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Evidence That the Endometrial Microbiota Has an Effect on Implantation Success or Failure
Abstract
(Abstracted from Am J Obstet Gynecol 2016;215(6):684–703)
In 2002, the vaginal microbiota was first identified using molecular methods that allowed detection of nonculturable bacteria. Alterations in vaginal microbiota could have clinical implications for reproductive and obstetric processes.
... Endometrial microbiome is one new topic in reproductive medicine (1)(2)(3)(4)(5). The endometrium and the vagina have unique separate microbiomes, although there is communication between these anatomical niches (5,6). ...
... Recent research suggests that the endometrial microbiome is essential in vitro fertilisation (IVF) success. The endometrial microbiome, its composition, and the quantity of some bacteria could be predictors of suc-cessful implantation in IVF treatment (2,4). Moreno et al. (3) reported that Lactobacillus negatively correlates with the appearance of pathogenic bacteria and positively correlates with the appearance of commensal bacteria, which may contribute to the stability of the endometrial ecosystem. ...
... In the study of Mitchell et al. (23), Lactobacillus spp was the most abundant bacteria in the endometrial cavity. A later study by Morenno et al. (2) reported a better implantation rate and a lower rate of spontaneous abortions in Lactobacillus dominant endometrium. Kyono et al. (24) and Hashimoto and Kyono (4) failed to confirm earlier suggested claims about the benefit of Lactobacillus dominant endometrium. ...
Background
The endometrial microbiome, its composition, and the quantity of some bacteria could be predictors of successful implantation in vitro fertilisation (IVF) treatment. The presence of Lactobacillus, which negatively correlates with pathogenic bacteria, could be a contributing factor to endometrial ecosystem stability. The study aimed to determine whether the quantity of Lactobacillus spp and Gardnerella vaginalis in the endometrium depends on estrogen levels. A secondary aim was to determine whether the decreased number of Lactobacillus spp leads to increased pathogenic bacteria such as Gardnerella vaginalis in the endometrial cavity.
Materials and Methods
This prospective study was conducted in a private IVF center in Tuzla, Bosnia and Herzegovina. Participants were recruited from February 2023 to December 2023. The tip of a double-lumen catheter was used to collect samples from the endometrium. QIAamp DNA Mini Kit was used for DNA isolation. A commercial real-time polymerase chain reaction (RT-PCR) kit was used to detect Lactobacillus spp and Gardnerella vaginalis quantitatively.
Results
In total, 92 participants were included in the study, 57 in the fresh cycle and 35 in the frozen cycle of IVF. The youngest participant was 18 years old, and the oldest was 45 years old. The mean age of participants was 34.3 years with a standard deviation of 5.7. After RT-PCR, 90 participants had positive tests on Lactobacillus spp, Gardnerella vaginalis was positive in 31 participants.
Conclusion
Supraphysiological estrogen levels do not significantly change the quantity of Lactobacillus spp and Gardnerella vaginalis in the endometrial cavity. Decreasing the number of Lactobacillus spp increased the number of pathogenic bacteria Gardnerella vaginalis in the endometrial cavity.
... and Prevotela spp. (24). In 96.7% of our patients LS was found in the endometrium, which correlates with the results of other research (92%) (24). ...
... (24). In 96.7% of our patients LS was found in the endometrium, which correlates with the results of other research (92%) (24). Some authors reported LS were presented in more than 80% of patients (2). ...
... The increase in the abundance of LS may represent a physiological phenomenon that positively modulates endometrial receptivity, which is certainly reduced due to older age. Lactobacillus domination in endometrial cavity has been linked with better implantation and pregnancy rate (24). The other study found no benefit from Lactobacillus dominance in the endometrial cavity (30). ...
Aim To investigate an influence of age and body mass index (BMI) as determinants of infertility treatment success in vitro fertilization (IVF) procedures confirmed so far, on the amount of Lactobacillus spp. (LS) and Gardnerella vaginalis (GV) in the endometrium in fresh IVF cycles at the time of embryo transfer.
Methods This a prospective single-centre study included patients who underwent fresh embryo transfer (ET) in a private IVF Centre. A catheter tip for embryo transfer was used for collecting samples from the endometrial cavity. Real time polymerase chain reaction (RT PCR) was used to determine LS and GV quantity. Patients were divided into two age groups: <35 years and ≥35 years. Normal BMI group included patients with 18.-24.9 kg/m2, and the in-creased BMI group patients with BMI ≥ 25kg/m2.
Results Tips for embryo transfer catheters were positive on LS in 55 (96.4%) patients. The median of quantification cycle of RT-PCR (Cq RT-PCR) for LS was 33, and 31 for the younger and older groups, respectively. Twenty-one (36.8%) patients tested positive for GV. The median of Cq RT-PCR for GV was 33 and 34 for the younger and older groups, respectively. There were 36 patients with normal and 18 with increased BMI. BMI showed no correlation with LS amount in the endometrial cavity.
Conclusion Aging affects the endome-trial microbiome resulting in an increase of Lactobacillus number, but not the number of GV.
... The sterile womb dogma has been recently challenged with the advent of sensitive molecular tools, including bacterial 16S rRNA gene profiling, which enables the identification of microbes that were considered uncultivable [16]. Although recent studies report the detection of metataxonomic signatures in 60-97% of non-malignant uteri [17][18][19][20][21][22][23][24], experimental design pitfalls have often failed to account for potential sources of contamination, including niche-to-niche contamination caused by transcervical sample collection or non-patient sources from airborne and "kitome" contaminants [25][26][27]. There is currently no consensus on a benign endometrial bacterial signature although commonly reported genera include Lactobacillus, Prevotella, Gardnerella, Bifidobacterium, Staphylococcus, and Streptococcus [18][19][20][21][22][23][24][28][29][30][31]. ...
... Although recent studies report the detection of metataxonomic signatures in 60-97% of non-malignant uteri [17][18][19][20][21][22][23][24], experimental design pitfalls have often failed to account for potential sources of contamination, including niche-to-niche contamination caused by transcervical sample collection or non-patient sources from airborne and "kitome" contaminants [25][26][27]. There is currently no consensus on a benign endometrial bacterial signature although commonly reported genera include Lactobacillus, Prevotella, Gardnerella, Bifidobacterium, Staphylococcus, and Streptococcus [18][19][20][21][22][23][24][28][29][30][31]. Intra-individual microbial correlations between the lower and upper genital tract, consistent with anatomical contingency, have recently been reported by Chen and colleagues [28]. ...
... Microbiome (2024) 12:118 Fusobacterium, Bacteroides and Peptoniphilus, which is in keeping with previous studies [10,11]. Lactobacillus reduction lends support to the more broadly described association between Lactobacillus depletion and adverse gynaecological and obstetric outcomes, including cervical cancer and precancerous lesions [13] as well as miscarriages [48], preterm labour [49] and in vitro fertilisation failure [24]. The biological significance of Lactobacillus communities includes pathogen antagonism by lactic acid, hydrogen peroxide and bacteriocin production but also immune and metabolic pathways as well as epigenetic regulation [50][51][52][53][54][55][56][57][58][59]. ...
Background
Endometrial cancer is a multifactorial disease with inflammatory, metabolic and potentially microbial cues involved in disease pathogenesis. The endometrial cancer microbiome has been poorly characterised so far and studies have often overestimated bacterial biomass due to lack of integration of appropriate contamination controls. There is also a scarcity of evidence on the functionality of microbial microenvironments in endometrial cancer. This work addresses that knowledge gap by interrogating the genuine, contamination-free microbial signatures in the female genital tract and rectum of women with endometrial cancer and the mechanistic role of microbiome on carcinogenic processes.
Results
Here we sampled different regions of the reproductive tract (vagina, cervix, endometrium, fallopian tubes and ovaries) and rectum of 61 patients (37 endometrial cancer; 24 benign controls). We performed 16S rRNA gene sequencing of the V1–V2 hypervariable regions and qPCR of the 16S rRNA gene to qualitatively and quantitatively assess microbial communities and used 3D benign and endometrial cancer organoids to evaluate the effect of microbial products of L. crispatus, which was found depleted in endometrial cancer patients following primary analysis, on endometrial cell proliferation and inflammation. We found that the upper genital tract of a subset of women with and without endometrial cancer harbour microbiota quantitatively and compositionally distinguishable from background contaminants. Endometrial cancer was associated with reduced cervicovaginal and rectal bacterial load together with depletion of Lactobacillus species relative abundance, including L. crispatus, increased bacterial diversity and enrichment of Porphyromonas, Prevotella, Peptoniphilus and Anaerococcus in the lower genital tract and endometrium. Treatment of benign and malignant endometrial organoids with L. crispatus conditioned media exerted an anti-proliferative effect at high concentrations but had minimal impact on cytokine and chemokine profiles.
Conclusions
Our findings provide evidence that the upper female reproductive tract of some women contains detectable levels of bacteria, the composition of which is associated with endometrial cancer. Whether this is a cause or consequence of cancer pathophysiology and what is the functional significance of this finding remain to be elucidated to guide future screening tools and microbiome-based therapeutics.
7srhokZSHNZrvrGZNmjDS4Video Abstract
... The most commonly discussed hypothesis is the 'lactobacillary' and 'nonlactobacillary' microbiome in the endometrium (Moreno et al., 2016). This means that the dominance of lactobacillus (relative abundance is more than 90%) within the microbiota contents of the endometrium was generally associated with a successful implantation and a high frequency of live-borns in patients having undergone in-vitro-fertilization ( This study aimed to assess the uterine microbiome in women with infertility who have experienced numerous failed attempts of in-vitrofertilization and healthy fertile women without an obstetric or gynecological history who had at least one successful vaginal delivery. ...
... In 7 out of 20 women from the group of women with invitro-fertilization failures (Figure 4). The absolute dominance of Lactobacillusmore than 90%was noted in a total of three women out of the entire sample (35 patients), which does not correlate with Moreno's data (Moreno et al., 2016). ...
... Lactobacillus in Group I patients did not differ significantly from the abundance of Lactobacilli in patients of Group II (33.3% and 29.4%, respectively). Also, it is not possible to make confident conclusions about the dominance of Lactobacillus over 90% in the composition of the uterine microbiome in healthy women, as Moreno claims from his observations(Moreno et al., 2016;Kyono et al., 2018). The category 'other ...
