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Atopobium vaginae but not commensal vaginal microbiota significantly induced proinflammatory cytokine secretion from 3-dimensional (3-D) vaginal epithelial cell aggregates. Detection of secreted proinflammatory cytokines in 3-D vaginal epithelial cell aggregate supernatants was performed following infection with the indicated vaginal microbiota (A. vaginae, Prevotella bivia, Lactobacillus iners, or Lactobacillus crispatus) or following Toll-like receptor agonist exposure. The concentrations of interleukin 6 (IL-6; A), interleukin 8 (IL-8; B), tumor necrosis factor α (TNF-α; C), interleukin 1β (IL1-β; D), and interleukin 1Ra (IL1-Ra; E) were measured by cytometric bead array analysis. Each graph represents the measured cytokine levels from 5 independently infected wells from 3 individual experiments, with data expressed as mean values (±SD). The cytokine concentrations in 3-D vaginal epithelial cell aggregate supernatants 24 hours after infection with the indicated vaginal microbiota were compared to those in untreated/uninfected supernatants, and statistical significance was determined by a 2-tailed t test with the Welch correction. *P < .05, **P
Source publication
Background:
Bacterial vaginosis increases the susceptibility to sexually transmitted infections and negatively affects women's reproductive health.
Methods:
To investigate host-vaginal microbiota interactions and the impact on immune barrier function, we colonized 3-dimensional (3-D) human vaginal epithelial cells with 2 predominant species of v...
Contexts in source publication
Context 1
... determine the impact of bacterial vaginosis-associated bac- terial strains and commensal colonization on the downstream PRR signaling pathways, we measured the cytokine secretion from 3-D vaginal epithelial cell aggregates 24 hours after infec- tion. The effects of bacterial vaginosis-associated bacterial strains and commensal colonization on proinammatory cytokine secretion from 3-D vaginal epithelial cell aggregates are shown in Figure 5. A. vaginae signicantly increased the se- cretion of IL-6, IL-8, and TNF-α but did not inuence the se- cretion of antiinammatory IL1-Ra. ...
Context 2
... effects of bacterial vaginosis-associated bacterial strains and commensal colonization on proinammatory cytokine secretion from 3-D vaginal epithelial cell aggregates are shown in Figure 5. A. vaginae signicantly increased the se- cretion of IL-6, IL-8, and TNF-α but did not inuence the se- cretion of antiinammatory IL1-Ra. However, the colonization of vaginal epithelial cell aggregates with P. bivia or Lactobacillus species did not increase the secretion of IL-6, IL-8, or TNF-α ( Figure 5). Microbial product exposure of 3-D vaginal epithelial cell aggregates resulted in the robust secretion of proinamma- tory cytokines. ...
Context 3
... product treatment did not result in increased IL-1β secretion from vag- inal epithelial cells. However, all vaginal microbiota signi- cantly increased IL-1β secretion ( Figure 5D). The treatment of 3-D vaginal epithelial cell aggregates with FSL-1 and poly I:C resulted in increased IL-1Ra secretion. ...
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Background
Bacterial vaginosis (BV) is the leading dysbiosis of the vaginal microbiome. The pathways leading towards the development of BV are not well understood. Gardnerella vaginalis is frequently associated with BV. G. vaginalis produces the cholesterol-dependent cytolysin (CDC), vaginolysin, which can lyse a variety of human cells and is thoug...
Introduction:
Here we present a longitudinal shotgun sequencing metagenomics study of 16 healthy, Danish women in the reproductive age. The aim of the study was to investigate whether lactobacilli, orally consumed, had any impact on the vaginal microbiome and its functional potential.
Materials and methods:
The 16 women aged 19-45 years were rec...
Background
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Methods
To determine the associatio...
Introduction . Rate of factors affecting preterm birth development has not been fully elucidated. The assessment was carried out by identifying 1-2 causes used to build up prognosis.
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Materials and Methods . The prospective comparative study was cond...
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Citations
... We observed premature birth and abortion in the two dysbiotic microbiota-transferred mice. The inflammation stimulatory activity of A. vaginae was shown in the human vaginal epithelial cell model [32]. It is argued that A. vaginae may be a robust immune response stimulator and contributes to adverse birth outcomes like G.vaginalis. ...
Objective
The vaginal microbiota dysbiosis induces inflammation in the uterus that triggers tissue damage and is associated with preterm birth. Progesterone is used to prevent labor in pregnant women at risk of preterm birth. However, the mechanism of action of progesterone still needs to be clarified. We aimed to show the immunomodulatory effect of progesterone on the inflammation of uterine tissue triggered by dysbiotic vaginal microbiota in a pregnant mouse model.
