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Microbiome analysis flowchart
The uterine microbiome is the commensal, nonpathogenic, bacteria, viruses, yeasts/fungi present in a healthy uterus, amniotic fluid and endometrium and the specific environment which they inhabit. It has been only recently confirmed that the uterus and its tissues are not sterile.[1] Due to improved 16S rRNA genesequencing techniques, detection of bacteria that are present in low numbers is possible.[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]
In 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
Bacteria, 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]
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:
Prophylactic 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
The immune response becomes more pronounced when bacteria are found that are not commensal.[5]
History
Investigations 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
Investigations 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.
Bar chart demonstrating increased publications focusing on the uterine microbiome. A search keyword of “uterine microbiome” was used on Web of Science, and this bar chart only included articles and review papers. The date range of this search is from January 1, 2013 to March 26, 2024.
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]
1 2 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.
The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional layer thickens and then is shed during menstruation in humans and some other mammals, including other apes, Old World monkeys, some species of bat, the elephant shrew and the Cairo spiny mouse. In most other mammals, the endometrium is reabsorbed in the estrous cycle. During pregnancy, the glands and blood vessels in the endometrium further increase in size and number. Vascular spaces fuse and become interconnected, forming the placenta, which supplies oxygen and nutrition to the embryo and fetus. The speculated presence of an endometrial microbiota has been argued against.
The uterus or womb is the organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic and fetal development of one or more embryos until birth. The uterus is a hormone-responsive sex organ that contains glands in its lining that secrete uterine milk for embryonic nourishment.
The human microbiome is the aggregate of all microbiota that reside on or within human tissues and biofluids along with the corresponding anatomical sites in which they reside, including the gastrointestinal tract, skin, mammary glands, seminal fluid, uterus, ovarian follicles, lung, saliva, oral mucosa, conjunctiva, and the biliary tract. Types of human microbiota include bacteria, archaea, fungi, protists, and viruses. Though micro-animals can also live on the human body, they are typically excluded from this definition. In the context of genomics, the term human microbiome is sometimes used to refer to the collective genomes of resident microorganisms; however, the term human metagenome has the same meaning.
Ureaplasma urealyticum is a bacterium belonging to the genus Ureaplasma and the family Mycoplasmataceae in the order Mycoplasmatales. This family consists of the genera Mycoplasma and Ureaplasma. Its type strain is T960. There are two known biovars of this species; T960 and 27. These strains of bacteria are commonly found as commensals in the urogenital tracts of human beings, but overgrowth can lead to infections that cause the patient discomfort. Unlike most bacteria, Ureaplasma urealyticum lacks a cell wall making it unique in physiology and medical treatment.
Adenomyosis is a medical condition characterized by the growth of cells that proliferate on the inside of the uterus (endometrium) atypically located among the cells of the uterine wall (myometrium), as a result, thickening of the uterus occurs. As well as being misplaced in patients with this condition, endometrial tissue is completely functional. The tissue thickens, sheds and bleeds during every menstrual cycle.
Vaginal bleeding is any expulsion of blood from the vagina. This bleeding may originate from the uterus, vaginal wall, or cervix. Generally, it is either part of a normal menstrual cycle or is caused by hormonal or other problems of the reproductive system, such as abnormal uterine bleeding.
Endometritis is inflammation of the inner lining of the uterus (endometrium). Symptoms may include fever, lower abdominal pain, and abnormal vaginal bleeding or discharge. It is the most common cause of infection after childbirth. It is also part of spectrum of diseases that make up pelvic inflammatory disease.
Implantation, also known as nidation, is the stage in the embryonic development of mammals in which the blastocyst hatches, attaches, adheres, and invades into the wall of the female's uterus. Implantation is the first stage of gestation, and, when successful, the female is considered to be pregnant. An implanted embryo is detected by the presence of increased levels of human chorionic gonadotropin (hCG) in a pregnancy test. The implanted embryo will receive oxygen and nutrients in order to grow.