Background: Thanks to new diagnostic technologies, it is of no doubt that the uterus is no longer considered to be sterile. A disturbed microbiome of endometrium can be a significant reason for preterm birth, infertility, the recurrence of pregnancy loss, and repeated implantation failures in in-vitro-fertilization programs. Aim: Study the endometrial microbiome features in healthy fertile women and in women with multiple in-vitro-fertilization failures. Methods: To assess the differences in the endometrial microbiota of 20 women with infertility and experiencing multiple unsuccessful attempts of in-vitro-fertilization and 15 fertile, healthy women, endometrial microbiome was studied using an NGS of 16S rRNA. Results and Discussion: Lactobacillus (29.4%), Comamonas (16.8%), and Mesorhizobium (6.0%) were the most abundant genera in group of healthy fertile patients, and Lactobacillus (33.3%), Ralstonia (7.9%) and Pediococcus (4.8%) were most abundant in the group of infertile patients. The mean relative abundance of Lactobacillus did not significantly differ between groups and comprised 33.3% in the group of infertile women and 29.4% in healthy fertile women. A considerably higher mean relative abundance of bacteria of the genus Brevundimonas and Ralstonia was recorded in the group of infertile women. The fertile women had a statistically significantly higher mean relative abundance of Acidovorax, Brevibacillus, Caulobacter, Comamonas, Delftia, Distigma, Pseudomonas, Schlegelella, and Thermus. Conclusions: The presented data confirm that endometrium is not a sterile tissue despite long-standing concepts concerning its sterility. Lactobacillus are dominant genera; however, there is no absolute dominance of Lactobacillus over 90%. The mean relative abundance of Lactobacillus in the uterine microbiome in fertile patients and patients with multiple in-vitro-fertilization failures did not differ.
... Gardnerella was present in the vagina but not in the endometrium of certain individuals. It also demonstrated that the endometrial microbiota is different from the vagina and is not a carry-over [31]. ...
... In our review, all of the studies showed the absence of lactobacilli predominance in the endometrium to be associated with infertility [31][32][33][34][35]. On the other hand, in women with infertility, there was evidence of an infection with chlamydia, mycobacterium tuberculosis, garderenella or E. coli in the cervix [5,[36][37][38][39][40]. ...
... There were a few studies demonstrating the association of endometrial microbiota with infertility. It was suggested by a total of 679 infertile women through five studies that low lactobacilli growth in endometrial microbiota was associated with infertility [31][32][33][34][35]. ...
The balance between different bacterial species is essential for optimal vaginal health. Microbiome includes the host genome along with microorganism genomes and incorporates the biotic and abiotic factors, reflecting the habitat as a whole. A significant difference exists in the composition and number of the human microbiota in healthy individuals. About one-tenth of the total body microbiota exists in the urogenital tract and these can be identified by microscopy and culture-based methods, quantitative PCR, next generation and whole genome sequencing. The trend of delaying the planning of pregnancy to a later age nowadays has resulted in magnifying the use of assisted reproductive treatment (ART). Hence, genital microbiota and its impact on fertility has generated immense interest in recent years. In this systematic review, we searched the available evidence on the microbiota of the genital tract in women undergoing ART and studied the outcomes of IVF in different microbial compositions. Despite the inconsistency of the studies, it is evident that vaginal, cervical and endometrial microbiota might play a role in predicting ART outcomes. However, there is no clear evidence yet on whether the diversity, richness, quantity, or composition of species in the maternal genital tract significantly affects the outcomes in ARTs.
... The endometrial microbiome plays an important role in both the health of the endometrium and the emergence of diseases. There are studies 11,12 showing that the profile of the endometrial microbiome changes in patients presenting with implantation failure. Consistent with this, Moreno et al 11 reported that the dominant bacteria in the endometrium of healthy individuals is Lactobacillus spp. ...
... There are studies 11,12 showing that the profile of the endometrial microbiome changes in patients presenting with implantation failure. Consistent with this, Moreno et al 11 reported that the dominant bacteria in the endometrium of healthy individuals is Lactobacillus spp. The high rate of Lactobacillus species in the endometrial flora compared to other pathogens significantly increases implantation and clinical pregnancy rates in IVF/ICSI patients 12 . ...
... In general, the growth of pathogenic bacteria other than Lactobacillus in the endometrium reduces implantation and clinical pregnancy rates. For example, detection of pathogens such as Bifidobacterium, Gardnerella or Streptococcus along with Lactobacillus in the endometrium reduces implantation, clinical pregnancy, and live birth rates, while causing a significant increase in abortion rates 11,13 . Although MRSE is detected with Lactobacilli, the reason for the high pregnancy rates may be related to the colonization rates of bacteria in the endometrium. ...
Objective:
Although host microbiome play a role in both hormonal status and fertility, this issue has not yet been clarified. Since the endometrium is a sterile tissue, it is accepted that microbiota does not grow under normal conditions. The aim of the study was to reveal the characteristics of endometrial microbiota according to serum AMH levels in women with implantation failure.
Patients and methods:
Forty-five women aged 20-30 years with two or more implantation failures were included in the study. They were divided into 3 groups according to their serum AMH values: Group 1 -AMH <1.3 ng/ml; Group 2 - AMH between 1.3-2.6 ng/ml; Group 3 - AMH >2.6 ng/ml. Twenty-two healthy fertile women who were the same age as the infertile group and applied for cervical smear screening were accepted as the control group. Following the embryo transfer, the tip of the catheter was inserted into the transport medium under sterile conditions. Sowing was carried out by touching the tips of the catheter to the blood agar medium. After the evaluation of the petri dishes at the end of 48 hours of incubation, colonies were stained with Gram stain. Microorganisms in the colonies were identified with the Vitek-2 device according to their gram-staining characteristics and their antibiograms were made.
Results:
A negative correlation was detected between low AMH values and the microbiome detection rates in endometrial cultures. In patients with low serum AMH levels, the chance of endometrial microbiota growth was higher in the endometrial culture medium. The most common bacteria were found to be MSSA, MRKNS and lactobacillus. Clinical pregnancy rates were found to be significantly higher in the group with high AMH levels. As AMH levels increased, positive flora detection rates decreased, while clinical pregnancy rates increased.
Conclusions:
Low serum AMH level increases the rate of positive endometrial microbiome in culture and decreases clinical pregnancy rates.
... Meanwhile, the microbiota in the human uterine cavity remains controversial. The comprehensive genome analysis demonstrated the inconsistent results between the studies, ranging from the predominance of Lactobacillus and Bacteroides to other species such as Acinetobacter, Pseudomonas, Cloacibacterium, and Comamonadaceae [3][4][5][6][7][8][9]. ...
... Recently, an increasing number of reports demonstrated an association between female genital tract dysbiosis and poor reproductive outcomes [5][6][7][8][9][10][11][12][13][14]. Moreno et al. [5], disclosed a positive association between Lactobacillusdominant (90% or more) microbiota (LDM) in the vaginal secretions (VS)/endometrial fluid (EF) and successful pregnancy in the following embryo transfer (ET) cycles in infertile women. ...
... Recently, an increasing number of reports demonstrated an association between female genital tract dysbiosis and poor reproductive outcomes [5][6][7][8][9][10][11][12][13][14]. Moreno et al. [5], disclosed a positive association between Lactobacillusdominant (90% or more) microbiota (LDM) in the vaginal secretions (VS)/endometrial fluid (EF) and successful pregnancy in the following embryo transfer (ET) cycles in infertile women. On the contrary, dysbiotic non-LDM (NLDM, 90% or less Lactobacillus species) in VS/EF is associated with recurrent pregnancy loss, preterm birth, and repeated implantation failure (RIF) which occurs in even 5% or more of infertile women undergoing three ET cycles of euploid blastocysts with morphologically normal endometrium [15]. ...
PurposeWe prospectively investigated if oral enteric coating lactoferrin supplementation improves the reproductive outcomes in infertile women with a history of repeated implantation failure (RIF) and non-Lactobacillus-dominant (Lactobacillus rate < 90%) microbiota (NLDM) in vaginal secretions (VS)/endometrial fluid (EF).Methods
Paired VS/EF samples were obtained from RIF women and control infertile women (non-RIF group) for microbiome analysis. Chronic endometritis (CE) was diagnosed histopathologically and hysteroscopically. In a pilot study, oral enteric coating lactoferrin (700 mg/day, at least 28 consecutive days) was administered to eligible patients with NLDM in VS/EF. Their reproductive outcomes in the subsequent vitrified-warmed embryo transfer cycles were followed up.ResultsWhile CE was more prevalent (OR 2.41, 95% CI 1.02–5.63, p = 0.042) in the RIF group (29.1%, n = 117) than in the non-RIF group (14.5%, n = 55), The NLDM rate was similar between the two groups (44.4 vs 52.7%). Lactoferrin supplementation improved NLDM in 43.2% of RIF women (n = 37). Within the RIF group, the live birth rate in the subsequent cycles was higher (OR 10.67, 95% CI 1.03 − 110.0, p = 0.046) in women with improved microbiota (57.1%, n = 14) than in those with unimproved microbiota (11.1%, n = 9).Conclusion
Unlike CE, NLDM was not unique to RIF but was common in infertile women. Although the therapeutic effect of the oral lactoferrin supplementation on NLDM was limited in a pilot study, the reproductive outcomes were better in RIF women who overcame NLDM than in those who failed. Randomized controlled trials are required to confirm the results.Trial registration number and date for prospectively registered trialsUMIN-CTR 000036990, June 7, 2019.
... The uterine cavity has long been thought to be sterile, but recent studies have reported that the endometrium may have a distinct microbiome (Chen et al., 2017;Mitchell et al., 2015;Moreno et al., 2016). As in the vagina, the dominant species in the endometrium are usually lactobacilli (Chen et al., 2017, Oberle et al., 2021, and an alteration of this composition may affect reproductive outcomes. ...
... As in the vagina, the dominant species in the endometrium are usually lactobacilli (Chen et al., 2017, Oberle et al., 2021, and an alteration of this composition may affect reproductive outcomes. In patients undergoing IVF, a non-Lactobacillus dominated endometrial microbiota has been associated with lower implantation rates, clinical pregnancy rates and live birth rates compared with a Lactobacillusdominated microbiota (Moreno et al., 2016). However, knowledge of the endometrial microbiota in RPL is scarce. ...
... The results also showed an association between endometrial and vaginal G. vaginalis colonization and RPL. G. vaginalis is typically dominant in bacterial vaginosis, which has been associated with early (Garcia-Grau et al., 2019;Haahr et al., 2019;Moreno at al., 2016;Ralph et al., 1999) and especially with late (Leitich and Kiss, 2007) miscarriages. Miscarriage has also been linked with Lactobacillus depletion and high bacterial diversity in vaginal samples collected during early pregnancy (Al-Memar et al., 2020). ...
Research question:
Is the composition of the endometrial or vaginal microbiota associated with recurrent pregnancy loss (RPL)?
