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The uterine microbiome refers to the community of commensal, nonpathogenic microorganisms—including bacteria, viruses, and yeasts/fungi—present in a healthy uterus, as well as in the amniotic fluid and endometrium. These microorganisms coexist in a specific environment within the uterus, playing a vital role in maintaining reproductive health.[1] In the past, the uterus was believed to be a sterile environment, free of any microbial life. Recent advancements in microbiological research, particularly the improvement of 16S rRNA gene sequencing techniques, have challenged this long-held belief. These advanced techniques have made it possible to detect bacteria and other microorganisms present in very low numbers.[2] Using this procedure that allows the detection of bacteria that cannot be cultured outside the body, studies of microbiota present in the uterus are expected to increase.[3]
Uterine microbiome and fertility
editIn the past, the uterine cavity had been traditionally considered to be sterile, but potentially susceptible to be affected by vaginal bacteria. However, this idea has been disproved. Moreover, it's been shown that endometrial and vaginal microbiota can differ in structure and composition in some women.
The microbiome of the innermost layer of the uterus, the endometrium, may influence its capacity to allow an embryo to implant. The existence of more than 10% of non-Lactobacillus bacteria in the endometrium is correlated with negative impacts on reproductive function and should be considered as an emerging cause of implantation failure and pregnancy loss.[4]
Characteristics
editBacteria, viruses and one genus of yeasts are a normal part of the uterus before and during pregnancy.[5] The uterus has been found to possess its own characteristic microbiome that differs significantly from the vaginal microbiome, consisting primarily of lactobacillus species, and at far fewer numbers.[6] In addition, the immune system is able to differentiate between those bacteria normally found in the uterus and those that are pathogenic. Hormonal changes have an effect on the microbiota of the uterus.[7]
Taxa
edit
Commensals
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The organisms listed below have been identified as commensals in the healthy uterus. Some also have the potential for growing to the point of causing disease:
Organism Commensal Transient Potential
pathogenReferences Escherichia coli x x [7] Escherichia spp. x x [7] Ureaplasma parvum x x [7] Fusobacterium nucleatum x [8] Prevotella tannerae x [5] Bacteroides spp. x [5] Streptomyces avermitilis x [7] Mycoplasma spp. x x [5] Neisseria lactamica x [7] Neisseria polysaccharea x [7] Epstein–Barr virus x x [5] Respiratory syncytial virus x x [5] Adenovirus x x [5] Candida spp. x x [5]
Pathogens
editOther taxa can be present, without causing disease or an immune response. Their presence is associated with negative birth outcomes.[5][7]
Pathogenic organism Increased risk of References Ureaplasma urealyticum Premature, preterm rupture of membranes
Preterm labor
cesarean section
Placental inflammation
Congenital pneumonia
bacteremia
meningitis
fetal lung injury
death of infant[5][9][10] Ureaplasma parvum [5] Haemophilus influenzae Premature, preterm rupture of membranes
preterm labor
preterm birthFusobacterium nucleatum Prevotella tannerae Bacteroides spp. Streptomyces avermitilis Mycoplasma hominis Congenital pneumonia
bacteremia
meningitis
<pelvic inflammatory disease
postpartum or postabortal fever[5][9] Neisseria lactamica [5] Neisseria polysaccharea Epstein–Barr virus Respiratory syncytial virus Adenovirus Candida spp. Atopobium spp. Unsuccessful reproductive outcomes in infertile patients (no pregnancy or clinical miscarriage) [11] Bifidobacterium spp. Chryseobacterium spp. Gardnerella spp. Klebsiella spp. Staphylococcus spp. Haemophilus spp. Streptomyces spp. Neisseria spp.
Clinical significance
editProphylactic antibiotics have been injected into the uterus to treat infertility. This has been done before the transfer of embryos with the intent to improve implantation rates. No association exists between successful implantation and antibiotic treatment.[12] Infertility treatments often progress to the point where a microbiological analysis of the uterine microbiota is performed. Preterm birth is associated with certain species of bacteria that are not normally part of the healthy uterine microbiome.[5]
The uterine microbiome appears to be altered in female patients who experience endometrial cancer, endometriosis, chronic endometriosis, and related gynecological pathologies, suggesting the clinical relevance of the uterine microbiome’s composition.[13] Next-generation sequencing has revealed the presence of certain bacterial taxa, such as Alteromonas, to be present in patients presenting with gynecological conditions.[14]
Clinically speaking, there is no universal protocol on how to treat uterine dysbiosis. However, use of antibiotics has been widespread. In the context of infertility, researchers have studied the effects of a treatment plan of antibiotics in conjunction with prebiotics and probiotics to increase Lactobacillus colonization in the endometrium. It was found that, while there was a Lactobacillus-dominated endometrium correlated with increased pregnancy rates, the data was not statistically significant. [15] Antibiotics have also been used to treat chronic endometritis and endometriosis.[13]
Interestingly, a link between the oral microbiome and the uterine microbiome has been uncovered. Fusobacterium nucleatum, a Gram-negative bacteria commensal to the oral microbiome, is associated with periodontal disease and has been linked with a wide variety of health outcomes, including unfavorable pregnancy outcomes.[16] [17]
Immune response
editThe immune response becomes more pronounced when bacteria are found that are not commensal.[5]
History
editInvestigations into reproductive-associated microbiomes began around 1885 by Theodor Escherich. He wrote that meconium from the newborn was free of bacteria. There was a general consensus at the time and even recently that the uterus was sterile and this was referred to as the sterile womb paradigm. Other investigations used sterile diapers for meconium collection. No bacteria were able to be cultured from the samples. Other studies showed that bacteria were detected and were directly proportional to the time between birth and the passage of meconium.[1]
Research
editInvestigations into the role of the uterine microbiome in the development of the infant microbiome are ongoing.[1] In recent years, the number of articles and review publications discussing the uterine microbiome has grown. Based on a Web of Science analysis, the highest number of documents published on the topic was in 2023, with a total of 23 papers.
