Beyond the reproductive tract: gut microbiome and its influence on gynecological health.

PURPOSE OF REVIEW: The analysis of microbiome in association with female health is today a "hot topic" with the main focus on microbes in the female reproductive tract. Nevertheless, recent studies are providing novel information of the possible influence of the gut microbiome on gynecological health outcomes, especially as we start to understand that the gut microbiome is an extended endocrine organ influencing female hormonal levels. This review summarizes the current knowledge of the gut microbes in association with gynecological health. RECENT FINDINGS: The gut microbiome has been associated with endometriosis, polycystic ovary syndrome, gynecological cancers, and infertility, although there is a lack of consistency and consensus among studies due to different study designs and protocols used, and the studies in general are underpowered. SUMMARY: The interconnection between the gut microbiome and reproductive health is complex and further research is warranted. The current knowledge in the field emphasizes the link between the microbiome and gynecological health outcomes, with high potential for novel diagnostic and treatment tools via modulation of the microenvironment.

Importancia del papel de Haemophilus no ducreyi en el tracto genital femenino y su relación con la clínica / Importance of the role of Haemophilus no ducreyi isolates in female genital tract and its clinical relationship

Antecedentes: Cada vez son más frecuentes los informes microbiológicos con agentes emergentes en episodios clínicos del aparato genital de sujetos con sospecha de infección, como son las especies de Haemophilus no ducreyi (HND). El objetivo de este trabajo es analizar la importancia clínica del aislamiento de estas especies en el tracto genital del sexo femenino. Pacientes y métodos: Se realizó un estudio observacional descriptivo y retrospectivo en un hospital universitario del sudeste español, donde se evalúan los aislamientos de HND en muestras de exudados genitales femeninos procedentes de atención sanitaria especializada entre 2016 y 2019. Se analizaron variables clínicas, epidemiológicas y microbiológicas de los episodios infecciosos de mujeres adultas y niñas. Resultados: Se encontraron 45 (25 mujeres y 20 niñas) aislamientos de HND, correspondiendo al 1% del total, siendo la especie más frecuente Haemophilus influenzae (64,4%). En mujeres predominaron la leucorrea y el dolor abdominal, y en el 72% hubo aislamiento polimicrobiano. En niñas se aisló frecuentemente de forma aislada, con presencia de eritema vulvovaginal, flujo patológico y prurito local. Destacó la alta tasa de resistencia de Haemophilus parainfluenzae a azitromicina (72,7%) y cotrimoxazol (18,2%) en mujeres adultas, y la resistencia a azitromicina en niñas (25%). Conclusiones: H. influenzae y H.parainfluenzae deben tenerse en cuenta como posible agente etiológico en casos de vaginitis y cervicitis en mujeres adultas, así como en sospecha de enfermedad pélvica inflamatoria. En niñas, H.influenzae representa uno de los agentes microbiológicos de las infecciones vulvovaginales. La tasa de resistencia a azitromicina de H.parainfluenzae y a cotrimoxazol de ambas especies se debe tener presente.(AU)

Background: The isolation of new pathogens in clinical samples from the genital tract of subjects with suspected infection, such as Haemophilus no ducreyi (HND) species, is becoming more frequent. The objective of this work is to analyze the pathogenic role and the clinical importance of the isolation of these species in female genital tract. Patients and methods: We carried out an observational, descriptive, and retrospective study from a Hospital in Granada (Spain). HND isolates in female genital samples between 2016 and 2019 from specialized care were studied. Clinical, epidemiological, and microbiological variables of clinical episodes of adult women and girls were analyzed. Results: Forty-five (25 women and 20 girls) isolates of HND were found, corresponding to 1%; the most frequent specie was Haemophilus influenzae (64.4%). In women, leukorrhea and abdominal pain was frequent and in 72% there was a polymicrobial isolate. In girls, it was frequently in isolation, with the presence of vulvovaginal erythema, pathological discharge, and local itching. We highlight the high rate of resistance of Haemophilus parainfluenzae to azithromycin (72.7%) and cotrimoxazole (18.2%) in adult women, in contrast to resistance to azithromycin in girls (25%). Conclusions: H. influenzae and H. parainfluenzae should be considered as a possible etiological agent in cases of vaginitis and cervicitis in adult women, as well as in suspected pelvic inflammatory disease. In girls, H.influenzae represents one of the microbiological agents within the etiologies of vulvovaginal infections. We highlight the rate of resistance to azithromycin in H.parainfluenzae and to cotrimoxazole in both species.(AU)

The influence of the female reproductive tract and sperm features on the design of microfluidic sperm-sorting devices.