Design:
Endometrial and vaginal samples were collected from 47 women with two or more consecutive pregnancy losses and 39 healthy control women without a history of pregnancy loss, between March 2018 and December 2020 at Helsinki University Hospital, Helsinki, Finland. The compositions of the endometrial and vaginal microbiota, analysed using 16S rRNA gene amplicon sequencing, were compared between the RPL and control women, and between individual vaginal and endometrial samples. The mycobiota composition was analysed using internal transcribed spacer 1 amplicon sequencing for a descriptive summary. The models were adjusted for body mass index, age and parity. False discovery rate-corrected P-values (q-values) were used to define nominal statistical significance at q < 0.05.
Results:
Lactobacillus crispatus was less abundant in the endometrial samples of women with RPL compared with controls (mean relative abundance 17.2% versus 45.6%, q = 0.04). Gardnerella vaginalis was more abundant in the RPL group than in controls in both endometrial (12.4% versus 5.8%, q < 0.001) and vaginal (8.7% versus 5.7%, q = 0.002) samples. The individual vaginal and endometrial microbial compositions correlated strongly (R = 0.85, P < 0.001). Fungi were detected in 22% of the endometrial and 36% of the vaginal samples.
Conclusions:
Dysbiosis of the reproductive tract microbiota is associated with RPL and may represent a novel risk factor for pregnancy losses.
... This may influence the implantation of the embryo and the initial formation of the placenta, potentially affecting fertility and the development of obstetric complications in later phases of gestation 4 . Recent studies suggested that, in an In Vitro Fertilization (IVF) context, a non-Lactobacillus-dominated endometrial microbiota (defined as < 90% Lactobacillus spp.) was associated with significant decrease in implantation, pregnancy and live birth rates 8 . ...
... The endometrial niche can be easily accessible, and this has boosted the interest on this local microbiome, with some groups hastily claiming for clinical applications 8 . However, insufficient attention has been given to the methodology of sampling. ...
... This sample size would allow us at least to confirm the findings of Moreno et al. who tested the capacity of the endometrial microbiome to predict pregnancy in 35 women (even if this was the secondary aim of our investigation). More specifically, if findings of Moreno et al. 8 could be replicated with our approach, we should expect 50% of women with normal endometrial microbiome (Lactobacillus-dominant). On this basis, setting the type I and II errors at 0.05 and 0.20, and expecting a general chance of pregnancy of 30% for the whole cohort, we would be able to demonstrate statistically significant differences in clinical pregnancy rates in the Lactobacillus-dominant and in the non Lactobacillusdominant women > 50% and < 15%, respectively. ...
There is growing interest on the potential clinical relevance of the endometrial microbiome. However, insufficient attention has been given to the methodology of sampling. To minimize contamination, we advocate the use of the double-lumen catheters commonly employed for the embryo transfer. Endometrial fluid samples obtained from 53 women scheduled for IVF were studied for microbiome characterization. Control samples from the vagina of these same women were concomitantly obtained. Samples were analysed by V3–V4–V6 regions of 16S rRNA gene sequencing with Next Generation Sequencing technique. Endometrial Lactobacillus-dominant cases were uncommon compared to previous evidence, being observed in only 4 (8%) women. Taxonomy markedly differed between the endometrial and vaginal microbiomes composition. The most common bacterial genera coincided in only 4 (8%) women. The comparison between women who did and did not subsequently become pregnant failed to identify any microorganism associated with the success of the procedure. However, the endometrial biodiversity resulted higher among pregnant women. Shannon’s Equitability index in pregnant and non pregnant women was 0.76 [0.57–0.87] and 0.55 [0.51–0.64], respectively (p = 0.002). In conclusion, the use of embryo transfer catheters for testing the endometrial microbiome is promising. The scant concordance with vaginal samples supports the validity of this approach. Moreover, our study highlighted a possible beneficial role of a higher biodiversity on endometrial receptivity.
... Однако кроме лактобацилл микробный пейзаж богат и другими представителями, такими как Bifidobacterium, Streptococcus, Prevotella, Gardnerella и др. [11,12]. Вместе с тем, несмотря на наличие других микроорганизмов, абсолютное преобладание лактобактерий играет важную роль в поддержании колонизационной резистентности и стабильности микробиома. ...
... Однако революционная роль лактобактерий полости матки была продемонстрирована результатами международного исследования, согласно которым абсолютное численное преобладание (более 90%) лактобацилл в полости матки напрямую коррелировало с успешной имплантацией [13]. При этом в случае превалирования условно-патогенной микрофлоры, включая стрептококки и гарднереллы, вероятно ассоциировано с неудачами имплантации и более низкими показателями живорождения [11]. ...
Chronic endometritis "from pathogenesis to therapy" still remains the most contrarian issue of modern gynaecology. The lack of a unified pathogenetic concept as well as diagnostic and therapeutic algorithms continue to support a multitude of scientific discussions around this unique nosology. Latent subclinical endometrial inflammatory changes are associated with the realization of reproductive failures, including repeated implantation failures and early reproductive losses. To date, a sufficient amount of scientific data has been accumulated demonstrating high efficacy and safety of antifibrotic therapy with the use of azoximer bovgialuronidase (Longidaza) in the complex treatment of chronic endometritis.
... The human body and its microbiota have developed a symbiotic relationship, leading to complex interactions throughout the body. While the uterine cavity was traditionally considered a sterile environment [2], recent studies have shown the presence of a unique microbial community colonization in this region [3][4][5][6][7]. Understanding the impact of the microbiota on the reproductive system has elevated our comprehension to a higher level. ...
... Additionally, a recent study suggested a possible link between the microbiota composition in the endometrial uid of patients undergoing in vitro fertilization and embryo transfer (IVF-ET) and implantation and pregnancy rates [5,8]. However, the role of uterine cavity microbiota in unexplained recurrent spontaneous abortion (URSA) remains unclear, and there are limited studies available as references. ...
Introduction
The majority of unexplained recurrent spontaneous abortion (URSA) cases have been attributed to immune abnormalities. Inappropriate changes in microbiota could lead to immune disorders. However, the specific role of uterine cavity microbiota in URSA remains unclear, and only a limited number of related studies are available for reference.
Methods
We utilized double-lumen embryo transfer tubes to collect uterine cavity fluid samples from pregnant women in their first trimester. Subsequently, we conducted 16S rRNA sequencing to analyze the composition and abundance of the microbiota in these samples.
Results
For this study, we enlisted 10 cases of URSA and 28 cases of induced miscarriages during early pregnancy. Microbial communities were detected in all samples of the URSA group (100%, n = 10), whereas none were found in the control group (0%, n = 28). Among the identified microbes, Lactobacillus and Curvibacter were the two most dominant species.
Conclusions
This study revealed that during early pregnancy, Lactobacillus and Curvibacter were the predominant colonizers in the uterine cavity of URSA patients and were associated with URSA. Consequently, alterations in the dominant microbiota may lead to adverse pregnancy outcomes.
... When the reproductive tract infect HPV, most of it will subside naturally after a period of time, but only a few women have persistent HPV in the vaginal microenvironment and occur SIL after many years. In addition to the factors of HR-HPV persistent infection, the change of microbial community in vaginal microenvironment also plays a very important role in the occurrence of SIL [1]. A variety of microbiome are planted in the vagina, which coordinate and restrict each other to maintain the balance of vaginal microecology. ...
... A variety of microbiome are planted in the vagina, which coordinate and restrict each other to maintain the balance of vaginal microecology. Lactobacillus is the most dominant bacterium colonized in the vaginal microecology [1]. It is not only colonized in the vaginal mucosa, but also widely colonized in the oral cavity [2], gastrointestinal tract [3,4], urinary tract [5,6], etc. Lactobacillus and other microorganisms jointly build mucosal microbial barrier and play an important resistance role in infection, inflammation and tumorigenesis [7]. ...
Objective
To study the potential mechanism of Lactobacillus crispatus inhibiting cervical squamous intraepithelial lesion (SIL) and screen the early warning factors of SIL.
Methods
The effects of Lactobacillus crispatus on the proliferation, apoptosis, cross pore migration and invasion and cytokines of cervical precancerous cells Ect1/E6E7 were detected respectively. The effect of Lactobacillus crispatus on the expression of differential proteins screened in Ect1/E6E7 cells were detected by Western blot.
Results
Lactobacillus crispatus significantly inhibited the proliferation, induced apoptosis and inhibited cell migration of Ect1/E6E7 cells in a time-dependent manner (P < 0.05), but had no significant effect on cell invasion. Lactobacillus crispatus significantly promoted the secretion of Th1 cytokines and inhibited the secretion of Th2 cytokines by Ect1/E6E7 cells (P < 0.05). In addition, compared with SiHa cells in the control group, the expression of differential proteins PCNA, ATM, LIG1 and HMGB1 in Ect1/E6E7cells decreased significantly, while the expression of TDG and OGG1 proteins increased significantly (P < 0.05). ABCG2 protein in Ect1/E6E7 cells was slightly higher than that in SiHa cells, but the difference was not statistically significant. What is interesting is that Lactobacillus crispatus significantly inhibited the expression of ABCG2, PCNA, ATM, LIG1, OGG1 and HMGB1 proteins in Ect1/E6E7 cells, and promoted the expression of TDG protein.
Conclusions
Lactobacillus crispatus may inhibit the function of Ect1/E6E7 cells through multiple pathways and exert the potential to reverse the progression of SIL.
... 12,13 A previous study has reported that during fresh embryo transfer, the dominance of Lactobacillus in the vagina may have better reproductive outcomes; conversely, the presence of a Lactobacillus-depauperate microbiota in a receptive endometrium may be associated with poor embryo implantation rate. 14,15 However, unlike the case of fresh embryo transfer, we wondered in the FET cycle if the balance of cervicovaginal microbiota also affected pregnancy success. It is worth investigating whether the composition and the health of the cervicovaginal microbiota would associate with the success rate of embryo implantation during the FET cycle. ...
... CST-IV microbiota is characterized by the loss of Lactobacillus dominance together with increased diverse facultative/anaerobic bacteria. 14 ...
Purpose:
The cervicovaginal microbiota is essential for maintaining the health of the female reproductive tract. However, whether cervicovaginal microbiota status prior to frozen embryo transfer (FET) associates with pregnancy outcomes is largely unexplored.
Methods:
Cervical mucus from 29 women who had undergone FET was collected. Microbial composition was analyzed using 16 S rRNA gene sequence to assess the correlation to the pregnancy outcomes.
Results:
CST-categorized Lactobacillus was the most dominant (41.71%) in the pregnant group, while CST-IV-based and BV-related Gardnerella (34.96%) prevailed in the non-pregnant group. The average abundance of Gardnerella compared non-pregnant to pregnant women was the highest (34.96% vs. 4.22%, p = 0.0015) among other CST-IV indicator bacteria. Multivariate analysis revealed that CST-IV-related bacteria have a significantly adverse effect on ongoing pregnancy outcomes (odds ratio, 0.083; 95% confidence index, 0.012-0.589, p = 0.013*).