The Daunert Lab, based at the University of Miami’s Sylvester Comprehensive Cancer Center, focuses on the role of the microbiome in endometrial cancer and the role the uterine microbiome plays in the success of an IVF cycle. Similarly, Dr. Maria Walther-Antonio’s lab at the Mayo Clinic focuses on the microbiome’s role in endometrial cancer. Notably, Dr. Walther- Antonio has confirmed that Porphyromas somerae is able to invade endometrial cells, indicating a possibility that this microbe contributes to the pathogenesis of endometrial cancer.[18]
The Carlos Simon Foundation, based in Valencia, Spain, is an women’s health research organization founded by reproductive endocrinologist Carlos Simon, MD PhD. A research team led by Dr. Inmaculada Moreno at the Carlos Simon Foundation studies the role of the endometrial microbiome in human reproduction. When research on the uterine microbiome was scarce, Dr. Moreno and her team analyzed the endometrial microbiota and discovered that there was a correlation between certain endometrial microbiota compositions and the outcome of implantation success or failure.[4] Six years later, they followed up with a paper revealing that specific pathogenic bacteria and depletion of Lactobacillus spp. in the endometrium correlated with impaired fertility.[11]
See also
editReferences and notes
edit- ^ a b c Perez-Muñoz, Maria Elisa; Arrieta, Marie-Claire; Ramer-Tait, Amanda E.; Walter, Jens (2017). "A critical assessment of the "sterile womb" and "in utero colonization" hypotheses: implications for research on the pioneer infant microbiome". Microbiome. 5 (1): 48. doi:10.1186/s40168-017-0268-4. ISSN 2049-2618. PMC 5410102. PMID 28454555.
- ^ Verstraelen, Hans; Vilchez-Vargas, Ramiro; Desimpel, Fabian; Jauregui, Ruy; Vankeirsbilck, Nele; Weyers, Steven; Verhelst, Rita; De Sutter, Petra; Pieper, Dietmar H.; Van De Wiele, Tom (2016). "Characterisation of the human uterine microbiome in non-pregnant women through deep sequencing of the V1-2 region of the 16S rRNA gene". PeerJ. 4: e1602. doi:10.7717/peerj.1602. ISSN 2167-8359. PMC 4730988. PMID 26823997.
- ^ Wassenaar, T.M.; Panigrahi, P. (2014). "Is a foetus developing in a sterile environment?". Letters in Applied Microbiology. 59 (6): 572–579. doi:10.1111/lam.12334. ISSN 0266-8254. PMID 25273890. S2CID 206169539.
- ^ a b Moreno I, Codoñer FM, Vilella F, Valbuena D, Martinez-Blanch JF, Jimenez-Almazán J, Alonso R, Alamá P, Remohí J, Pellicer A, Ramon D, Simon C. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol. 2016 Dec;215(6):684-703. doi: 10.1016/j.ajog.2016.09.075.
- ^ a b c d e f g h i j k l m n o Payne, Matthew S.; Bayatibojakhi, Sara (2014). "Exploring Preterm Birth as a Polymicrobial Disease: An Overview of the Uterine Microbiome". Frontiers in Immunology. 5: 595. doi:10.3389/fimmu.2014.00595. ISSN 1664-3224. PMC 4245917. PMID 25505898.
- ^ Elnashar, Aboubakr Mohamed (2021-01-13). "Impact of endometrial microbiome on fertility". Middle East Fertility Society Journal. 26 (1): 4. doi:10.1186/s43043-020-00050-3. ISSN 2090-3251. S2CID 231671185.
- ^ a b c d e f g h Yarbrough, V. L.; Winkle, S.; Herbst-Kralovetz, M. M. (2014). "Antimicrobial peptides in the female reproductive tract: a critical component of the mucosal immune barrier with physiological and clinical implications". Human Reproduction Update. 21 (3): 353–377. doi:10.1093/humupd/dmu065. ISSN 1355-4786. PMID 25547201.