Methods
Healthy (n = 6) and dysbiotic (n = 7) vaginal microbiota samples isolated from pregnant women were transferred to control (n = 10) and dysbiotic (n = 14) pregnant mouse groups. The dysbiotic microbiota transferred group was treated with 1 mg progesterone (n = 7). Flow cytometry and immunohistochemistry analyses were used to evaluate inflammatory processes. Vaginal microbiota samples were analyzed by 16 S rRNA sequencing.
Results
Vaginal exposure to dysbiotic microbiota resulted in macrophage accumulation in the uterus and cellular damage in the placenta. Even though TNF and IL-6 elevations were not significant after dysbiotic microbiota transplantation, progesterone treatment decreased TNF and IL-6 expressions from 49.085 to 31.274% (p = 0.0313) and 29.279–21.216% (p = 0.0167), respectively. Besides, the macrophage density in the uterus was reduced, and less cellular damage in the placenta was observed.
Conclusion
Analyzing the vaginal microbiota before or during pregnancy may support the decision for initiation of progesterone therapy. Our results also guide the development of new strategies for preventing preterm birth.
... It was associated with higher levels of inflammatory cytokines 70 . It has been reported that Fannyhessea vaginae can activate the proinflammatory transcription factor NF-kB in the cervicovaginal epithelial cells, triggering abundant inflammation and innate immune responses 71,72 . ...
The presence of dysbiotic cervicovaginal microbiota has been observed to be linked to the persistent development of cervical carcinogenesis mediated by the human papillomavirus (HPV). Nevertheless, the characteristics of the cervical microbiome in individuals diagnosed with cervical cancer (CC) are still not well understood. Comprehensive analysis was conducted by re-analyzing the cervical 16S rRNA sequencing datasets of a total of 507 samples from six previously published studies. We observed significant alpha and beta diversity differences in between CC, cervical intraepithelial neoplasia (CIN) and normal controls (NC), but not between HPV and NC in the combined dataset. Meta-analysis revealed that opportunistic pernicious microbes Streptococcus, Fusobacterium, Pseudomonas and Anaerococcus were enriched in CC, while Lactobacillus was depleted compared to NC. Members of Gardnerella, Sneathia, Pseudomonas, and Fannyhessea have significantly increased relative abundance compared to other bacteria in the CIN group. Five newly identified bacterial genera were found to differentiate CC from NC, with an area under the curve (AUC) of 0.8947. Moreover, co-occurrence network analysis showed that the most commonly encountered Lactobacillus was strongly negatively correlated with Prevotella. Overall, our study identified a set of potential biomarkers for CC from samples across different geographic regions. Our meta-analysis provided significant insights into the characteristics of dysbiotic cervicovaginal microbiota undergoing CC, which may lead to the development of noninvasive CC diagnostic tools and therapeutic interventions.
... Additionally, LA may indirectly impact HIV, by suppressing growth of BV-associated bacteria [41] and preventing BV and cervicovaginal in ammation, which is associated with an increased risk of HIV acquisition in both males and females [13,23]. Furthermore, the virucidal activity of LA may synergise with the immunomodulatory effects of LA [39] and vaginal lactobacilli [100][101][102] to suppress in ammation-related HIV target cell activation (e.g. from resident memory CD4 + T cell reservoirs) [103], and recruitment [104,105], to further protect from HIV transmission. ...
Background. An optimal vaginal microbiota dominated by Lactobacillus spp. protects women against acquiring and transmitting HIV in contrast to a nonoptimal vaginal microbiota exemplified by bacterial vaginosis (BV); however, the virucidal activity of carboxylic acid metabolites present in vaginal fluid is not well defined. Here we determined the HIV-1 virucidal activity of lactic acid (LA), short chain fatty acids (SCFAs) and succinic acid under conditions observed in women with a Lactobacillus-dominated vaginal microbiota compared to women with BV and examined the mechanism by which LA inactivates HIV-1. The ability of LA to inactivate HSV-2 and HPV16 was also examined.
Results: LA was >10-fold more potent at inactivating an HIV-1 transmitted/founder strain than SCFAs (acetic, butyric, and propionic acid) and succinic acid when tested at an equivalent 20 mM of protonated acid at pH 4.2 (p£0.05). While LA decreased HIV-1 infectivity by >10³-fold, virions were intact, expressing a similar gp120:p24 ratio, and showed a 2-fold decrease in CD4 binding compared to the untreated control (p£0.05). Treatment of recombinant gp120 with LA revealed no major conformational changes by small angle X-ray scattering. LA treatment of HIV-1 at pH 3.8 resulted in an 80% decrease in virion-associated reverse transcriptase activity compared to untreated virus, which was more potent than acetic acid or HCl-adjusted media at pH 3.8. LA decreased HIV-1 virion-associated RNA levels by ~50% compared to untreated virus (p<0.001), acetic acid or HCl acidified media, with this effect potentiated in the presence of cervicovaginal fluid. In contrast, HSV-2 virucidal activity of LA was similar to acetic acid and HCl-acidified media while HPV16 was acid-resistant.