Conclusions:
The study found that the CST-IV microbiota, with significantly increasing Gardnerella and the loss of Lactobacilli as the dominant bacteria, can potentially contribute to pregnancy failure. Therefore, dysbiotic microbiota may be a risk factor in women undergoing FET. Assessing the health of the cervicovaginal microbiota prior to FET would enable couples to make a more thoughtful decision on the timing and might improve pregnancy outcomes.
... The results of our study demonstrated that 87.7% of women had uterine microflora. Microbial communities can be found in the uterine cavity and the results of our study are consistent with the results of other authors [17][18][19][20][21][22][23][24]. ...
... There is still no clear opinion about the composition of the microbiota of the upper and lower genital tracts. Moreno et al. found that microbial composition of the vagina and endometrium was different in 20% of the examined samples [17,20]. Differences between these biotopes were found by Wee et al., who compared the uterine microbiota with vaginal and cervical samples in fertile and infertile women [28]. ...
Background:
Inefficiency of in vitro fertilization (IVF) programs can be caused by implantation failures. The uterine microbiota can influence the implantation process. However, it still remains unclear whether opportunistic microorganisms detected in the endometrium have a negative impact on the implantation success. The aim of our study was to evaluate the influence of the uterine microbiota on the embryo implantation success in patients undergoing assisted reproductive technologies.
Methods:
The study included 130 women diagnosed with infertility. The patients were divided into three groups: group I included women with the first IVF attempt (n = 39); group II included patients with recurrent implantation failure following embryo transfer with ovarian stimulation (n = 27); group III consisted of women with recurrent implantation failure following frozen-thawed embryo transfer (n = 64). We performed microbiological examination of the embryo transfer catheter which was removed from the uterine cavity after embryo transfer; cervical discharge of all the patients was studied as well. Thirty patients were selected for metagenomic sequencing.
Results:
The study showed that the uterine cavity is not free of microorganisms. A total of 44 species of microorganisms were detected: 26 species of opportunistic organisms and 18 species of commensals (14 species of lactobacilli and 4 species of bifidobacteria). Obligate anaerobic microorganisms and Gardnerella vaginalis were detected more frequently in group I compared to group III (strict anaerobes-15.4 and 1.6%; G. vaginalis-12.8 and 1.6%, respectively) (p < 0.05). However, this fact did not have a negative influence on the pregnancy rate: it was 51.3% in group I, it was 29.6% and 35.9% in women with recurrent implantation failures, respectively.
Conclusion:
Opportunistic microorganisms which were revealed in low or moderate titers (103-105 CFU/ml) in the uterine cavity and cervical canal did not affect the pregnancy rate in the women in the study groups. The microflora of the uterine cavity and cervical canal differed in qualitative composition in 87.9% of patients, therefore, we can suggest that the uterine cavity may form its own microbiota. The microbiota of the uterine cavity is characterized by fewer species diversity compared to the microbiota of the cervical canal.
... As a consequence, the prevalence of chronic endometritis is higher in women with adenomyosis, 18 contributing to a higher rate of infertility, fallopian tube closure, and during pregnancy to a higher rate of miscarriages, intrauterine infections and preterm birth. 19,20 Thus, the clinical manifestation and consequences of adenomyosis may still recognize a pathogenetic role in the alteration of the cervical mucus barrier. ...
Data indicate a link between the cervix and pathologies like adenomyosis and endometriosis. Uterine flexion on the cervix, diameter and stiffness of the internal cervical orifice represent an obstacle to downstream menstrual flow, that when excessive increases the intensity of uterine contractions. Evidence indicates that intense uterine contractions damage the endometrial myometrial junction, favoring endometrial entrance into the myometrium, to induce adenomyosis, and retrograde menstrual flow into the peritoneal cavity, to induce endometriosis. As a consequence of local hyperestrogenism in women with adenomyosis the cervical mucus barrier is reduced. Because of an increased prevalence of non‐lactobacilli dominated vagino‐types, the ascent of vaginal pathogens is also increased. Richness of endometrial and pelvic microbiota, lead to a higher rate of endometritis, and subclinical chronic pelvic infections in women with adenomyosis and concomitant endometriosis, respectively. Studies targeting the cervix as an actor on the pathogenesis of adenomyosis and endometriosis are warranted.
... A predominance of Lactobacillus species in the endometrial microbiota increases the embryo implantation rate (Lactobacillus genus >90%), whereas a microbial community dominated by non-Lactobacillus species decreases the embryo implantation rate, ongoing pregnancy rate, and live birth rate. 50 Compared with the uterine microbiota in a healthy pregnancy, the microbial spectrum of uterine samples before a miscarriage exhibits higher bacterial diversity and lower abundance of lactobacilli. Recent studies have shown that the bacterial communities differ in various parts of the uterus in women, with lactobacilli mainly found in the vagina and cervix. ...
Successful embryo implantation relies on embryo quality, endometrial receptivity, and the synchronized development of both. In recent years, methods for assessing endometrial receptivity have considerably advanced, shifting from traditional imaging techniques to modern molecular biology approaches. The evaluation of endometrial thickness, morphology, subendometrial blood flow, and peristalsis before implantation has become less prominent, whereas molecular markers such as pinopodes, integrin αvβ3, its ligand osteopontin, and homologous box gene A10 are widely used in clinical practice for assessing endometrial receptivity. To provide a comprehensive overview, this narrative review systematically searched PubMed and Web of Science for studies on endometrial receptivity assessment in infertile women over the past two decades, with a focus on both clinical and experimental research. This narrative review has examined recent advancements in morphological markers, endometrial receptivity–related genes, endometrial microbiota, and other emerging indicators, emphasizing their potential in optimizing embryo implantation and improving the success rates of assisted reproductive technologies. Notably, endometrial receptivity array testing and uterine microbiome analysis have gained substantial attention for their potential in personalized diagnosis and treatment. This review aims to provide scientific insights for precise infertility diagnostics and individualized treatment strategies while offering recommendations for future research development.
... The cervix, on the other hand, is known to be colonized by various microorganisms and serves as a barrier to prevent the ascension of potentially harmful bacteria (Hare, 1988 various mechanisms. These include altering the local immune environment, affecting the receptivity of the endometrium, and potentially interfering with implantation and early pregnancy (Moreno et al., 2016). ...
This comprehensive review aims to examine the multifaceted factors affecting infertility among young women across different countries and racial groups. An in-depth review of recent literature was conducted, synthesizing findings from diverse studies on biological, environmental, and societal factors influencing fertility in young women. The review highlights the significant impact of age, reproductive health history, sexually transmitted infections, lifestyle factors, and environmental toxins on fertility. It also explores the effects of chronic diseases such as congenital heart disease, chronic kidney disease, and rheumatoid arthritis on reproductive health as well as emerging factors like elevated serum uric acid levels. The review also addresses the impact of anti-cancer therapies, bacterial colonization, and HIV on fertility. The findings underscore the need for a multidisciplinary approach to fertility preservation and treatment. Healthcare providers should consider a wide range of factors when assessing and treating fertility issues in young women. The review also highlights the importance of preconception counselling and early intervention, particularly for women with chronic health conditions. This review provides a comprehensive overview of both well-established and emerging factors affecting fertility in young women, integrating insights from diverse populations and medical conditions and emphasizes the need for tailored approaches to fertility care.
... The normal process of cervical maturation is a result of localized inflammatory responses [3][4][5]. With the advancement of human microbiome technology, a body of converging evidence suggests that the vaginal microbiota alterations inhibit chemokine secretion and chemotaxis and increase proinflammatory cytokine levels, leading to inflammation and mediating a variety of diseases [6][7][8]. Interactions between the vaginal microbiota and local immunity trigger inflammation, mediating spontaneous preterm birth, characterized by cervical dilatation [9]. Moreover, during cervical ripening, inflammatory infiltration and cytokine production lead to the release of metalloproteinases, which subsequently degrade collagen, resulting in cervical softening [10]. ...
Background
Cervical ripening is a multifactorial outcome, and the association between cervical ripening and vaginal microbiota remains unexplored in term primiparous women. A new sequencing technology, microbiome 2bRAD sequencing (2bRAD-M) that provides a higher level of species discrimination compared to amplicon sequencing. We applied 2bRAD-M to analyze the vaginal microbiota in a population with variations in cervical ripeness and to explore potential microbiota factors influencing cervical ripening.
Methods
A total of 30 full-term primigravid women participated in this study, with 15 belonging to the low scoring group of cervical ripeness and 15 to the high scoring group. Clinical information was collected from the participants, and the vaginal microbiota and community structure of both groups were analyzed using 2bRAD-M sequencing. Microbiota diversity and differential analyses were conducted to explore potential factors influencing cervical ripening.
Results
A total of 605 species were detected. There was no difference in vaginal microbiota diversity between the two groups, and the vaginal microbial composition was structurally similar. In the two groups, Lactobacillus crispatus and Lactobacillus iners were identified as the two pivotal species through random forest analysis. Concurrent, extensive and close connections between species within the two groups were observed in the correlation analysis, influencing the aforementioned two species. Pairwise comparisons showed that Sphingomonas (P = 0.0017) and three others were abundant in high scoring group, while Alloprevotella (P = 0.0014), Tannerella (P = 0.0033), Bacteroides (P = 0.0132), Malassezia (P = 0.0296), Catonella (P = 0.0353) and Pseudomonas (P = 0.0353) and so on showed higher abundance in low scoring group. Linear discriminant analysis effect size identified 29 discriminative feature taxa.
Conclusion
For the first time, vaginal microbiota was sequenced using 2bRAD-M. With a relatively simple structure, a more stable vaginal microbiota is associated with higher cervical ripeness, and certain microorganisms, such as Sphingomonas, may play a beneficial role in cervical ripening.
... Microbiome studies examining infertility found different endometrial and vaginal bacterial compositions associated with implantation and pregnancy rates (13) as well as different lactobacilli-dominated vaginal compositions, associated with pregnancy rates in women with unexplained infertility (14). BV has also been shown to be associated with increased risk for sexually transmitted infections (16) pelvic in ammatory disease (17), and preterm labor (18). ...
Objective: To describe the microbiome of the vagina and fallopian tubes, and its relation with hydrosalpinx.
Methods: Case-control study was conducted in women who underwent salpingectomy for hydrosalpinx (case) or other indications (controls). Samples were obtained during surgery and were subjected to 16S rRNA amplicon sequencing, and analyses of alpha diversity and beta diversity measures were compared between sites and groups. Differential abundances of bacteria associated with vaginal dysbiosis was compared between cases and controls.