Although medical advancements have successfully helped a lot of couples with their infertility by assisted reproductive technologies (ART), sperm selection, a crucial stage in ART, has remained challenging. Therefore, we aimed to investigate novel sperm separation methods, specifically microfluidic systems, as they do sperm selection based on sperm and/or the female reproductive tract (FRT) features without inflicting any damage to the selected sperm during the process. In this review, after an exhaustive studying of FRT features, which can implement by microfluidics devices, the focus was centered on sperm selection and investigation devices. During this study, we tried not to only point to the deficiencies of these systems, but to put forth suggestions for their improvement as well.

Evidence for cGAS-STING Signaling in the Female Genital Tract Resistance to Chlamydia trachomatis Infection.

Sexually transmitted Chlamydia trachomatis can ascend to the upper genital tract due to its resistance to innate immunity in the lower genital tract. C. trachomatis can activate the cGAS-STING signaling pathway in cultured cells via either cGAS or STING. This study was designed to evaluate the role of the cGAS-STING pathway in innate immunity against C. trachomatis in the mouse genital tract. Following intravaginal inoculation, C. trachomatis significantly declined by day 5 following a peak infection on day 3, while the mouse-adapted Chlamydia muridarum continued to rise for >1 week, indicating that C. trachomatis is susceptible to the innate immunity in the female mouse genital tract. This conclusion was supported by the observation of a similar shedding course in mice deficient in adaptive immunity. Thus, C. trachomatis can be used to evaluate innate immunity in the female genital tract. It was found that mice deficient in either cGAS or STING significantly increased the yields of live C. trachomatis bacteria on day 5, indicating an essential role of the cGAS-STING signaling pathway in innate immunity of the mouse genital tract. Comparison of live C. trachomatis bacteria recovered from different genital tissues revealed that the cGAS-STING-dependent immunity against C. trachomatis was restricted to the mouse lower genital tract regardless of whether C. trachomatis was inoculated intravaginally or transcervically. Thus, we have demonstrated an essential role of the cGAS-STING signaling pathway in innate immunity against chlamydial infection, laying a foundation for further illuminating the mechanisms of the innate immunity in the female lower genital tract.

Comparison of Female Genital Tract Cytokine and Microbiota Signatures Induced by Initiation of Intramuscular DMPA and NET-EN Hormonal Contraceptives - a Prospective Cohort Analysis.

Background: Cervicovaginal inflammation, bacterial microbiota and hormonal contraceptives all influence sexual and reproductive health. To date, the effects of intramuscular depo-medroxyprogesterone acetate (DMPA-IM) versus injectable norethisterone enanthate (NET-EN) on vaginal microbiota or cytokines have not been compared back-to-back, although in-vitro data suggest that DMPA-IM and NET-EN have different pharmacokinetic and biologic activities. This study aimed at comparing the effects of DMPA-IM versus NET-EN initiation on cervicovaginal cytokines and microbiota in women at high risk for sexually transmitted infections (STIs) assigned to the respective contraceptives. Methods: We collected socio-demographic characteristics and vaginal samples from women initiating DMPA-IM (ECHO Trial; n = 53) and NET-EN (UChoose Trial; n = 44) at baseline and after two consecutive injections to assess cytokine concentrations by Luminex, vaginal microbiota by 16S rRNA gene sequencing, STIs, bacterial vaginosis (BV) and candidiasis. Results: Cytokine concentrations did not change significantly after initiating DMPA-IM or NET-EN, although NET-EN versus DMPA-IM-associated profiles were distinct. While the abundance of bacterial taxa associated with optimal and non-optimal microbiota fluctuated with DMPA-IM use, overall community composition did not significantly change with either contraceptive. HSV-2 serology, chlamydial infection, gonorrhoea and candidiasis did not influence the associations between contraceptive type and cervicovaginal cytokines or microbiota. Conclusions: Both DMPA-IM and NET-EN use did not lead to broad inflammatory or microbiota changes in the female genital tract of sub-Saharan African women. This suggests that NET-EN is likely a viable option for contraception in African women at high risk of BV and STIs.