Conclusions: These findings reveal LA’s potent and specific HIV-1 virucidal activity, mediated by its membrane permeant properties, compared to SCFAs and succinic acid, with implications for the vaginal transmission of HIV-1 to partners and neonates during birth.
... A prior study also noted higher levels of the hormones E2 and progesterone (P) in premenopausal women with a BRCA mutation [26]; the suggestion is that P might impact vaginal epithelial cells, potentially counteracting estrogen and leading to an imbalanced microbiome. Additionally, it was found that gut bacteria could influence estrogen metabolism, thereby affecting vaginal epithelial cells [27]. Fannyhesea and Citrobacter, which are bacterial vaginosis-associated genera, have been extensively investigated [28,29] and found to be positively correlated with E2 in this study. ...
The vaginal microbiome plays an essential role in the reproductive health of human females. As infertility increases worldwide, understanding the roles that the vaginal microbiome may have in infertility and in vitro fertilization (IVF) treatment outcomes is critical. To determine the vaginal microbiome composition of 1411 individuals (1255 undergoing embryo transplantation) and their associations with reproductive outcomes, clinical and biochemical features are measured, and vaginal samples are 16S rRNA sequenced. Our results suggest that both too high and too low abundance of Lactobacillus is not beneficial for pregnancy; a moderate abundance is more beneficial. A moderate abundance of Lactobacillus crispatus and Lactobacillus iners (~80%) (with a pregnancy rate of I‐B: 54.35% and III‐B: 57.73%) is found beneficial for pregnancy outcomes compared with a higher abundance (>90%) of Lactobacillus (I‐A: 44.81% and III‐A: 51.06%, respectively). The community state type (CST) IV‐B (contains a high to moderate relative abundance of Gardnerella vaginalis) shows a similar pregnant ratio (48.09%) with I‐A and III‐A, and the pregnant women in this CST have a higher abundance of Lactobacillus species. Metagenome analysis of 71 samples shows that nonpregnant women are detected with more antibiotic‐resistance genes, and Proteobacteria and Firmicutes are the main hosts. The inherent differences within and between women in different infertility groups suggest that vaginal microbes might be used to detect infertility and potentially improve IVF outcomes.
... It seems that BVAB trigger mucosal innate immune response, increasing production of cytokines and defensins to eliminate pathogens. But excessive inflammatory response might lead to a disturbance of the vaginal immunological barrier and increasing susceptibility to STIs (Doerflinger et al., 2014). ...
Bacterial vaginosis (BV) is an infection of the genital tract characterized by disturbance of the normally Lactobacilli-dominated vaginal flora due to the overgrowth of Gardnerella and other anaerobic bacteria. Gardnerella vaginalis, an anaerobic pathogen and the major pathogen of BV, produces sialidases that cleave terminal sialic acid residues off of human glycans. By desialylation, sialidases not only alter the function of sialic acid-containing glycoconjugates but also play a vital role in the attachment, colonization and spread of many other vaginal pathogens. With known pathogenic effects, excellent performance of sialidase-based diagnostic tests, and promising therapeutic potentials of sialidase inhibitors, sialidases could be used as a biomarker of BV. This review explores the sources of sialidases and their role in vaginal dysbiosis, in aims to better understand their participation in the pathogenesis of BV and their value in the diagnosis and treatment of BV.
... BV-related sialidase-positive bacteria can break down mucus and damage the cervical epithelial tissue, producing biogenic amines and causing oxidative stress, thus increasing the risk of HPV persistent infection and lesion development [12]. Conversely, Lactobacillus can release antibacterial peptides, bacteriocins, hydrogen peroxide, and surfactants to reduce the synthesis of oncogenic substances and inhibit the proliferation of malignant cells [25][26][27]. BV may also affect the immunologic balance in cervical tissue by activating the pro-inflammatory transcription factor NF-κB in cervicovaginal epithelial cells, triggering abundant inflammation and innate immune responses [27]. A clinical trial involving 60 women of reproductive age in the United States and Africa explored the relationship between BV, HPV, and CIN progression. ...