Results: Nine women with hydrosalipnx, and 23 women without hydrosalpinx were included in the study. The mean age of studied women was 41 (range: 29-54), and most (89%) were premenopausal. After in silico decontamination, only 30% of control fallopian tubes samples, and 10% of case fallopian tubes samples, had evidence of bacterial presence. The vaginal microbiota of control patients showed greater abundance of lactobacilli whereas the vaginal microbiome of case patients contained relatively more bacterial vaginosis associated bacteria such as Prevotella, Gardenrella and Atopobium. A significant difference was found in alpha and beta diversity between the vaginal and FT microbiomes in control patients, as fallopian tubes samples were more diverse. We found that women with hydrosalpinx had a more “dysbiotic” vaginal microbiome, and in women without hydrosalpinx, microbial composition within the vagina and FT differed, possibly representing two distinct ecological environments.
Conclusion: women undergoing salpingectomy for various reasons harbored bacteria within their FT, women with hydrosalpinx generally did not. This suggests that even though infection may be an underlying cause of hydrosalpinx, bacteria may not be present by the time patients require surgery.
... SASP factors induce senescence both in the cells themselves and in those that surround them via both autocrine and paracrine mechanisms, respectively [56,57], as well as promoting chronic inflammation and carcinogenesis [56]. Few reports have analyzed the effects of SASP factors on the uterus, but some have found that the inflammatory response to bacterial infection of the uterus and vaginal lining can lead to endometritis and reduced receptivity [58,59], suggesting that persistent bacterial exposure can induce the production of SASP factors and provoke chronic disease. Here, we used endometrial organoids as in vitro model for investigating how the endometrium responds to three specific cytokines whose expression is upregulated via (See figure on next page.) ...
Background
We previously identified Il17RB, a member of the IL17 superfamily, as a candidate marker gene for endometrial aging. While IL17RB has been linked to inflammation and malignancies in several organ systems, its function in the endometrium has not been investigated and is thus poorly understood. In the present study, we performed a functional analysis of this receptor with the aim of determining the effects of its age-associated overexpression on the uterine environment.
Methods
We analyzed IL17RB-related signaling pathways and downstream gene expression in an immortalized human endometrial glandular epithelial cell line (“hEM”) forced to express the receptor via lentiviral transduction (“IL17RB-hEM”). We also prepared endometrial organoids from human endometrial tissue sourced from hysterectomy patients (“patient-derived EOs”) and exposed them to cytokines that are upregulated by IL17RB expression to investigate changes in organoid-forming capacity and senescence markers. We analyzed RNA-seq data (GEO accession number GSE132886) from our previous study to identify the signaling pathways associated with altered IL17RB expression. We also analyzed the effects of the JNK pathway on organoid-forming capacity.
Results
Stimulation with interleukin 17B enhanced the NF-κB pathway in IL17RB-hEM, resulting in significantly elevated expression of the genes encoding the senescence associated secretory phenotype (SASP) factors IL6, IL8, and IL1β. Of these cytokines, IL1β inhibited endometrial organoid growth. Bioinformatics analysis showed that the JNK signaling pathway was associated with age-related variation in IL17RB expression. When IL17RB-positive cells were cultured in the presence of IL17B, their organoid-forming capacity was slightly but non-significantly lower than in unexposed IL17RB-positive cells, but when IL17B was paired with a JNK inhibitor (SP600125), it was restored to control levels. Further, IL1β exposure significantly reduced organoid-forming capacity and increased p21 expression in endometrial organoids relative to non-exposure (control), but when IL1β was paired with SP600125, both indicators were restored to levels comparable to the control condition.
Conclusions
We have revealed an association between IL17RB, whose expression increases in the endometrial glandular epithelium with advancing age, and cellular senescence. Using human endometrial organoids as in vitro model, we found that IL1β inhibits cell proliferation and leads to endometrial senescence via the JNK pathway.
... Firmicutes com uma baixa diversidade e uma alta abundância, no trato superior pode-se observar uma maior gama de Actinobacteria, Bacteroidetes e Proteobacteria em alta diversidade, porém em baixa quantidade (Chen et al., 2017;Liptáková et al., 2022;Plesniarski; Siddik; Su, 2021; Punzón-Jiménez; Labarta, 2021)Nessa perspectiva, em contraste com a parte inferior, o trato genital superior possui cerca de menos da metade da sua microbiota composta por espécies de Lactobacillus e o restante por diferentes gêneros de microrganismos predominantemente anaeróbios ou facultativos, como Pseudomonas, Acinetobacter, Vagococcus, Sphingobium, Comamonadaceae, Arthrobacter, Dysgonomonas, Shewanella, Delftia e Sphingomonas. Além disso, quando trata-se do microbioma isolado de cada parte do Brazilian Journal of Health Review, Curitiba, v. 7, n. 3, p. 01-27, may/jun., 2024 trato superior, sabe-se que o endométrio é o sítio onde encontra-se a maior concentração de lactobacilos, enquanto as tubas uterinas praticamente são isentas do mesmo microrganismo, mas pode apresentar outras espécies não comuns no microbioma endometrial, como os Staphylococcus e demais espécies da família Micrococcaceae (Chen et al., 2017;Kyono et al., 2018;Moreno et al., 2016;Peric et al., 2019;Teh et al., 2023). ...
A microbiota do trato genital feminino é uma comunidade diversa de microrganismos que desempenha um papel crucial na saúde das mulheres, influenciando a função reprodutiva e a defesa contra patógenos. Sua composição em situações normais é repleta de bactérias do gênero Lactobacillus, como Lactobacillus crispatus e Lactobacillus iners, que auxiliam no pH vaginal ácido e produzem subprodutos metabólicos benéficos, competindo com microrganismos patogênicos. Alterações nessa microbiota, causadas por fatores ambientais, podem levar à disbiose e diversas condições clínicas. Compreender essa microbiota e sua relação com a bioquímica bacteriana é crucial para o diagnóstico e tratamento dessas doenças, assim como para o desenvolvimento de estratégias preventivas, retratando de forma fidedigna quais microrganismos então presentes e como eles se beneficiam metabolicamente em determinadas situações patogênicas. Este artigo explora o perfil bacteriano do trato genital feminino, destacando a influência da microbiota e da atividade bioquímica metabólica bacteriana na saúde feminina e os mecanismos que levam a doenças quando essa microbiota está desequilibrada. Apesar de não estar completamente elucidado esses mecanismos, entender o perfil dessa microbiota a nível metabólico pode ser promissor para fins diagnósticos e terapêuticos, a fim de se obter novas alternativas de diagnóstico e tratamentos personalizados para medicina.
... Важно отметить, что до недавнего времени общепринятая гипотеза о стерильности матки была опровергнута. Было доказано, что микробиота полости матки по качественному составу соотносится с таковой во влагалище (хотя и не во всем!) [28][29][30]. Между тем у пациенток с РЭ отмечаются выраженные изменения состава микробиома с выявлением «специфических» ассоциаций Firmicutes, Spirochaetes, Atopobium, Proteobacteria (Bacteroides и Porphyromonas) [31]. Было выявлено, что бактерии Atopobium и Porphyromonas могут напрямую способствовать повышению экспрессии ряда цитокинов -интерлейкина (ИЛ)-1α, ИЛ-1β, ИЛ-17α, фактора некроза опухоли α, что может потенцировать ключевые процессы онкогенеза в эндометрии на фоне персистирующего низкоинтенсивного воспаления. ...
Polycystic ovary syndrome is a proven risk factor for both endometrial hyperplasia and cancer. The article reflects the current paradigm of etiology, pathogenesis and management of patients with endometrial hyperplasia on the background of polycystic ovary syndrome, according to the data of domestic and foreign literature.
... The upper genital tract harbors low-biomass microbiota, and the indigenous endometrial microbiota remains unclear [9][10][11]. The abundance of Lactobacillus in the endometrium is associated with increases in implantation, pregnancy, ongoing pregnancy and live birth [12][13][14][15][16]. CE is significantly correlated with altered endometrial microbiota [17], characterized by higher abundance of certain bacterial taxa and decreased Lactobacillus, potentially disrupting microbiota balance and favoring pathogenic bacterial proliferation [18,19]. ...
Background
Chronic endometritis (CE) is associated with poor reproductive outcomes, yet the role of endometrial microbiota in patients with recurrent implantation failure (RIF) and CE remains unclear. This study aims to characterize endometrial microbiota in RIF patients with CE and assess its implications for reproductive outcomes.
Methods
In this prospective study, we enrolled RIF patients both with and without CE. Endometrial and cervical samples were collected for 16 S rRNA gene sequencing. Microbiota composition was compared between groups using diversity indices, phylum, and genus-level analysis. Canonical correlation analysis (CCA) and Spearman’s correlation coefficients were used to assess relationships between CE, reproductive outcomes, and microbiota. Predictive functional profiling was performed to evaluate metabolic pathways associated with CE.
Results
Endometrial microbiota in CE patients exhibited greater diversity and evenness compared to non-CE patients. Principal coordinates analysis (PCoA) revealed distinct clustering between CE and non-CE groups. Linear discriminant analysis (LDA) identified Proteobacteria, Aminicenantales, and Chloroflexaceae as characteristic of CE, while Lactobacillus, Acinetobacter, Herbaspirillum, Ralstonia, Shewanela, and Micrococcaceae were associated with non-CE. CCA demonstrated associations between CE, adverse reproductive outcomes, and specific bacterial taxa. Microbial metabolic pathways significantly differed between CE and non-CE groups, with enrichment in pathways related to cofactors, vitamins, secondary metabolites, and the immune system in CE patients.
Conclusion
RIF patients with CE exhibit distinct endometrial microbiota compositions associated with adverse reproductive outcomes. The increased microbial diversity and altered metabolic pathways in CE suggest a potential correlation with reproductive outcomes, although further studies are necessary to elucidate the causal relationship between microbiota alterations and fertility. Modulating the endometrial microbiome may represent a novel therapeutic strategy to improve IVF outcomes in patients with CE.
... 35 and Actinobacteria. 54,58,59 Compared with the vaginal microbiota, the endometrial microbiota presents a significantly lower density-with approximately 10 000 times fewer bacteria-but it displays a higher degree of bacterial diversity. 54,60 Some studies have previously examined the microbiota in the female reproductive tract of women with adenomyosis 13-16 revealing differences compared with control groups. ...