Probiotic lactobacilli in formulas and hygiene products for the health of the urogenital tract.

Lactobacilli are the predominant microorganisms of the healthy human vagina. A novel alternative for the prevention and treatment of female urogenital tract infections (UGTI) is the inclusion of these microorganisms as active pharmaceutical ingredients in probiotic formulas, and more recently in female hygienic products. Probiotics are defined as "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host." A list of requirements must be considered during the development of probiotic product/formula for the female urogenital tract (UGT). This review aims to resume the requirements, probiotic characteristics, and clinical trial applied to determine the effect of probiotic and potentially probiotic strains on different woman's physiological and pathological conditions, and in preterm birth prevention. A revision of female hygienic products available in the world market is included, together with novel studies applying nanotechnology for Lactobacillus incorporation in hygienic products. Further studies and well-designed clinical trials are urgently required to complement the current knowledge and applications of probiotics in the female UGT. The use of probiotic formulas and products will improve and restore the ecological equilibrium of the UGT microbiome to prevent and treat UGTI in women under different conditions.

Gastrointestinal Chlamydia-Induced CD8+ T Cells Promote Chlamydial Pathogenicity in the Female Upper Genital Tract.

Chlamydia is known to both ascend to the upper genital tract and spread to the gastrointestinal tract following intravaginal inoculation. Gastrointestinal Chlamydia was recently reported to promote chlamydial pathogenicity in the genital tract since mice intravaginally inoculated with an attenuated Chlamydia strain, which alone failed to develop pathology in the genital tract, were restored to develop hydrosalpinx by intragastric coinoculation with wild-type Chlamydia. Gastrointestinal Chlamydia promoted hydrosalpinx via an indirect mechanism since Chlamydia in the gut did not directly spread to the genital tract lumen. In the current study, we further investigated the role of CD8+ T cells in the promotion of hydrosalpinx by gastrointestinal Chlamydia. First, we confirmed that intragastric coinoculation with wild-type Chlamydia promoted hydrosalpinx in mice that were inoculated with an attenuated Chlamydia strain in the genital tract 1 week earlier. Second, the promotion of hydrosalpinx by intragastrically coinoculated Chlamydia was blocked by depleting CD8+ T cells. Third, adoptive transfer of gastrointestinal Chlamydia-induced CD8+ T cells was sufficient for promoting hydrosalpinx in mice that were intravaginally inoculated with an attenuated Chlamydia strain. These observations have demonstrated that CD8+ T cells induced by gastrointestinal Chlamydia are both necessary and sufficient for promoting hydrosalpinx in the genital tract. The study has laid a foundation for further revealing the mechanisms by which Chlamydia-induced T lymphocyte responses (as a 2nd hit) promote hydrosalpinx in mice with genital Chlamydia-triggered tubal injury (as a 1st hit), a continuing effort in testing the two-hit hypothesis as a chlamydial pathogenic mechanism.

The Microbiome and Gynecologic Cancer: Current Evidence and Future Opportunities.

