ijms24065947. PubMed DOI PMC

Osadchiy V., Belarmino A., Kianian R., Sigalos J.T., Ancira J.S., Kanie T., Mangum S.F., Tipton C.D., Hsieh T.-C.M., Mills J.N., et al. Semen microbiota are dramatically altered in men with abnormal sperm parameters. Sci. Rep. 2024;14:1068. doi: 10.1038/s41598-024-51686-4. PubMed DOI PMC

Doroftei B., Ilie O.D., Armeanu T., Stoian I.L., Anton N., Babici R.G., Ilea C. A Narrative Review Discussing the Obstetric Repercussions Due to Alterations of Personalized Bacterial Sites Developed within the Vagina, Cervix, and Endometrium. J. Clin. Med. 2023;12:5069. doi: 10.3390/jcm12155069. PubMed DOI PMC

Faught B.M., Reyes S. Characterization and Treatment of Recurrent Bacterial Vaginosis. J. Women’s Health. 2019;28:1218–1226. doi: 10.1089/jwh.2018.7383. PubMed DOI

Rahman N., Mian M.F., Nazli A., Kaushic C. Human vaginal microbiota colonization is regulated by female sex hormones in a mouse model. Front. Cell. Infect. Microbiol. 2023;13:1307451. doi: 10.3389/fcimb.2023.1307451. PubMed DOI PMC

Shen J., Song N., Williams C.J., Brown C.J., Yan Z., Xu C., Forney L.J. Effects of low dose estrogen therapy on the vaginal microbiomes of women with atrophic vaginitis. Sci. Rep. 2016;6:24380. doi: 10.1038/srep34119. PubMed DOI PMC

Gustin A.T., Thurman A.R., Chandra N., Schifanella L., Alcaide M., Fichorova R., Doncel G.F., Gale M., Jr., Klatt N.R. Recurrent bacterial vaginosis following metronidazole treatment is associated with microbiota richness at diagnosis. Am. J. Obstet. Gynecol. 2022;226:225.e1–225.e15. doi: 10.1016/j.ajog.2021.09.018. PubMed DOI PMC

Tuniyazi M., Zhang N. Possible Therapeutic Mechanisms and Future Perspectives of Vaginal Microbiota Transplantation. Microorganisms. 2023;11:1427. doi: 10.3390/microorganisms11061427. PubMed DOI PMC

Meng Y., Sun J., Zhang G. Vaginal microbiota transplantation is a truly opulent and promising edge: Fully grasp its potential. Front. Cell. Infect. Microbiol. 2024;14:1280636. doi: 10.3389/fcimb.2024.1280636. PubMed DOI PMC

Martinelli S., Nannini G., Cianchi F., Staderini F., Coratti F., Amedei A. Microbiota Transplant and Gynecological Disorders: The Bridge between Present and Future Treatments. Microorganisms. 2023;11:2407. doi: 10.3390/microorganisms11102407. PubMed DOI PMC

Wrønding T., Vomstein K., Bosma E.F., Mortensen B., Westh H., Heintz J.E., Mollerup S., Petersen A.M., Ensign L.M., DeLong K., et al. Antibiotic-free vaginal microbiota transplant with donor engraftment, dysbiosis resolution and live birth after recurrent pregnancy loss: A proof of concept case study. eClinicalMedicine. 2023;61:102070. doi: 10.1016/j.eclinm.2023.102070. PubMed DOI PMC

Lyra A., Ala-Jaakkola R., Yeung N., Datta N., Evans K., Hibberd A., Lehtinen M.J., Forssten S.D., Ibarra A., Pesonen T., et al. A Healthy Vaginal Microbiota Remains Stable during Oral Probiotic Supplementation: A Randomised Controlled Trial. Microorganisms. 2023;11:499. doi: 10.3390/microorganisms11020499. PubMed DOI PMC

Husain S., Allotey J., Drymoussi Z., Wilks M., Fernandez-Felix B.M., Whiley A., Dodds J., Thangaratinam S., McCourt C., Prosdocimi E.M., et al. Effects of oral probiotic supplements on vaginal microbiota during pregnancy: A randomised, double-blind, placebo-controlled trial with microbiome analysis. BJOG. 2020;127:275–284. doi: 10.1111/1471-0528.15675. PubMed DOI PMC

Marcotte H., Larsson P.G., Andersen K.K., Zuo F., Mikkelsen L.S., Brandsborg E., Gray G., Laher F., Otwombe K. An exploratory pilot study evaluating the supplementation of standard antibiotic therapy with probiotic lactobacilli in south African women with bacterial vaginosis. BMC Infect. Dis. 2019;19:824. doi: 10.1186/s12879-019-4425-1. PubMed DOI PMC