Introduction
Alterations in microbiota composition have been implicated in a variety of human diseases. Patients with adenomyosis present immune dysregulation leading to a persistent chronic inflammatory response. In this context, the hypothesis that alterations in the microbiota may be involved in the pathogenesis of adenomyosis, by affecting the epigenetic, immunologic, and biochemical functions of the host, has recently been postulated. The aim of the present study was to compare the microbiota composition in the vagina, endometrium, and gut of individuals with and without adenomyosis.
Material and Methods
Cross‐sectional study including 38 adenomyosis patients and 46 controls, performed between September 2021 and October 2022 in a university hospital‐based research center. The diagnosis of adenomyosis was based on sonographic criteria. Fecal, vaginal, and endometrial samples were collected. Study of the microbiota using 16S rRNA gene sequencing.
Results
Patients with adenomyosis exhibited a significant reduction in the gut microbial alpha diversity compared with healthy controls (Chao1 p = 0.012, Fisher p = 0.005, Observed species p = 0.005). Beta‐diversity analysis showed significant differences in the compositions of both gut and vaginal microbiota between adenomyosis patients and the control group (Adonis p‐value = 0.001; R² = 0.03 and Adonis p‐value = 0.034; R² = 0.04 respectively). Specific bacterial taxa were found to be either overrepresented (Rhodospirillales, Ruminococcus gauvreauii group, Ruminococcaceae, and Actinomyces) or underrepresented in the gut and endometrial microbiota of adenomyosis patients compared with controls. Distinct microbiota profiles were identified among patients with internal and external adenomyosis phenotypes.
Conclusions
The study revealed reduced gut microbiota diversity in adenomyosis patients, accompanied by distinct compositions in gut and vaginal microbiota compared with controls. Overrepresented or underrepresented bacterial taxa were noted in the gut and endometrial microbiota of adenomyosis patients, with variations in microbiota profiles among those with internal and external adenomyosis phenotypes. These findings suggest a potential association between microbiota and adenomyosis, indicating the need for further research to comprehensively understand the implications of these differences.
... Thus far, most studies have reported that the uterine microbiota mainly consists of Lactobacilli (35,36). However, results of different studies in terms of the composition of the uterine microbiota are not consistent. ...
Microorganisms are ubiquitous in the human body; they are present in various areas including the gut, mouth, skin, respiratory tract, and reproductive tract. The interaction between the microbiome and reproductive health has become an increasingly compelling area of study. Disruption of the female genital tract microbiome can significantly impact the metabolism of amino acids, carbohydrates, and lipids, increasing susceptibility to reproductive tract diseases such as vaginitis, chronic endometritis, endometrial polyps, endometriosis, and polycystic ovary syndrome. The gut microbiome, considered an endocrine organ, plays a crucial role in the reproductive endocrine system by interacting with hormones like estrogen and androgens. Imbalances in the gut microbiome composition can lead to various diseases and conditions, including polycystic ovary syndrome, endometriosis, and cancer, although research on their mechanisms remains limited. This review highlights the latest advancements in understanding the female genital tract and gut microbiomes in gynecological diseases. It also explores the potential of microbial communities in the treatment of reproductive diseases. Future research should focus on identifying the molecular mechanisms underlying the association between the microbiome and reproductive diseases to develop new and effective strategies for disease prevention, diagnosis, and treatment related to female reproductive organs.
... Endometriosis is a common gynaecological condition, defined by the presence of endometrial-like tissue outside the uterus, most commonly on the pelvic and ovarian viscera, which is associated with pelvic pain and infertility (1)(2)(3)(4)(5)(6). ...
... Additionally, restoring the ecological balance may decrease the proliferation of pathogens within the bovine's vagina [9]. Understanding normal microbiota composition during various phases of estrous cycle can further help in restoring normal vaginal balance in case of various infections like metritis, pyometra, and endometritis etc., [10]. With the help of metagenomics [11], it has now become very easy to understand the diversity difference in various phases of Estrous cycle for harnessing the power of bene cial vaginal probiotic consortium [12]. ...
Background: Using 16s rRNA sequencing of the V3-V4 hypervariable region, the present study is aimed to check vaginal microbiota diversity throughout different stages of the estrous cycle, with attention to hormonal changes and microorganism diversity. Metagenomic research was conducted on vaginal swab samples obtained from healthy cows' at different stages of the estrous cycle.
Results: Total sixteen cows were synchronized with dobble PG regime. Nine cows demonstrated estrus within 96 hours and were eligible for the experiment. Vaginal samples for metagenomics and blood samples for hormonal analysis were collected during estrus, metestrus, diestrus and proestrus of synchronized Estrous cycle. The study's findings revealed that the diestrus phase has a different diversity than the other three estrous cycle phases, implying that hormones affect bacterial diversity. Proteobacteria and Firmicutes are the most abundant phyla at the phylum level, accounting for 94 % of bacterial diversity. Actinobacteriota, Patescibacteria, Cyanobacteria, Bacteroidota, and others are fewer common phyla. Proteobacteria are most common throughout the estrus, metestrus, and proestrus stages of the estrous cycle at the phylum level, there was no discernible distinction between the follicular and luteal phases. After statistical correction, Bacillaceae, Alcaligenes, and Enterobacteriaceae & Morganellacea families are more significant. At the diestrus stage, the Family Enterobacteriaceae is lower than at other stages; otherwise, all statistically significant genera are high at diestrus stages. The luteal phase had higher levels of Micrococcus, Stenotrophomonas, UGC-010, Massilia, and Methylobacillus than the follicular phase, however, statistical analysis revealed no substantial difference between the two phases. Lactobacillus genus is present on two samples including the estrus stage and diestrus stages.
Conclusions: This study represents an important step towards the understanding of microbial diversity within different stages of the estrous cycle of the dairy cow. The study results revealed dynamics of metabiota during estrous cycle.
... An abnormal vaginal microbiome or bacterial vaginosis (BV) leads to a significantly decreased pregnancy rate with IVF (prospective multicenter study [55]). If Lactobacillus species are not the dominant bacterial species on the endometrium, the probability of implantation after embryo transfer is significantly lower and the probability of miscarriage increases (prospective case-controlled study of vaginal and/or endometrial microbiome [56]) [57]. A recent prospective multicenter observational study of the endome-trial microbiome came to a similar conclusion [58]. ...
Purpose The aim of this guideline is to standardize the diagnosis and therapy of recurrent miscarriage (RM) using evidence from the recent literature. This is done by using consistent definitions, objective evaluations and standardized treatment protocols.
Methods When this guideline was compiled, special consideration was given to previous recommendations in prior versions of this guideline and the recommendations of the European Society of Human Reproduction and Embryology, the Royal College of Obstetricians and Gynecologists, the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine, and a detailed individual search of the literature about the different topics was carried out.
Recommendations Recommendations about the diagnostic and therapeutic procedures offered to couples with RM were developed based on the international literature. Special attention was paid to known risk factors such as chromosomal, anatomical, endocrinological, physiological coagulation, psychological, infectious and immune disorders. Recommendations were also developed for those cases where investigations are unable to find any abnormality (idiopathic RM).
... In recent years, it was also discovered that the uterus, previously thought to be a sterile environment, has its own microbiota. A healthy woman's microbiota consists primarily of Firmicutes, Bacteroides, Proteobacteria, and Actinobacteria, according to a study by Baker et al., and a review by Moreno et al. identified the five most represented genera in the endometrial microbiota [62][63][64]. ...
Understanding of the gut microbiome’s role in human physiology developed rapidly in recent years. Moreover, any alteration of this microenvironment could lead to a pathophysiological reaction of numerous organs. It results from the bidirectional communication of the gastrointestinal tract with the central nervous system, called the gut–brain axis. The signals in the gut–brain axis are mediated by immunological, hormonal, and neural pathways. However, it is also influenced by microorganisms in the gut. The disturbances in the gut–brain axis are associated with gastrointestinal syndromes, but recently their role in the development of different types of pain was reported. The gut microbiome could be the factor in the central sensitization of chronic pain by regulating microglia, astrocytes, and immune cells. Dysbiosis could lead to incorrect immune responses, resulting in the development of inflammatory pain such as endometriosis. Furthermore, chronic visceral pain, associated with functional gastrointestinal disorders, could result from a disruption in the gut microenvironment. Any alteration in the gut–brain axis could also trigger migraine attacks by affecting cytokine expression. Understanding the gut microbiome’s role in pain pathophysiology leads to the development of analgetic therapies targeting microorganisms. Probiotics, FODMAP diet, and fecal microbiota transplantation are reported to be beneficial in treating visceral pain.
... Infertility caused by chronic endometritis is mainly due to the long-term inflammatory state of endometrium caused by the disorders of uterine microflora, which reduces endometrial receptivity and interferes with blastocyst development [178]. Compared with healthy women, infertile patients with chronic endometritis have lower vaginal microbial diversity and abundance, especially Lactobacillus, which determines the embryo implantation rate and pregnancy rate [179][180][181]. ...
Recently, with the development of the social economy, the incidence of infertility has increased year by year. With its complex etiology and diversified syndromes, infertility has become one of the most important diseases that plague the physical and mental health of women of childbearing age worldwide. Endometrial factors as an important part affecting female reproductive capacity, due to which induced repeated abortion and multiple uterine cavity operations occur, can destruct endometrium, failing to provide a normal implantation environment for zygote, thus resulting in infertility. Many patients failed to achieve expected results after receiving conventional treatments such as hormone therapy, assisted reproductive technology (ART), granulocyte colony-stimulating factor (G-CSF) therapy, and cell therapy, then turn to complementary and alternative medicine (CAM) therapies for help. Aiming at clarifying the effectiveness and mechanisms of CAM therapy in the treatment of infertility caused by endometrial factors, our paper systematically searched and studied present related literature on the PubMed, CNKI, and other databases, focusing on the aspects of clinical application and mechanism explorations and highlighting the therapeutic effects of Chinese herbal medicine (CHM), acupuncture, and moxibustion on such diseases. Moreover, this paper also introduces the CAM treatments of traditional Chinese medicine (TCM) retention enema, neuromuscular electrical stimulation (NMES), photobiomodulation therapy, dietary intervention, and other measures for infertility caused by endometrial factors, in order to provide a reference for subsequent basic research and clinical work.
... Follicular fluid microbiome which can affect the outcome of IVF treatment due to the presence of Lactobacillus species and associated with improved embryo quality, leading to extremely high embryo transfer and pregnancy rates. Endometrium, originally considered a sterile site, and the presence of microbiota and Lactobalillus species has shown that it improves the implantation rate [10]. ...
Background
To assess bacterial diversity in infertile couples with their biochemical pregnancy outcomes. Using a retrospective case-control study design, participants were recruited for collection of vaginal swab, follicular fluid, endometrial fluid, and semen samples. The microbial composition was analyzed by 16S ribosomal RNA (rRNA) gene amplification with (MinION) Oxford Nanopore Ltd.