PURPOSE OF REVIEW: We review the emerging evidence regarding the relationship between the microbiota of the gastrointestinal and female reproductive tracts and gynecologic cancer. RECENT FINDINGS: The microbiome has essential roles in maintaining health. In recent years, the microbiota of the gastrointestinal and female reproductive tracts have been linked to many diseases, including gynecologic cancer. Alterations to the bacterial populations in a microbiota, or dysbiosis, have been shown to favor a pro-carcinogenic state through altered immune responses, dysregulated hormone metabolism, and modulation of the cell cycle. Pre-clinical and clinical studies have emerged, demonstrating that specific bacteria or microbial communities may be associated with increased risk for uterine, ovarian, and cervical cancers. Notably, numerous studies have linked a non-Lactobacillus-dominant vaginal microbiota, composed of anaerobic bacteria, with HPV infection, persistence, and development of invasive cervical cancer. Similarly, next-generation high-throughput sequencing techniques have enabled the characterization of unique microbiotas in patients with malignant and benign gynecologic conditions, shedding light on new associations between bacterial species and gynecologic cancers. Harnessing the power of the microbiome for early diagnosis, therapeutic intervention and modulation creates tremendous potential to optimize gynecologic cancer outcomes in the future.

The impact of the female genital tract microbiome in women health and reproduction: a review.

PURPOSE: The aim of this review is to gather the available research focusing on female genital tract (FGT) microbiome. Research question focuses in decipher which is the role of FGT microbiota in eubiosis, assisted reproduction techniques (ARTs), and gynaecological disorders, and how microbiome could be utilised to improve reproduction outcomes and to treat fertility issues. METHODS: PubMed was searched for articles in English from January 2004 to April 2021 for "genital tract microbiota and reproduction", "endometrial microbiome", "microbiome and reproduction" and "microbiota and infertility". Manual search of the references within the resulting articles was performed. RESULTS: Current knowledge confirms predominance of Lactobacillus species, both in vagina and endometrium, whereas higher variability of species is both found in fallopian tubes and ovaries. Microbial signature linked to different disorders such endometriosis, bacterial vaginosis, and gynaecological cancers are described. Broadly, low variability of species and Lactobacillus abundance within the FGT is associated with better reproductive and ART outcomes. CONCLUSION: Further research regarding FGT microbiome configuration needs to be done in order to establish a more precise link between microbiota and eubiosis or dysbiosis. Detection of bacterial species related with poor reproductive outcomes, infertility or gynaecological diseases could shape new tools for their diagnosis and treatment, as well as resources to assess the pregnancy prognosis based on endometrial microbiota. Data available suggest future research protocols should be standardised, and it needs to include the interplay among microbiome, virome and mycobiome, and the effect of antibiotics or probiotics on the microbiome shifts.

Reduced Uterine Tissue Damage during Chlamydia muridarum Infection in TREM-1,3-Deficient Mice.

Genital infections with Chlamydia trachomatis can lead to uterine and oviduct tissue damage in the female reproductive tract. Neutrophils are strongly associated with tissue damage during chlamydial infection, while an adaptive CD4 T cell response is necessary to combat infection. Activation of triggering receptor expressed on myeloid cells-1 (TREM-1) on neutrophils has previously been shown to induce and/or enhance degranulation synergistically with Toll-like receptor (TLR) signaling. Additionally, TREM-1 can promote neutrophil transepithelial migration. In this study, we sought to determine the contribution of TREM-1,3 to immunopathology in the female mouse genital tract during Chlamydia muridarum infection. Relative to control mice, trem1,3-/- mice had no difference in chlamydial burden or duration of lower-genital-tract infection. We also observed a similar incidence of hydrosalpinx 45 days postinfection in trem1,3-/- compared to wild-type (WT) mice. However, compared to WT mice, trem1,3-/- mice developed significantly fewer hydrometra in uterine horns. Early in infection, trem1,3-/- mice displayed a notable decrease in the number of uterine glands containing polymorphonuclear cells and uterine horn lumens had fewer neutrophils, with increased granulocyte colony-stimulating factor (G-CSF). trem1,3-/- mice also had reduced erosion of the luminal epithelium. These data indicate that TREM-1,3 contributes to transepithelial neutrophil migration in the uterus and uterine glands, promoting the occurrence of hydrometra in infected mice.

Circulating immunity protects the female reproductive tract from Chlamydia infection.