Rafiee M., Sereshki N., Alipour R., Ahmadipanah V., Pashoutan Sarvar D., Wilkinson D. The effect of probiotics on immunogenicity of spermatozoa in couples suffering from recurrent spontaneous abortion. BMC Immunol. 2022;23:32. doi: 10.1186/s12865-022-00506-3. PubMed DOI PMC

Giannella L., Grelloni C., Quintili D., Fiorelli A., Montironi R., Alia S., Delli Carpini G., Di Giuseppe J., Vignini A., Ciavattini A. Microbiome Changes in Pregnancy Disorders. Antioxidants. 2023;12:463. doi: 10.3390/antiox12020463. PubMed DOI PMC

Qi F., Fan S., Fang C., Ge L., Lyu J., Huang Z., Zhao S., Zou Y., Huang L., Liu X., et al. Orally administrated Lactobacillus gasseri TM13 and Lactobacillus crispatus LG55 can restore the vaginal health of patients recovering from bacterial vaginosis. Front. Immunol. 2023;14:1125239. doi: 10.3389/fimmu.2023.1125239. PubMed DOI PMC

Hertz F.B., Holm J.B., Pallejá A., Björnsdóttir M.K., Mikkelsen L.S., Brandsborg E., Frimodt-Møller N. Vaginal microbiome following orally administered probiotic. APMIS. 2022;130:605–611. doi: 10.1111/apm.13261. PubMed DOI PMC

Li Z., Zheng Y., Zhang M., Wu K., Zhang L., Yao Y., Zheng C. Gut microbiota-derived metabolites associate with circulating immune cell subsets in unexplained recurrent spontaneous abortion. Heliyon. 2024;10:e24571. doi: 10.1016/j.heliyon.2024.e24571. PubMed DOI PMC

Zargar M., Ghafourian M., Behrahi F., Nikbakht R., Salehi A.M. Association of recurrent implantation failure and recurrent pregnancy loss with peripheral blood natural killer cells and interferon-gamma level. Obstet. Gynecol. Sci. 2024;67:112–119. doi: 10.5468/ogs.23120. PubMed DOI PMC

Wang W., Zhou X., Zhang Y., Chen Z., Huang J., Zhang X., Kwak-Kim J. The characteristics of antigenic specificity of memory regulatory t cells in women with unexplained recurrent pregnancy loss. J. Reprod. Immunol. 2022;154:103694. doi: 10.1016/j.jri.2022.103694. PubMed DOI

Tian Z., Zhang X., Yao G., Jin J., Zhang T., Sun C., Wang Z., Zhang Q. Intestinal flora and pregnancy complications: Current insights and future prospects. iMeta. 2024;3:e167. doi: 10.1002/imt2.167. PubMed DOI PMC

.Lu X., Shi Z., Jiang L., Zhang S. Maternal gut microbiota in the health of mothers and offspring: From the perspective of immunology. Front. Immunol. 2024;15:1362784. doi: 10.3389/fimmu.2024.1362784. PubMed DOI PMC

Esparvarinha M., Madadi S., Aslanian-Kalkhoran L., Nickho H., Dolati S., Pia H., Danaii S., Taghavi S., Yousefi M. Dominant immune cells in pregnancy and pregnancy complications: T helper cells (TH1/TH2, TH17/Treg cells), NK cells, MDSCs, and the immune checkpoints. Cell Biol. Intern. 2023;47:507–519. doi: 10.1002/cbin.11955. PubMed DOI

Jin M., Li D., Ji R., Liu W., Xu X., Feng X. Changes in Gut Microorganism in Patients with Positive Immune Antibody-associated Recurrent Abortion. BioMed. Res. Int. 2020:4673250. doi: 10.1155/2020/4673250. PubMed DOI PMC

Zhang L., Li Q., Su Y., Zhang X., Qu J., Liao D., Zou Q., Zou H., Liu X., Li C., et al. Proteomic profiling analysis of human endometrium in women with unexplained recurrent spontaneous abortion. J. Proteom. 2023;288:104996. doi: 10.1016/j.jprot.2023.104996. PubMed DOI

Ali S., Majid S., Ali M.N., Taking S., Rehman M.U., Arafah A. Cytokine imbalance at the materno-embryonic interface as a potential immune mechanism for recurrent pregnancy loss. Int. Immunopharmacol. 2021;90:107118. doi: 10.1016/j.intimp.2020.107118. PubMed DOI

Dingle K., Kassem O.M., Azizieh F., AbdulHussain G., Raghupathy R. Quantitative analyses of cytokine profiles reveal hormone-mediated modulation of cytokine profiles in recurrent spontaneous miscarriage. Cytokine. 2023;164:156160. doi: 10.1016/j.cyto.2023.156160. PubMed DOI

Mazziotta C., Tognon M., Martini F., Torreggiani E., Rotondo J.C. Probiotics Mechanism of Action on Immune Cells and Beneficial Effects on Human Health. Cells. 2023;12:184. doi: 10.3390/cells12010184. PubMed DOI PMC