Results
Our findings revealed that age and endometrial thickness had a significant impact on the pregnancy success rate of pregnant (P) and non-pregnant (NP) patients receiving IVF, with high levels of luteinizing hormone, estrogen, and progesterone in the P group. In addition, the partial least squares discriminant analysis (PLS-DA) revealed a difference in microbial composition between the P and NP groups, as well as a higher microbial abundance in non-pregnant patients compared to pregnant patients. After comparison between pregnant patients and non-pregnant patients, pregnant patients had a higher abundance of Firmicutes and Proteobacteria and a lower abundance of Actinobacteria , Fusobacterium , and Bacteroidetes at the phylum level. Non-pregnant patients had a lower abundance of the probiotics lactobacillus and a higher abundance of infections Prevotella and Gardnerella at the genus level. As a result, a disordered microbiota in non-pregnant patients, characterized by a decrease in probiotics and an increase in pathogens, could be used as a possible marker for a higher IVF failure rate.
Conclusion
Alteration of the microbiota of the reproductive tract or the presence of certain microbes, regardless of the degree of pathogenicity that can affect fertilization, as well as implantation and subsequent embryonic development. This could result in failed fertility treatments and a lower live birth (LBR) rate.
... There is a non-negligible association between preterm delivery and intrauterine infection (Goldenberg et al., 2000). Endometrial microbiota has been shown to be highly stable during the acquisition of endometrial receptivity, and the pathological alterations that characterize it are associated with poor outcomes (Moreno et al., 2016). Macrophage depletion in mouse models resulted in susceptibility of decidual tissue to L. monocytogenes infection during early gestation (Qiu et al., 2009), suggesting the indispensable role of the macrophages in the host immune response during the very early decidualization to prevent preterm births. ...
Macrophages are professional phagocytes with a wide distribution in all tissues throughout the body. Macrophages play a crucial role in homeostasis and numerous physiological processes beyond innate and adaptive immunity, including cellular debris removal, metabolic regulation, tissue repair, and tissue remodeling. Uterine macrophages are a heterogeneous and highly plastic subset of immune cells regulated by the local microenvironment and, in addition to their anti-inflammatory and anti-infective functions, support the establishment and maintenance of pregnancy. Comprehensive reviews have summarized the role of decidual macrophages during pregnancy. However, the distribution of macrophages in the endometrium prior to pregnancy, their functional remodeling, and the knock-on effects on subsequent pregnancies have not been elucidated. In this review, we focus on 1) how the phenotypes of endometrial macrophages and their interactions with other endometrial cells indicate or contribute to the subsequent pregnancy, 2) the adaptive switching of endometrial macrophages during the initial establishment of pregnancy, 3) and the pregnancy complications and pregnancy-related disorders associated with endometrial macrophages.
... Several studies have shown that around 70% of the vaginal microbiota in pregnant and non-pregnant women is composed of Lactobacillus (38-40). The substitution of Lactobacillus by pathogenic or opportunistic microorganisms is associated with the development of bacterial vaginosis and lower urinary tract infections, and the presence of non-Lactobacillus species has been associated with poor reproductive health and/or complications in pregnancy (41)(42)(43)(44). In this regard, the presence of E. coli in the female reproductive tract has been found to be a risk factor for the progression of pregnancy (17,45,47). ...
The presence of Escherichia coli in the vaginal microbiome has been associated with pregnancy complications. In previous works, we demonstrated that Shiga toxin-producing Escherichia coli (STEC) can produce abortion and premature delivery in rats and that Shiga toxin type 2 (Stx2) can impair human trophoblast cell lines. The hypothesis of this work was that STEC may colonize the lower female reproductive tract and be responsible for adverse pregnancy outcomes. Thus, the aim of this work was to evaluate the presence and prevalence of virulence factor genes from STEC in the endocervix of asymptomatic pregnant women. For that purpose, endocervical swabs were collected from pregnant women during their prenatal examination. Swab samples were enriched in a differential medium to select Enterobacteria. Then, positive samples were analyzed by PCR to detect genes characteristic of Escherichia sp. (such as uidA and yaiO), genes specific for portions of the rfb (O-antigen-encoding) regions of STEC O157 (rfb O157), and STEC virulence factor genes (such as stx1, stx2, eae, lpfA O113, hcpA, iha, sab, subAB). The cytotoxic effects of stx2-positive supernatants from E. coli recovered from the endocervix were evaluated in Vero cells. Our results showed that 11.7% of the endocervical samples were positive for E. coli. Additionally, we found samples positive for stx2 and other virulence factors for STEC. The bacterial supernatant from an isolate identified as E. coli O113:NT, carrying the stx2 gene, exhibited cytotoxic activity in Vero, Swan 71 and Hela cells. Our results open a new perspective regarding the presence of STEC during pregnancy.
Studies in humans and large animals indicate a relationship between the uterine microbiome composition and endometrial receptivity. Despite many studies have been performed, the analysis of the uterine microbiome remains challenging due to the very low microbial biomass. Studies in other biological systems showed that RNA-based microbiome analysis complements DNA-based results and provides information about active bacteria in a sample. Thus, the aim of this study was to establish a highly sensitive and specific 16S rRNA gene V3-V4 amplicon PCR from equine uterine cytobrush samples and to compare DNA- and RNA-based 16S rRNA microbiome analysis. An optimized 16S rRNA gene V3-V4 amplicon PCR protocol from equine uterine cytobrush samples was developed, which was able to detect less than 38 bacterial genome copies using a bacterial DNA community standard. For the RNA-based amplicon generation protocol starting from cDNA, at least a 10-fold higher sensitivity was estimated compared to DNA-based approach. The comparison of using RNA and DNA isolated from the same uterine cytobrush samples as input for 16S V3-V4 amplicon sequencing revealed a much higher number of amplicon sequence variants as well as taxonomic units for the RNA-based approach. This resulted in significant differences in alpha (Simpson, Chao1) and beta diversity between RNA- and DNA-based analysis. Differential abundance analysis revealed significant differences between DNA and RNA samples at all taxonomic levels. Despite these differences, the overall microbiome composition was similar between the paired DNA and RNA samples. Many differences were probably found due to the higher sensitivity of the RNA-based approach. Furthermore, the DNA-based analysis is biased by the rRNA gene copy numbers (1–21), and the RNA-based analysis by the number of ribosomes per cell, which was reflected in the differences in the microbiome composition between the approaches. In addition, the results suggested that the DNA-based analysis is detecting cell-free bacterial DNA and/or DNA of dead bacteria that could be present in the samples. Altogether, the obtained results indicate advantages of a combined DNA- and RNA-based microbiome analysis, offering complementary and valuable information in the context of fertility-related studies of the uterine microbiome.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-025-00969-5.
The endometrial microbiome plays an essential role in fertility and successful embryo implantation. We present a case of recurrent implantation failure (RIF) in a 32-year-old female undergoing in vitro fertilization (IVF). Endometrial microbiota analysis revealed significant dysbiosis, characterized by a depletion of Lactobacillus spp. and overrepresentation of potentially pathogenic bacteria. Following a tailored antibiotic regimen and subsequent probiotic therapy, microbiota balance was restored. The patient achieved successful embryo implantation and sustained a viable pregnancy. This case illustrates the relevance of the endometrial microbiome in reproductive outcomes and supports the integration of microbiota profiling in fertility workups.
Chronic endometritis (CE) and endometrial dysbiosis (ED) are major causes of recurrent implantation failure (RIF). CE is diagnosed via hysteroscopy or the endometrial CD138 test; ED is examined using endometrial microbiome testing with next-generation sequencing. ED is characterized by a reduction in Lactobacillus species. However, correlations between the results of the three tests and the efficacy of treatment against CE and ED in pregnancy outcomes remain unclear. We analyzed 73 patients with RIF who underwent all three tests (hysteroscopy, endometrial CD138 test, and endometrial microbiome test). Patients with CE received antibiotics, whereas those with ED received antibiotics and vaginal Lactobacillus probiotics. The incidences of CE diagnosed using hysteroscopy and the CD138 test were 56.2 and 49.3%, respectively, and the prevalence of ED was 53.4%. No correlations were observed among the test-positive individuals in these three tests. Among patients with ED, 88.9% had a post-treatment clinical pregnancy, a significantly higher rate than that in patients without ED (p = 0.021). Multivariate analysis demonstrated that ED was associated with clinical pregnancy (odds ratio (OR): 6.29, p = 0.031). In conclusion, the three tests detected different populations of patients with RIF. ED diagnosed using the endometrial microbiome test was associated with favorable pregnancy outcomes after testing.
Purpose
To evaluate the impact of Endometrial Microbiome Metagenomic Analysis and Analysis of Infectious Chronic Endometritis (EMMA & ALICE) on pregnancy outcomes following recommended treatments in women with recurrent implantation failure (RIF) or recurrent pregnancy loss (RPL).
Methods
This prospective, multicenter cohort study included 527 women under 42 years old with RIF or RPL across 14 IVF centers in Japan. Endometrial samples were analyzed using EMMA & ALICE, and patients received antibiotics, probiotics, or no treatment based on test results. Pregnancy outcomes were assessed using Kaplan–Meier survival analysis and multivariate generalized linear models.
Results
Amongst participants, 43.4% had a normal Lactobacillus‐dominated microbiota, 20.9% had dysbiosis, and 35.7% had mild dysbiosis or ultralow biomass. Kaplan–Meier analysis revealed significantly higher ongoing pregnancy rates in the dysbiosis group treated with antibiotics and probiotics compared to other groups (p = 0.031). Post‐treatment, ongoing pregnancy rates in the dysbiosis and mild dysbiosis groups were comparable to the normal group.
Conclusions
EMMA & ALICE‐guided antimicrobial and probiotic treatments improved pregnancy outcomes, enabling the dysbiosis group to achieve pregnancy earlier than the normal group. Addressing uterine dysbiosis may reduce the time to pregnancy in patients with RIF and RPL.
Trial registration
University Hospital Medical Information Network (UMIN), UMIN000036917.
Although numerous studies have demonstrated the impact of microbiome manipulation on human health, research on the microbiome’s influence on female health remains relatively limited despite substantial disease burden. In light of this, we present a selected review of clinical trials and preclinical studies targeting both the vaginal and gut microbiomes for the prevention or treatment of various gynecologic conditions. Specifically, we explore studies that leverage microbiota transplants, probiotics, prebiotics, diet modifications, and engineered microbial strains. A healthy vaginal microbiome for females of reproductive age consists of lactic acid-producing bacteria predominantly of the Lactobacillus genus, which serves as a protective barrier against pathogens and maintains a balanced ecosystem. The gut microbiota’s production of short-chain fatty acids, metabolism of primary bile acids, and modulation of sex steroid levels have significant implications for the interplay between host and microbes throughout the body, ultimately impacting reproductive health. By harnessing interventions that modulate both the vaginal and gut microbiomes, it becomes possible to not only maintain homeostasis but also mitigate pathological conditions. While the field is still working toward making broad clinical recommendations, the current studies demonstrate that manipulating the microbiome holds great potential for addressing diverse gynecologic conditions.