Anatomical positioning of memory lymphocytes within barrier tissues accelerates secondary immune responses and is thought to be essential for protection at mucosal surfaces. However, it remains unclear whether resident memory in the female reproductive tract (FRT) is required for Chlamydial immunity. Here, we describe efficient generation of tissue-resident memory CD4 T cells and memory lymphocyte clusters within the FRT after vaginal infection with Chlamydia Despite robust establishment of localized memory lymphocytes within the FRT, naïve mice surgically joined to immune mice, or mice with only circulating immunity following intranasal immunization, were fully capable of resisting Chlamydia infection via the vaginal route. Blocking the rapid mobilization of circulating memory CD4 T cells to the FRT inhibited this protective response. These data demonstrate that secondary protection in the FRT can occur in the complete absence of tissue-resident immune cells. The ability to confer robust protection to barrier tissues via circulating immune memory provides an unexpected opportunity for vaccine development against infections of the FRT.

Comparative study on lesions of reproductive disorders of cows and female dromedary camels slaughtered at Addis Ababa, Adama and Akaki abattoirs with bacterial isolation and characterization.

BACKGROUND: Reproduction is a basic prerequisite to efficient livestock production. Reproductive performance depends on the normal structure and function of genital organs. A cross-sectional study was conducted from November 2016 to May 2017 to identify and compare the frequency of reproductive tract pathological lesions and to isolate bacteria associated to uterine lesions in female dromedary camels and cows slaughtered at Akaki camel slaughterhouse and Addis Ababa and Adama municipal abattoirs. Purposive sampling technique was employed to include and examine the reproductive tracts of all slaughtered animals (280; 140 cows and 140 camels) during the study period. RESULT: The study examined a total of 280 (140 cows and 140 camels) reproductive tracts. Various pathological lesions with different degrees of severity were observed in 48 (34.2%) and 51 (36.4%) of dromedary camels and cows, respectively. In dromedary camels, the most prevalent lesion was uterine lesions (21.4%) followed by ovarian lesions (7.14%); while in cows, ovarian lesions were the most prevalent (16.4%) followed by uterine lesions (14.2%). In general, 56 bacteria were isolated from cows' uterine lesion, the Staphylococcus species (28.5%), Streptococci species (19.6%), Coynebacterium species (8.9%), Escherichia coli (26.78%), Salmonella species (10.7%) and Klebsiella species (5.35%) being the most representative isolates. In camels, however, 45 bacteria were isolated from uterine lesions with higher prevalence of Escherichia coli (35.5%), Staphylococcus species (26.6%), Streptococcus species (13.3%), Pseudomonas species (6.6%), Proteus species (4.4%), Salmonella species (8.8%) and Klebsiella species (4.4%). Bacteriological data showed that the major isolates were similar, although slightly more frequent in occurrence in cows. Microscopically, uterine inflammatory lesions evidenced endometrial glands degeneration, epithelium sloughing, peri-glandular cuffing, and inflammatory cells infiltration. CONCLUSIONS: In female dromedary camels and cows, pathological lesions of the reproductive tract showed great prevalence, with similarity in bacterial isolates in both species. The role of each reproductive lesion and bacterial isolates as causal agents of reproductive failures in these livestock species, however, needs further investigation.

Microbiome and PCOS: State-of-Art and Future Aspects.

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease. The hypothesis that alterations in the microbiome are involved in the genesis of PCOS has been postulated. Aim of this review is to summarize the available literature data about the relationship between microbiome and PCOS. A search on PubMed and Medline databases was performed from inception to November 20Most of evidence has focused on the connection of intestinal bacteria with sex hormones and insulin-resistance: while in the first case, a relationship with hyperandrogenism has been described, although it is still unclear, in the second one, chronic low-grade inflammation by activating the immune system, with increased production of proinflammatory cytokines which interfere with insulin receptor function, causing IR (Insulin Resistance)/hyperinsulinemia has been described, as well as the role of gastrointestinal hormones like Ghrelin and peptide YY (PYY), bile acids, interleukin-22 and Bacteroides vulgatus have been highlighted. The lower genital tract microbiome would be affected by changes in PCOS patients too. The therapeutic opportunities include probiotic, prebiotics and synbiotics, as well as fecal microbiota transplantation and the use of IL-22, to date only in animal models, as a possible future drug. Current evidence has shown the involvement of the gut microbiome in PCOS, seen how humanized mice receiving a fecal transplant from women with PCOS develop ovarian dysfunction, immune changes and insulin resistance and how it is capable of disrupting the secondary bile acid biosynthesis. A future therapeutic approach for PCOS may involve the human administration of IL-22 and bile acid glycodeoxycholic acid.

