scholarly journals Bacterial vaginosis and health-associated bacteria modulate the immunometabolic landscape in 3D model of human cervix

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Paweł Łaniewski ◽  
Melissa M. Herbst-Kralovetz
Keyword(s):  
Epithelial Cell ◽  
Bacterial Vaginosis ◽  
Pathogenic Bacteria ◽  
Cell Model ◽  
Female Reproductive Tract ◽  
Gardnerella Vaginalis ◽  
Obstetric Outcomes ◽  
Phenyllactic Acid ◽  
Increased Risk ◽  
Human Cervix

AbstractBacterial vaginosis (BV) is an enigmatic polymicrobial condition characterized by a depletion of health-associated Lactobacillus and an overgrowth of anaerobes. Importantly, BV is linked to adverse gynecologic and obstetric outcomes: an increased risk of sexually transmitted infections, preterm birth, and cancer. We hypothesized that members of the cervicovaginal microbiota distinctly contribute to immunometabolic changes in the human cervix, leading to these sequelae. Our 3D epithelial cell model that recapitulates the human cervical epithelium was infected with clinical isolates of cervicovaginal bacteria, alone or as a polymicrobial community. We used Lactobacillus crispatus as a representative health-associated commensal and four common BV-associated species: Gardnerella vaginalis, Prevotella bivia, Atopobium vaginae, and Sneathia amnii. The immunometabolic profiles of these microenvironments were analyzed using multiplex immunoassays and untargeted global metabolomics. A. vaginae and S. amnii exhibited the highest proinflammatory potential through induction of cytokines, iNOS, and oxidative stress-associated compounds. G. vaginalis, P. bivia, and S. amnii distinctly altered physicochemical barrier-related proteins and metabolites (mucins, sialic acid, polyamines), whereas L. crispatus produced an antimicrobial compound, phenyllactic acid. Alterations to the immunometabolic landscape correlate with symptoms and hallmarks of BV and connected BV with adverse women’s health outcomes. Overall, this study demonstrated that 3D cervical epithelial cell colonized with cervicovaginal microbiota faithfully reproduce the immunometabolic microenvironment previously observed in clinical studies and can successfully be used as a robust tool to evaluate host responses to commensal and pathogenic bacteria in the female reproductive tract.

scholarly journals Human Three-Dimensional Endometrial Epithelial Cell Model To Study Host Interactions with Vaginal Bacteria and Neisseria gonorrhoeae

2017 ◽  
Vol 85 (3) ◽  
Author(s):  
Paweł Łaniewski ◽  
Adriana Gomez ◽  
Geoffrey Hire ◽  
Magdalene So ◽  
Melissa M. Herbst-Kralovetz
Keyword(s):  
Epithelial Cell ◽  
Neisseria Gonorrhoeae ◽  
Pathogenic Bacteria ◽  
Three Dimensional ◽  
Female Reproductive Tract ◽  
Content Type ◽  
Endometrial Epithelial Cell ◽  
Proinflammatory Mediators ◽  
Microbe Interactions ◽  
Host Microbe Interactions

ABSTRACT Colonization of the endometrium by pathogenic bacteria ascending from the lower female reproductive tract (FRT) is associated with many gynecologic and obstetric health complications. To study these host-microbe interactions in vitro, we developed a human three-dimensional (3-D) endometrial epithelial cell (EEC) model using the HEC-1A cell line and the rotating wall vessel (RWV) bioreactor technology. Our model, composed of 3-D EEC aggregates, recapitulates several functional/structural characteristics of human endometrial epithelial tissue, including cell differentiation, the presence of junctional complexes/desmosomes and microvilli, and the production of membrane-associated mucins and Toll-like receptors (TLRs). TLR function was evaluated by exposing the EEC aggregates to viral and bacterial products. Treatment with poly(I·C) and flagellin but not with synthetic lipoprotein (fibroblast-stimulating lipoprotein 1 [FSL-1]) or lipopolysaccharide (LPS) significantly induced proinflammatory mediators in a dose-dependent manner. To simulate ascending infection, we infected EEC aggregates with commensal and pathogenic bacteria: Lactobacillus crispatus, Gardnerella vaginalis, and Neisseria gonorrhoeae. All vaginal microbiota and N. gonorrhoeae efficiently colonized the 3-D surface, localizing to crevices of the EEC model and interacting with multiple adjacent cells simultaneously. However, only infection with pathogenic N. gonorrhoeae and not infection with the other bacteria tested significantly induced proinflammatory mediators and significant ultrastructural changes to the host cells. The latter observation is consistent with clinical findings and illustrated the functional specificity of our system. Additionally, we highlighted the utility of the 3-D EEC model for the study of the pathogenesis of N. gonorrhoeae using a well-characterized ΔpilT mutant. Overall, this study demonstrates that the human 3-D EEC model is a robust tool for studying host-microbe interactions and bacterial pathogenesis in the upper FRT.