... Conversely, Lactobacillus can release antibacterial peptides, bacteriocins, hydrogen peroxide, and surfactants to reduce the synthesis of oncogenic substances and inhibit the proliferation of malignant cells [25][26][27]. BV may also affect the immunologic balance in cervical tissue by activating the pro-inflammatory transcription factor NF-κB in cervicovaginal epithelial cells, triggering abundant inflammation and innate immune responses [27]. A clinical trial involving 60 women of reproductive age in the United States and Africa explored the relationship between BV, HPV, and CIN progression. ...
Background
The balance of vaginal microecology is closely related to human papillomavirus (HPV) infection and cervical lesions. This study aims to investigate the relationship between bacterial vaginosis (BV) and HPV infection.
Methods
In total, 1,310 individuals from the National Health and Nutrition Examination Survey (NHANES, 2003–2004) were included in this study. Logistic regression and subgroup analyses were used to examine the association between BV and HPV infection.
Results
A significant positive association was observed between BV and HPV infection in women after adjustment for other confounders (OR = 1.47, 95% confidence interval [CI]: 1.15–1.88). In subgroup analyses, we have found this positive correlation was most prominent among Mexican Americans (OR = 1.83, 95% CI: 1.08–3.08) and non-Hispanic blacks (OR = 1.81, 95% CI: 1.08–3.04).
Conclusions
This cross-sectional study demonstrated a positive association between BV and HPV infection in women.
... L. iners has been implicated in the activation of innate immunity (53), as well as transitions to a state of BV (54), but it remains unclear whether L. iners is a beneficial or harmful member in the vaginal microbiota. Holm et al. (55) proposed that different strains of L. iners may contribute to different phenotypes in the vaginal environment, which can either support stability or promote dysbiosis, and may be influenced by whether the L. iners strains were isolated from a healthy or dysbiotic environment (55). ...
Menstrual toxic shock syndrome (mTSS) is a rare but life-threatening disease associated with the use of high-absorbency tampons. The production of the Staphylococcus aureus toxic shock syndrome toxin-1 (TSST-1) superantigen is involved in nearly all cases of mTSS and is tightly controlled by regulators responding to the environment. In the prototypic mTSS strain S. aureus MN8, the major repressor of TSST-1 is the carbon catabolite protein A (CcpA), which responds to glucose concentrations in the vaginal tract. Healthy vaginal Lactobacillus species also depend on glucose for both growth and acidification of the vaginal environment through lactic acid production. We hypothesized that interactions between the vaginal microbiota [herein referred to as community state types (CSTs)] and S. aureus MN8 depend on environmental cues and that these interactions subsequently affect TSST-1 production. Using S. aureus MN8 ΔccpA growing in various glucose concentrations, we demonstrate that the supernatants from different CSTs grown in vaginally defined medium (VDM) could significantly decrease tst expression. When co-culturing CST species with MN8 ∆ccpA, we show that Lactobacillus jensenii completely inhibits TSST-1 production in conditions mimicking healthy menstruation or mTSS. Finally, we show that growing S. aureus in “unhealthy” or “transitional” CST supernatants results in higher interleukin 2 (IL-2) production from T cells. These findings suggest that dysbiotic CSTs may encourage TSST-1 production in the vaginal tract and further indicate that the CSTs are likely important for the protection from mTSS.
IMPORTANCE
In this study, we investigate the impact of the vaginal microbiota against Staphylococcus aureus in conditions mimicking the vaginal environment at various stages of the menstrual cycle. We demonstrate that Lactobacillus jensenii can inhibit toxic shock syndrome toxin-1 (TSST-1) production, suggesting the potential for probiotic activity in treating and preventing menstrual toxic shock syndrome (mTSS). On the other side of the spectrum, “unhealthy” or “transient” bacteria such as Gardnerella vaginalis and Lactobacillus iners support more TSST-1 production by S. aureus, suggesting that community state types are important in the development of mTSS. This study sets forward a model for examining contact-independent interactions between pathogenic bacteria and the vaginal microbiota. It also demonstrates the necessity of replicating the environment when studying one as dynamic as the vagina.
... We investigated the L. iners-dominated longitudinal profile separately from the other Lactobacillus-dominated profiles because it is hypothesized that not all vaginal Lactobacillus spp. are equally protective; L. iners has been associated with increased BV and sexually transmitted infection incidence in comparison to L. crispatus-dominated vaginal microbiota [53, [77][78][79][80]. The reduced protective capabilities of L. iners may be due to its ability to only make L-lactic acid and its tendency to be a tipping point to BV states [25, 36, [81][82][83]. ...