Protection and Risk: Male and Female Genital Microbiota and Sexually Transmitted Infections.

Unique compositional and functional features of the cervicovaginal microbiota have been associated with protection against and risk for sexually transmitted infections (STI). In men, our knowledge of the interaction between the penile microbiota and STI is less developed. The current state of our understanding of these microbiota and their role in select STIs is briefly reviewed, along with strategies that leverage existing findings to manipulate genital microbiota and optimize protection against STIs. Finally, we focus on major research gaps and present a framework for future studies.

The Complex Link between the Female Genital Microbiota, Genital Infections, and Inflammation.

The female genital tract microbiota is part of a complex ecosystem influenced by several physiological, genetic, and behavioral factors. It is uniquely linked to a woman's mucosal immunity and plays a critical role in the regulation of genital inflammation. A vaginal microbiota characterized by a high abundance of lactobacilli and low overall bacterial diversity is associated with lower inflammation. On the other hand, a more diverse microbiota is linked to high mucosal inflammation levels, a compromised genital epithelial barrier, and an increased risk of sexually transmitted infections and other conditions. Several bacterial taxa such as Gardnerella spp., Prevotella spp., Sneathia spp., and Atopobium spp. are well known to have adverse effects; however, the definitive cause of this microbial dysbiosis is yet to be fully elucidated. The aim of this review is to discuss the multiple ways in which the microbiota influences the overall genital inflammatory milieu and to explore the causes and consequences of this inflammatory response. While there is abundant evidence linking a diverse genital microbiota to elevated inflammation, understanding the risk factors and mechanisms through which it affects genital health is essential. A robust appreciation of these factors is important for identifying effective prevention and treatment strategies.

The role of genital mycoplasma infection in female infertility: A systematic review and meta-analysis.

PROBLEM: Recent studies show that lower genital tract infection with genital mycoplasma may be associated with the pathology of female infertility. However, this association remains controversial due to the variable prevalence, sample sizes, and different methods used to diagnose genital mycoplasma infection. The aim of the present meta-analysis was to gain better understanding of the specific impact of genital mycoplasma on female infertility. METHOD OF STUDY: A systematic review of literature on the association of genital mycoplasma (Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma parvum, and Ureaplasma urealyticum) infection and female infertility was performed using three electronic databases: PubMed, Scopus, and CINAHL, from January 2000 to January 2020. Pooled odds ratio (OR) and 95% confidence intervals for genital mycoplasma infection and female infertility were derived from a fixed effects model. RESULTS: This meta-analysis included eight studies conducted in six countries. Based on the results, women with infertility had a statistically higher odds of having any genital mycoplasma infection (p < .0001) compared to the control group. The pooled OR of all the included studies was 3.82 (95% CI: 2.55, 5.72). There was an unremarkable heterogeneity in all the studies included in this meta-analysis (I2  = 0%, p = .48). A subgroup analysis also showed that M. genitalium, M. hominis, and U. urealyticum infections are significantly associated with female infertility. CONCLUSION: Our meta-analysis showed a significant association between M. genitalium, M. hominis, and U. urealyticum infections and female infertility. This evidence supports the development of guidelines for the diagnosis and treatment of genital mycoplasma infections to prevent female infertility.

The Role of Genital Tract Microbiome in Fertility: A Systematic Review.