scholarly journals Diagnosing Bacterial Vaginosis with a Novel, Clinically-Actionable Molecular Diagnostic Tool

2018 ◽  
Author(s):  
Joseph P. Jarvis ◽  
Doug Rains ◽  
Steven J. Kradel ◽  
James Elliott ◽  
Evan E. Diamond ◽  
...  
Keyword(s):  
Bacterial Vaginosis ◽  
Pathogenic Bacteria ◽  
Reproductive Age ◽  
Medical Decision ◽  
Molecular Diagnostic ◽  
Diagnostic Tools ◽  
Lactobacillus Species ◽  
Research Subjects ◽  
Asymptomatic Patients ◽  
Increased Risk

Abstract/SummaryBacterial vaginosis is a common condition among women of reproductive age and is associated with potentially serious side-effects, including an increased risk of preterm birth. Recent advancements in microbiome sequencing technologies have produced novel insights into the complicated mechanisms underlying bacterial vaginosis and have given rise to new methods of diagnosis. Here we report on the validation of a quantitative, molecular diagnostic algorithm based on the relative abundances of ten potentially pathogenic bacteria and four commensal Lactobacillus species in research subjects (n = 172) classified as symptomatic (n = 149) or asymptomatic (n = 23). We observe a clear and reinforcing pattern among patients diagnosed by the algorithm that is consistent with the current understanding of biological dynamics and dysregulation of the vaginal microbiome during infection. Using this enhanced assessment of the underlying biology of infection, we demonstrate improved diagnostic sensitivity (93%) and specificity (90%) relative to current diagnostic tools. Our algorithm also appears to provide enhanced diagnostic capabilities in ambiguous classes of patients for whom diagnosis and medical decision-making is complicated, including asymptomatic patients and those deemed “intermediate” by Nugent scoring. Ultimately, we establish CLS2.0q as a quantitative, sensitive, specific, accurate, robust, and flexible algorithm for the clinical diagnosis of bacterial vaginosis – importantly, one that is also ideal for the differential diagnosis of non-BV infections with clinically similar presentations.

scholarly journals An Updated Conceptual Model on the Pathogenesis of Bacterial Vaginosis

2019 ◽  
Vol 220 (9) ◽  
pp. 1399-1405 ◽  
Author(s):  
Christina A Muzny ◽  
Christopher M Taylor ◽  
W Edward Swords ◽  
Ashutosh Tamhane ◽  
Debasish Chattopadhyay ◽  
...  
Keyword(s):  
Bacterial Vaginosis ◽  
Conceptual Model ◽  
Sexual Transmission ◽  
Gardnerella Vaginalis ◽  
Extensive Literature ◽  
Sexually Transmitted ◽  
Virulent Strains ◽  
Prevotella Bivia ◽  
Increased Risk ◽  
Immunodeficiency Virus