Vaginal flora, vaginal microbiota or vaginal microbiome are the microorganisms that colonize the vagina. They were discovered by the German gynecologist Albert Döderlein in 1892 and are part of the overall human flora. The amount and type of bacteria present have significant implications for an individual's overall health. The primary colonizing bacteria of a healthy individual are of the genus Lactobacillus, such as L. crispatus, and the lactic acid they produce is thought to protect against infection by pathogenic species.
A cervical mucus plug (operculum) is a plug that fills and seals the cervical canal during pregnancy. It is formed by a small amount of cervical mucus that condenses to form a cervical mucus plug during pregnancy.
Female genital disease is a disorder of the structure or function of the female reproductive system that has a known cause and a distinctive group of symptoms, signs, or anatomical changes. The female reproductive system consists of the ovaries, fallopian tubes, uterus, vagina, and vulva. Female genital diseases can be classified by affected location or by type of disease, such as malformation, inflammation, or infection.
Müllerian duct anomalies are those structural anomalies caused by errors in Müllerian duct development during embryonic morphogenesis. Factors that precipitate include genetics, and maternal exposure to teratogens.
The initial acquisition of microbiota is the formation of an organism's microbiota immediately before and after birth. The microbiota are all the microorganisms including bacteria, archaea and fungi that colonize the organism. The microbiome is another term for microbiota or can refer to the collected genomes.
The vaginal flora in pregnancy, or vaginal microbiota in pregnancy, is different from the vaginal flora before sexual maturity, during reproductive years, and after menopause. A description of the vaginal flora of pregnant women who are immunocompromised is not covered in this article. The composition of the vaginal flora significantly differs in pregnancy. Bacteria or viruses that are infectious most often have no symptoms.
A t-shaped uterus is a type of uterine malformation wherein the uterus is shaped resembling the letter T. This is typically observed in DES-exposed women. It is recognised in the ESHRE/ESGE classification, and is associated with failed implantation, increased risk of ectopic pregnancy, miscarriage and preterm delivery. There is a surgical procedure to correct the malformation.
The Human Microbiome Project (HMP), completed in 2012, laid the foundation for further investigation into the role the microbiome plays in overall health and disease. One area of particular interest is the role which delivery mode plays in the development of the infant/neonate microbiome and what potential implications this may have long term. It has been found that infants born via vaginal delivery have microbiomes closely mirroring that of the mother's vaginal microbiome, whereas those born via cesarean section tend to resemble that of the mother's skin. One notable study from 2010 illustrated an abundance of Lactobacillus and other typical vaginal genera in stool samples of infants born via vaginal delivery and an abundance of Staphylococcus and Corynebacterium, commonly found on the skin surfaces, in stool samples of infants born via cesarean section. From these discoveries came the concept of vaginal seeding, also known as microbirthing, which is a procedure whereby vaginal fluids are applied to a new-born child delivered by caesarean section. The idea of vaginal seeding was explored in 2015 after Maria Gloria Dominguez-Bello discovered that birth by caesarean section significantly altered the newborn child's microbiome compared to that of natural birth. The purpose of the technique is to recreate the natural transfer of bacteria that the baby gets during a vaginal birth. It involves placing swabs in the mother's vagina, and then wiping them onto the baby's face, mouth, eyes and skin. Due to the long-drawn nature of studying the impact of vaginal seeding, there are a limited number of studies available that support or refute its use. The evidence suggests that applying microbes from the mother's vaginal canal to the baby after cesarean section may aid in the partial restoration of the infant's natural gut microbiome with an increased likelihood of pathogenic infection to the child via vertical transmission.
The placental microbiome is the nonpathogenic, commensal bacteria claimed to be present in a healthy human placenta and is distinct from bacteria that cause infection and preterm birth in chorioamnionitis. Until recently, the healthy placenta was considered to be a sterile organ but now genera and species have been identified that reside in the basal layer.
Repeated implantation failure (RIF) is the repeated failure of the embryo to implant onto the side of the uterus wall following IVF treatment. Implantation happens at 6–7 days after conception and involves the embedding of the growing embryo into the mothers uterus and a connection being formed. A successful implantation can be determined by using an ultrasound to view the sac which the baby grows in, inside the uterus.
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