The human microbiome plays a crucial role in determining the health status of every human being, and the microbiome of the genital tract can affect the fertility potential before and during assisted reproductive treatments (ARTs). This review aims to identify and appraise studies investigating the correlation of genital microbiome to infertility. Publications up to February 2021 were identified by searching the electronic databases PubMed/MEDLINE, Scopus and Embase and bibliographies. Only full-text original research articles written in English were considered eligible for analysis, whereas reviews, editorials, opinions or letters, case studies, conference papers, and abstracts were excluded. Twenty-six articles were identified. The oldest studies adopted the exclusive culture-based technique, while in recent years PCR and RNA sequencing based on 16S rRNA were the most used technique. Regardless of the anatomical site under investigation, the Lactobacillus-dominated flora seems to play a pivotal role in determining fertility, and in particular Lactobacillus crispatus showed a central role. Nonetheless, the presence of pathogens in the genital tract, such as Chlamydia trachomatis, Gardnerella vaginalis, Ureaplasma species, and Gram-negative stains microorganism, affected fertility also in case of asymptomatic bacterial vaginosis (BV). We failed to identify descriptive or comparative studies regarding tubal microbiome. The microbiome of the genital tract plays a pivotal role in fertility, also in case of ARTs. The standardization of the sampling methods and investigations approaches is warranted to stratify the fertility potential and its subsequent treatment. Prospective tubal microbiome studies are warranted.

Probiotic intervention as a potential therapeutic for managing gestational disorders and improving pregnancy outcomes.

Recent molecular investigations have significantly developed our knowledge of the characteristics of the reproductive microbiome and their associations with host responses to provide an ideal milieu for the development of the embryo during the peri-implantation period and throughout pregnancy as well as to provide a successful in vitro fertilization and appropriate reproductive outcomes. In this context, the establishment of microbial homeostasis in the female reproductive tract, in various physiological periods, is a substantial challenge, which appears the application of probiotics can facilitate the achievement of this goal. So that, currently, probiotics due to its safe and natural features can be considered as a novel biotherapeutic approach. In this review, we comprehensively discuss the bacterial, fungal, and viral diversity detected in the reproductive tract, and their associations with the establishment of dysbiosis/eubiosis conditions as well as we present the significant outcomes on probiotic intervention as an efficient biotherapeutic strategy for management of gestational disorders and improve pregnancy outcomes.

Chlamydia-Specific IgA Secretion in the Female Reproductive Tract Induced via Per-Oral Immunization Confers Protection against Primary Chlamydia Challenge.

Chlamydia trachomatis is an obligate intracellular pathogen that causes sexually transmitted disease. In women, chlamydial infections may cause pelvic inflammatory disease (PID), ectopic pregnancy, and infertility. The role of antibodies in protection against a primary Chlamydia infection is unclear and was a focus of this work. Using the C. muridarum mouse infection model, we show that intestinal mucosa is infected via intranasal (i.n.) or per-oral (p.o.) Chlamydia inoculation and that unlike the female reproductive tract (FRT) mucosa, it halts systemic Chlamydia dissemination. Moreover, p.o. immunization or infection with Chlamydia confers protection against per-vaginal (p.v.) challenge, resulting in significantly decreased bacterial burden in the FRT, accelerated Chlamydia clearance, and reduced hydrosalpinx pathology. In contrast, subcutaneous (s.c.) immunization conferred no protection against the p.v. challenge. Both p.o. and s.c. immunizations induced Chlamydia-specific serum IgA. However, IgA was found only in the vaginal washes and fecal extracts of p.o.-immunized animals. Following a p.v. challenge, unimmunized control and s.c.-s.c.-immunized animals developed Chlamydia-specific intestinal IgA yet failed to develop IgA in the FRT, indicating that IgA response in the FRT relies on the FRT to gastrointestinal tract (GIT) antigen transport. Vaginal secretions of p.o.-immunized animals neutralize Chlamydia in vivo, resulting in significantly lower Chlamydia burden in the FRT and Chlamydia transport to the GIT. We also show that infection of the GIT is not necessary for induction of protective immunity in the FRT, a finding that is important for the development of p.o. subunit vaccines to target Chlamydia and possibly other sexually transmitted pathogens.