Abstract Bacterial vaginosis (BV) is the most common cause of vaginal discharge. It is associated with an increased risk of preterm delivery, pelvic inflammatory disease, and an increased risk of acquisition of sexually transmitted infections including human immunodeficiency virus (HIV). The epidemiology of BV supports sexual transmission. However, its etiology remains unknown. At the center of the debate is whether BV is caused by a primary pathogen or a polymicrobial consortium of microorganisms that are sexually transmitted. We previously published a conceptual model hypothesizing that BV is initiated by sexual transmission of Gardnerella vaginalis. Critics of this model have iterated that G. vaginalis is found in virginal women and in sexually active women with a normal vaginal microbiota. In addition, colonization does not always lead to BV. However, recent advances in BV pathogenesis research have determined the existence of 13 different species within the genus Gardnerella. It may be that healthy women are colonized by nonpathogenic Gardnerella species, whereas virulent strains are involved in BV development. Based on our results from a recent prospective study, in addition to an extensive literature review, we present an updated conceptual model for the pathogenesis of BV that centers on the roles of virulent strains of G. vaginalis, as well as Prevotella bivia and Atopobium vaginae.

scholarly journals Taxonomical and Functional Assessment of the Endometrial Microbiota in A Context of Recurrent Reproductive Failure: A Case Report

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 205 ◽  
Author(s):  
Iolanda Garcia-Grau ◽  
David Perez-Villaroya ◽  
Davide Bau ◽  
Marta Gonzalez-Monfort ◽  
Felipe Vilella ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Reproductive Tract ◽  
16S Rrna Gene Sequencing ◽  
Reproductive Failure ◽  
Female Reproductive Tract ◽  
Gardnerella Vaginalis ◽  
Rrna Gene ◽  
Microbial Profile ◽  
Genetic Features ◽  
Metagenome Sequencing

Investigation of the microbial community in the female reproductive tract has revealed that the replacement of a community dominated by Lactobacillus with pathogenic bacteria may be associated with implantation failure or early spontaneous abortion in patients undergoing assisted reproductive technology (ART) treatment. Herein we describe taxonomically and functionally the endometrial microbiome of an infertile patient with repeated reproductive failures (involving an ectopic pregnancy and two clinical miscarriages). The microbiological follow-up is presented over 18-month in which the microbiota was evaluated in six endometrial fluid samples. The microbial profile of 16S rRNA gene sequencing showed a persistent infection with Gardnerella and other bacterial taxa such as Atopobium and Bifidobacterium. In addition, taxonomic and functional analysis by whole metagenome sequencing in the endometrial fluid sample collected before one clinical miscarriage suggested the presence of multiple Gardnerella vaginalis clades with a greater abundance of clade 4, usually associated with metronidazole resistance. These results revealed a persistent G. vaginalis endometrial colonization presenting genetic features consistent with antimicrobial resistance, biofilm formation, and other virulence factors, which could be related to the reproductive failure observed.

scholarly journals Finding a Balance in the Vaginal Microbiome: How Do We Treat and Prevent the Occurrence of Bacterial Vaginosis?

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 719
Author(s):  
Rebecca Jane Joseph ◽  
Hooi-Leng Ser ◽  
Yi-He Kuai ◽  
Loh Teng-Hern Tan ◽  
Valliammai Jayanthi Thirunavuk Arasoo ◽  
...  
Keyword(s):  
Bacterial Vaginosis ◽  
Reproductive Tract ◽  
Vaginal Microbiota ◽  
Female Reproductive Tract ◽  
Gardnerella Vaginalis ◽  
Vaginal Microbiome ◽  
Health Issues ◽  
Healthy State ◽  
Vaginal Health ◽  
Pathogenic Microbes

Bacterial vaginosis (BV) has been reported in one-third of women worldwide at different life stages, due to the complex balance in the ecology of the vaginal microbiota. It is a common cause of abnormal vaginal discharge and is associated with other health issues. Since the first description of anaerobic microbes associated with BV like Gardnerella vaginalis in the 1950s, researchers have stepped up the game by incorporating advanced molecular tools to monitor and evaluate the extent of dysbiosis within the vaginal microbiome, particularly on how specific microbial population changes compared to a healthy state. Moreover, treatment failure and BV recurrence rate remain high despite the standard antibiotic treatment. Consequently, researchers have been probing into alternative or adjunct treatments, including probiotics or even vaginal microbiota transplants, to ensure successful treatment outcomes and reduce the colonization by pathogenic microbes of the female reproductive tract. The current review summarizes the latest findings in probiotics use for BV and explores the potential of vaginal microbiota transplants in restoring vaginal health.