Virk M.S., Virk M.A., He Y., Tufail T., Gul M., Qayum A., Rehman A., Rashid A., Ekumah J.-N., Han X., et al. The Anti-Inflammatory and Curative Exponent of Probiotics: A Comprehensive and Authentic Ingredient for the Sustained Functioning of Major Human Organs. Nutrients. 2024;16:546. doi: 10.3390/nu16040546. PubMed DOI PMC

Di Pierro F., Sinatra F., Cester M., Da Ros L., Pistolato M., Da Parè V., Fabbro L., Maccari D., Dotto S., Sossai S., et al. Effect of L. crispatus M247 Administration on Pregnancy Outcomes in Women Undergoing IVF: A Controlled, Retrospective, Observational, and Open-Label Study. Microorganisms. 2023;11:2796. doi: 10.3390/microorganisms11112796. PubMed DOI PMC

Barati M., Jabbari M., Ghavidel A.A., Nikmehr P., Arzhang P., Aynehchi A., Babashahi M., Mosharkesh E., Roshanravan N., Shabani M., et al. The engineered probiotics for the treatment of chronic diseases: A systematic review. J. Food Biochem. 2022;46:e14343. doi: 10.1111/jfbc.14343. PubMed DOI

Kemp M.W., Newnham J.P., Challis J.G., Jobe A.H., Stock S.J. The clinical use of corticosteroids in pregnancy. Hum. Reprod. Update. 2016;22:240–259. doi: 10.1093/humupd/dmv047. PubMed DOI

Giulini S., Grisendi V., Sighinolfi G., Di Vinci P., Tagliasacchi D., Botticelli L., La Marca A., Facchinetti F. Chronic endometritis in recurrent implantation failure: Use of prednisone and IVF outcome. J. Reprod. Immunol. 2022;153:103673. doi: 10.1016/j.jri.2022.103673. PubMed DOI

Hart R.J. Nutritional supplements and IVF: An evidence-based approach. Reprod. Biomed. Online. 2023;48:103770. doi: 10.1016/j.rbmo.2023.103770. PubMed DOI

Piekarska K., Dratwa M., Radwan P., Radwan M., Bogunia-Kubik K., Nowak I. Pro- and anti-inflammatory cytokines and growth factors in patients undergoing in vitro fertilization procedure treated with prednisone. Front. Immunol. 2023;14:1250488. doi: 10.3389/fimmu.2023.1250488. PubMed DOI PMC

Su Q., Pan Z., Yin R., Li X. The value of G-CSF in women experienced at least one implantation failure: A systematic review and meta-analysis. Front. Endocrinol. 2024;15:1370114. doi: 10.3389/fendo.2024.1370114. PubMed DOI PMC

Yao K., Sun Y., Ye X., Wu Y. Interferon-λ contributes to endometrial receptivity. Reproduction. 2023;165:569–582. doi: 10.1530/REP-22-0463. PubMed DOI

Nnamonu E.I., Mgbenka B.O., Mbegbu E.C. Impact of omega-3 fatty acids preconception intake on some fertility parameters and foetuses quality of female rats. Iran. J. Vet. Res. 2020;21:115–119. PubMed PMC

Trop-Steinberg S., Gal M., Azar Y., Kilav-Levin R., Heifetz E.M. Effect of omega-3 supplements or diets on fertility in women: A meta-analysis. Heliyon. 2024;10:e29324. doi: 10.1016/j.heliyon.2024.e29324. PubMed DOI PMC

Mu F., Huo H., Wang M., Wang F. Omega-3 fatty acid supplements and recurrent miscarriage: A perspective on potential mechanisms and clinical evidence. Food Sci. Nutr. 2023;11:4460–4471. doi: 10.1002/fsn3.3464. PubMed DOI PMC

Kello N., Cho Y.M. Natural supplements in antiphospholipid syndrome: A case for further study. Clin. Immunol. 2024;258:109848. doi: 10.1016/j.clim.2023.109848. PubMed DOI

Chen P., Yang M., Chen R., Chen P., Chen L., Fang C., Li T. Endometrial microbial alterations disrupt endometrial immune homeostasis by overactivation of Eicosapentaenoic acid biosynthesis leading to altered endometrial receptivity. J. Reprod. Immunol. 2023;155:103787. doi: 10.1016/j.jri.2022.103787. PubMed DOI

Izadifar Z., Cotton J., Chen S., Horvath V., Stejskalova A., Gulati A., LoGrande N.T., Budnik B., Shahriar S., Doherty E.R., et al. Mucus production, host-microbiome interactions, hormone sensitivity, and innate immune responses modeled in human cervix chips. Nat. Commun. 2024;15:4578. doi: 10.1038/s41467-024-48910-0. PubMed DOI PMC

Endometriosis: An Immunologist's Perspective

Exploring the Immunological Aspects and Treatments of Recurrent Pregnancy Loss and Recurrent Implantation Failure