Bacterial vaginosis, characterized in part by low levels of vaginal Lactobacillus species, has been associated with pro-inflammatory cytokines which could fuel uterine fibroid development. However, prior work on the associations between uterine fibroids and vaginal bacteria is sparse. Most studies have focused on assessment of individual taxa in a single sample. To address research gaps, we sought to compare short, longitudinal profiles of the vaginal microbiota in uterine fibroid cases versus controls with assessment for hormonal contraceptives (HCs), a possible confounder associated with both protection from fibroid development and increases in Lactobacillus -dominated vaginal microbiota. This is a secondary analysis of 83 reproductive-age cisgender women who presented for transvaginal ultrasound (TVUS) and self-collected mid-vaginal swabs daily for 1–2 weeks before TVUS (Range: 5–16 days, n = 697 samples). Sonography reports detailed uterine fibroid characteristics (N = 21 cases). Vaginal microbiota was assessed by 16S rRNA gene amplicon sequencing and longitudinal microbiota profiles were categorized by hierarchical clustering. We compared longitudinal profiles of the vaginal microbiota among fibroid cases and controls with exact logistic regression. Common indications for TVUS included pelvic mass (34%) and pelvic pain (39%). Fibroid cases tended to be older and report Black race. Cases less often reported HCs versus controls (32% vs. 58%). A larger proportion of cases had low- Lactobacillus longitudinal profiles (48%) than controls (34%). In unadjusted analysis, L . iners -dominated and low- Lactobacillus profiles had higher odds of fibroid case status compared to other Lactobacillus -dominated profiles, however these results were not statistically significant. No association between vaginal microbiota and fibroids was observed after adjusting for race, HC and menstruation. Results were consistent when number of fibroids were considered. There was not a statistically significant association between longitudinal profiles of vaginal microbiota and uterine fibroids after adjustment for common confounders; however, the study was limited by small sample size.
... Некоторые бактерии, ассоциированные с ТССМ IV, такие как Atopobium, могут активировать транскрипцию провоспалительного ядерного фактора-kB, фактора некроза опухоли-α, интерлейкинов-6 и -8 и макрофагального воспалительного белка-3α [24][25][26]. Таким образом, преобладание анаэробов в микробиоме влагалища приводит к активации провоспалительных цитокинов в слизистой шейки матки. Fusobacterium, еще одна бактерия, ассоциированная с ТССМ IV, секретирует фермент сиалидазу и вызывает расщепление слизи, следовательно, предрасполагает эпителий шейки матки к вирусной инфекции [27]. ...
Abstract. High-risk carcinogenic papillomaviruses (HR HPV) persistence raises concerns about the development of cervical intraepithelial neoplasia (CIN) and the subsequent development of cervical cancer (CC). It is generally accepted that the predominance of one or another microbiome causes the elimination or persistence of HPV patterns. In connection with this assumption, the vaginal microbiome has a key influence on the progression of CIN to CC. Analysis compiled from international experience in the study of the vaginal microbiome suggests that correction of the vaginal microbiome represents a new branch in the prevention and treatment of HPV-induced cervical intraepithelial neoplasia.
Keywords: vaginal microbiome, community state type, cervical intraepithelial neoplasia
Резюме.Персистенция вирусов папилломы человека высокого канцерогенного риска (ВПЧ ВКР) причинно связана с развитием цервикальной интраэпителиальной неоплазии (ЦИН) и последующим развитием рака шейки матки (РШМ). Принято считать, что преобладание того или иного микробиома вызывает элиминацию либо персистенцию имеющегося ВПЧ. В связи с этим предполагается, что микробиом влагалища ключевым образом влияет на прогрессирование ЦИН в РШМ. Анализ, собранный на основе международного опыта в изучении микробиома влагалища, позволяет предположить, что коррекция влагалищного микробиома представляет собой новую ветвь в профилактике и лечении ВПЧ-индуцированной интраэпителиальной неоплазии шейки матки.
Ключевые слова: влагалищный микробиом, типовое состояние сообщества микробиома, интраэпителиальная неоплазия шейки матки
... Trichomonas vaginalis, laktobasili önemli ölçüde azaltan ve şiddetli inflamasyona neden olan vajinal florada dengesizliğe yol açmaktadır. İnflamatuar transkripsiyon faktörlerinin sürekli aktivasyonu da servikal doku hasarına yol açabilmekte ve dolayısıyla HPV 16'nın duyarlılığını ve kanserojenik potansiyelini artırmaktadır (21,22) . (23) çalışmasında normal serviksi olan 562 kadın, serviks kanseri tarama programına alınmıştır. ...