- ^ Prince, Amanda L.; Antony, Kathleen M.; Chu, Derrick M.; Aagaard, Kjersti M. (2014). "The microbiome, parturition, and timing of birth: more questions than answers". Journal of Reproductive Immunology. 104–105: 12–19. doi:10.1016/j.jri.2014.03.006. ISSN 0165-0378. PMC 4157949. PMID 24793619.
- ^ a b "Ureaplasma Infection: Background, Pathophysiology, Epidemiology". eMedicine. 17 November 2017. Retrieved 7 December 2017.
- ^ Pryhuber, Gloria S. (2015). "Postnatal Infections and Immunology Affecting Chronic Lung Disease of Prematurity". Clinics in Perinatology. 42 (4): 697–718. doi:10.1016/j.clp.2015.08.002. ISSN 0095-5108. PMC 4660246. PMID 26593074.
- ^ a b Moreno, Inmaculada; Garcia-Grau, Iolanda; Perez-Villaroya, David; Gonzalez-Monfort, Marta; Bahçeci, Mustafa; Barrionuevo, Marcelo J.; Taguchi, Sagiri; Puente, Elena; Dimattina, Michael; Lim, Mei Wei; Meneghini, Georgina; Aubuchon, Mira; Leondires, Mark; Izquierdo, Alexandra; Perez-Olgiati, Martina (2022-01-04). "Endometrial microbiota composition is associated with reproductive outcome in infertile patients". Microbiome. 10 (1): 1. doi:10.1186/s40168-021-01184-w. ISSN 2049-2618. PMC 8725275. PMID 34980280.
- ^ Franasiak, Jason M.; Scott, Richard T. (2015). "Reproductive tract microbiome in assisted reproductive technologies". Fertility and Sterility. 104 (6): 1364–1371. doi:10.1016/j.fertnstert.2015.10.012. ISSN 0015-0282. PMID 26597628.
- ^ a b Molina, Nerea M.; Sola-Leyva, Alberto; Saez-Lara, Maria Jose; Plaza-Diaz, Julio; Tubić-Pavlović, Aleksandra; Romero, Barbara; Clavero, Ana; Mozas-Moreno, Juan; Fontes, Juan; Altmäe, Signe (2020-04-11). "New Opportunities for Endometrial Health by Modifying Uterine Microbial Composition: Present or Future?". Biomolecules. 10 (4): 593. doi:10.3390/biom10040593. ISSN 2218-273X. PMC 7226034. PMID 32290428.
- ^ Fang, Rui-Li; Chen, Lin-Xing; Shu, Wen-Sheng; Yao, Shu-Zhong; Wang, Si-Wen; Chen, Yu-Qing (2016). "Barcoded sequencing reveals diverse intrauterine microbiomes in patients suffering with endometrial polyps". American Journal of Translational Research. 8 (3): 1581–1592. ISSN 1943-8141. PMC 4859642. PMID 27186283.
- ^ Kyono, Koichi; Hashimoto, Tomoko; Kikuchi, Suguru; Nagai, Yoko; Sakuraba, Yoshiyuki (January 2019). "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". Reproductive Medicine and Biology. 18 (1): 72–82. doi:10.1002/rmb2.12250. ISSN 1445-5781. PMC 6332758. PMID 30655724.
- ^ Bearfield, Caroline; Davenport, Elizabeth S.; Sivapathasundaram, Vythil; Allaker, Robert P. (May 2002). "Possible association between amniotic fluid micro-organism infection and microflora in the mouth". BJOG: An International Journal of Obstetrics and Gynaecology. 109 (5): 527–533. doi:10.1111/j.1471-0528.2002.01349.x. ISSN 1470-0328. PMID 12066942.
- ^ Han, Yiping W.; Redline, Raymond W.; Li, Mei; Yin, Lihong; Hill, Gale B.; McCormick, Thomas S. (April 2004). "Fusobacterium nucleatum Induces Premature and Term Stillbirths in Pregnant Mice: Implication of Oral Bacteria in Preterm Birth". Infection and Immunity. 72 (4): 2272–2279. doi:10.1128/IAI.72.4.2272-2279.2004. ISSN 0019-9567. PMC 375172. PMID 15039352.
- ^ Crooks, Taylor A.; Madison, Joseph D.; Walsh, Dana M.; Herbert, William G.; Jeraldo, Patricio R.; Chia, Nicholas; Cliby, William A.; Kaufmann, Scott H.; Walther-Antonio, Marina R. S. (2021). "Porphyromonas somerae Invasion of Endometrial Cancer Cells". Frontiers in Microbiology. 12. doi:10.3389/fmicb.2021.674835. ISSN 1664-302X. PMC 8343132. PMID 34367083.