Lay summary
Manipulating the microbiome has recently entered popular culture, with various diets thought to aid the microbes that live within us. These microbes live in different locations of our body and accordingly help us digest food, modulate our immune system, and influence reproductive health. The role of the microbes living in and influencing the female reproductive tract remains understudied despite known roles in common conditions such as vulvovaginal candidiasis (affecting 75% of females in their lifetime), bacterial vaginosis (25% of females in their lifetime), cervical HPV infection (80% of females in their lifetime), endometriosis (6–10% of females of reproductive age), and polycystic ovary syndrome (10–12% of females of reproductive age). Here, we review four different approaches used to manipulate the female reproductive tract and gastrointestinal system microbiomes: microbiota transplants, probiotics, prebiotics, and dietary interventions, and the use of engineered microbial strains. In doing so, we aim to stimulate discussion on new ways to understand and treat female reproductive health conditions.
Background
Today, the thickness of the endometrium as a key factor plays an important role in pregnancy outcomes of infertile patients. Based on this, it has been shown that endometrial compaction affect fertility success in patients. In this study, the impact of endometrial compaction on pregnancy outcomes has been evaluated.
Material and methods
This prospective cohort study included 250 patients undergoing embryo transfer, who referred to the infertility center of Shariati Hospital in Tehran between 2021–2022. They were examined from the point of view of the relationship between endometrial thickness changes and fertility rate in FET and Fresh cycles. After preparing the endometrium, its thickness was evaluated by ultrasound.
Result
The results showed that the percentage of chemical and clinical pregnancy in the compact group was higher compared to the non-compact one, which was statistically significant (p < 0.05). The rate of pregnancy in four groups of 5, 10, 15, and %20 compaction was 77(30.4%), 49(19.4%), 28(11.1%), and 14(5.5%), respectively.
Conclusion
Finally, endometrial compaction can be associated with an increase in chemical and clinical pregnancy rate in infertile patients. In addition, secondary thickness has predictive value for clinical pregnancy.
The uterine epithelium is composed of a single layer of hormone responsive polarized epithelial cells that line the lumen and form tubular glands. Endometrial epithelial organoids (EEO) can be generated from uterine epithelia and recapitulate cell composition and hormone responses in vitro. As such, the development of EEO represents a major advance for facilitating mechanistic studies in vitro. However, a major limitation for the use of EEO cultured in basement membrane extract and other hydrogels is the inner location of apical membrane, thereby hindering direct access to the apical surface of the epithelium to study interactions with the embryo or infectious agents such as viruses and bacteria. Here, a straightforward strategy was developed that successfully reverses the polarity of EEO. The result is an apical-out organoid that preserves a distinct apical-basolateral orientation and remains responsive to ovarian steroid hormones. Our investigations highlight the utility of polarity-reversed EEO to study interactions with E. coli and blastocysts. This method of generating apical-out EEO lays the foundation for developing new in vitro functional assays, particularly regarding epithelial interactions with embryos during pregnancy or other luminal constituents in a pathological or diseased state.
Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, and its incidence and mortality are rising. Obesity is more tightly associated with EC than any other cancer. Thus, the rising prevalence of obesity and associated risk factors, including diabetes and insulin resistance, cause alarm. The metabolic derangements of obesity increase the bioavailability of estrogen, hyperinsulinemia, and inflammation in a complex system with direct and indirect effects on the endometrium, resulting in proliferation and, ultimately, carcinogenesis. In addition, the gut dysbiosis associated with obesity helps contribute to these metabolic derangements, priming an individual for developing EC and perhaps affecting treatment efficacy. More recent studies are beginning to explore obesity's effect on the local tumor microbiome of EC and its role in carcinogenesis. Significant and sustained weight loss in individuals can considerably decrease the risk of EC, likely through reversal of the altered metabolism and dysbiosis resulting obesity. Bariatric surgery is the gold standard for successful weight loss and highlights how reversing of the systemic effects of obesity can reduce EC risk. However, the current limited availability, knowledge, and imposed stigma of bariatric surgery prohibits population-level reductions in EC. Therefore, effective and maintainable non-surgical dietary and pharmacologic interventions are needed.
Vaginal canal (VC) is exposed to the external environment affected by habitual factors like hygiene and sexual behaviour as well as physiological factors like puberty, menstrual cycle, pregnancy, child birth and menopause. Healthy VC harbours beneficial microflora supported by vaginal epithelium and cervical fluid. Connatural antimicrobial peptide (AMPs) of female reproductive tract (FRT) conjunctly with these beneficial microbes provide protection from a large number of infectious diseases. Such infections may either be caused by native microbes of the VC or transitory microbes like bacteria or virus which are not a part of VC microflora. This review highlight’s the role of hormones, enzymes, innate immunological factors, epithelial cells and vaginal mucus that support beneficial microbes over infectious ones thus, helping to maintain homeostasis in VC and further protect the FRT. We also discuss the prospective use of vaginal probiotics and AMPs against pathogens which can serve as a potential cure for vaginal infections.
Pregnancy is established during the periconceptional period as a continuum beginning with blastocyst attachment to the endometrial epithelial surface followed by embryo invasion and placenta formation. This period sets the foundation for the child and mother's health during pregnancy. Emerging evidence indicates that prevention of downstream pathologies in both the embryo/newborn and pregnant mother may be possible at this stage. In this review, we discuss current advances in the periconceptional space, including the preimplantation human embryo and maternal endometrium. We also discuss the role of the maternal decidua, the periconceptional maternal-embryonic interface, the dialogue between these elements, and the importance of the endometrial microbiome in the implantation process and pregnancy. Finally, we discuss the myometrium in the periconceptional space and review its role in determining pregnancy health.
PurposeA Lactobacillus-dominated microbiota in the endometrium was reported to be associated with favorable reproductive outcomes. We investigated in this study whether 16S ribosomal RNA (rRNA) gene sequencing analysis of the uterine microbiome improves pregnancy outcomes.Methods
This prospective cohort study recruited a total of 195 women with recurrent implantation failure (RIF) between March 2019 and April 2021 in our fertility center. Analysis of the endometrial microbiota by 16S rRNA gene sequencing was suggested for all patients who had three or more failed embryo transfers (ETs). One hundred and thirty-one patients underwent microbial 16S rRNA gene sequencing (study group) before additional transfers, while 64 patients proceeded to ET without that analysis (control group). The primary outcome was to compare the cumulative clinical pregnancy rate of two additional ETs.Main resultsAn endometrial microbiota considered abnormal was detected in 30 patients (22.9%). All but one of these 30 patients received antibiotics according to the bacterial genus detected in their sample, followed by treatment with probiotics. As a result, the cumulative clinical pregnancy rate (study group: 64.5% vs. control group: 33.3%, p = 0.005) and the ongoing pregnancy rate (study group: 48.9% vs. control group: 32.8%, p = 0.028) were significantly increased in the study group compared to the control group.Conclusion
Personalized treatment recommendations based on the microbial 16S rRNA gene sequencing of the uterine microbiota can improve IVF outcomes of patients with RIF.Trial registrationThe University Hospital Medical Information Network (UMIN) Clinical Trial Registry: UMIN000036050 (date of registration: March 1, 2019).
Problem:
In recent years, the incidence of female infertility has risen sharply, which is affected by many factors. It was recognized that female reproductive tract microbes play a role in the process of female conception. If the reproductive tract microbes could solve a certain proportion of infertility, it would certainly reduce the pain and economic burden of many patients. The objective of this study was to investigate the microbial community composition of follicular fluid in infertile patients and its potential impact on infertility.
Method of study:
Follicular fluid from 49 primary infertility and 52 secondary infertility patients was collected by a negative pressure needle, and the microbiota was analyzed by 16S rDNA sequencing.
Results:
It was found that Lactobacillus, especially L. crispatus, might have a positive effect on female pregnancy. Considering the presence or absence of male factors and different body mass indices, L. iners might inhibit female pregnancy. However, L. iners seemed to play a positive role in egg maturation, while Gardnerella and Cutibacterium acnes might have a negative effect on female pregnancy.
Conclusions:
This study suggested the potential role of Lactobacillus in follicular fluid in improving female infertility and provided a theoretical basis for the future microbiological treatment of female infertility.
Cervical cancer is the third leading cause of female cancers globally, resulting in more than 300,000 deaths every year. The majority of all cervical cancers are caused by persistent infections with high-risk human papillomaviruses (hrHPV) that can progress to cancer via a series of premalignant lesions. Most women, however, clear this infection within a year, concomitant with disease regression. Both hrHPV clearance and disease regression have been associated with the composition of the cervicovaginal microenvironment, which is defined by the host immune system and the cervicovaginal microbiome (CVM). A healthy microbiome is generally characterized by a high abundance of Lactobacillus species, and a change in the composition may cause bacterial vaginosis (BV), which is associated with an increased susceptibility to persistent hrHPV infections and disease. In this review, the composition of the CVM is discussed, with emphasis on the possible causes that drive changes in the cervicovaginal microbiota in relation to hrHPV infections, disease progression, and disease regression. The literature search focused on the composition of the CVM and its correlation with hrHPV infections and neoplastic lesions as well as the current efforts to adjust the microbiome against adverse viral outcomes.
Age-related changes in human vaginal microbiota composition have been reported, and such changes might be influenced by humidity, external stimuli, hormone levels, drug to use, and other factors. However, there is no report about the vaginal microbiota composition of female beagles at different ages. To investigate the effects of aging on the vaginal microbiota independent of other effects, we analyzed the vaginal microbiomes of 23 beagles at a wide range of ages from 1 year to 7 years old (except the 3rd year), 1–2 y were categorized into youth stage (YS), 4–5 y were categorized into middle stage (MS), and 6–7 y were categorized into elderly stage (ES) based on age. Samples were collected by scraping the vaginal mucosa of YS (n = 8), MS (n = 5) and ES (n = 10), and analyzed by 16S-rRNA gene high-throughput-sequencing. The diversity of the vaginal microbiome in female beagles was found to continuously change with age. We also found associations between age and specific members and functions of the vaginal microbiome. The metabolism of terpenoids and polyketide and the cell motility are significantly enhanced with age. Our results suggest that the proportion of Tenericutes might be a biomarker which could distinguish between YS and others
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