scholarly journals The Female Vaginal Microbiome in Health and Bacterial Vaginosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaodi Chen ◽  
Yune Lu ◽  
Tao Chen ◽  
Rongguo Li
Keyword(s):  
Bacterial Vaginosis ◽  
Therapeutic Strategies ◽  
Reproductive Age ◽  
Gardnerella Vaginalis ◽  
Obstetric Outcomes ◽  
Antimicrobial Compounds ◽  
Vaginal Microbiome ◽  
Sharp Decline ◽  
Women Of Reproductive Age ◽  
Sexually Transmitted

The vaginal microbiome is an intricate and dynamic microecosystem that constantly undergoes fluctuations during the female menstrual cycle and the woman’s entire life. A healthy vaginal microbiome is dominated by Lactobacillus which produce various antimicrobial compounds. Bacterial vaginosis (BV) is characterized by the loss or sharp decline in the total number of Lactobacillus and a corresponding marked increase in the concentration of anaerobic microbes. BV is a highly prevalent disorder of the vaginal microbiota among women of reproductive age globally. BV is confirmed to be associated with adverse gynecologic and obstetric outcomes, such as sexually transmitted infections, pelvic inflammatory disease, and preterm birth. Gardnerella vaginalis is the most common microorganism identified from BV. It is the predominant microbe in polymicrobial biofilms that could shelter G. vaginalis and other BV-associated microbes from adverse host environments. Many efforts have been made to increase our understanding of the vaginal microbiome in health and BV. Thus, improved novel and accurate diagnosis and therapeutic strategies for BV have been developed. This review covers the features of vaginal microbiome, BV, BV-associated diseases, and various strategies of diagnosis and treatment of BV, with an emphasis on recent research progresses.

scholarly journals Microbial Composition Predicts Genital Tract Inflammation and Persistent Bacterial Vaginosis in South African Adolescent Females

2017 ◽  
Vol 86 (1) ◽  
Author(s):  
Katie Lennard ◽  
Smritee Dabee ◽  
Shaun L. Barnabas ◽  
Enock Havyarimana ◽  
Anna Blakney ◽  
...  
Keyword(s):  
Bacterial Vaginosis ◽  
South African ◽  
Adolescent Females ◽  
Gardnerella Vaginalis ◽  
Rrna Gene ◽  
Vaginal Microbiome ◽  
Microbial Composition ◽  
Content Type ◽  
Specificity And Sensitivity ◽  
Increased Risk

ABSTRACTYoung African females are at an increased risk of HIV acquisition, and genital inflammation or the vaginal microbiome may contribute to this risk. We studied these factors in 168 HIV-negative South African adolescent females aged 16 to 22 years. Unsupervised clustering of 16S rRNA gene sequences revealed three clusters (subtypes), one of which was strongly associated with genital inflammation. In a multivariate model, the microbiome compositional subtype and hormonal contraception were significantly associated with genital inflammation. We identified 40 taxa significantly associated with inflammation, including those reported previously (Prevotella,Sneathia,Aerococcus,Fusobacterium, andGemella) as well as several novel taxa (including increased frequencies of bacterial vaginosis-associated bacterium 1 [BVAB1], BVAB2, BVAB3,Prevotella amnii,Prevotella pallens,Parvimonas micra,Megasphaera,Gardnerella vaginalis, andAtopobium vaginaeand decreased frequencies ofLactobacillus reuteri,Lactobacillus crispatus,Lactobacillus jensenii, andLactobacillus iners). Women with inflammation-associated microbiomes had significantly higher body mass indices and lower levels of endogenous estradiol and luteinizing hormone. Community functional profiling revealed three distinct vaginal microbiome subtypes, one of which was characterized by extreme genital inflammation and persistent bacterial vaginosis (BV); this subtype could be predicted with high specificity and sensitivity based on the Nugent score (≥9) or BVAB1 abundance. We propose that women with this BVAB1-dominated subtype may have chronic genital inflammation due to persistent BV, which may place them at a particularly high risk for HIV infection.

scholarly journals Gardnerella vaginalis and Prevotella bivia Trigger Distinct and Overlapping Phenotypes in a Mouse Model of Bacterial Vaginosis

2019 ◽  
Vol 220 (7) ◽  
pp. 1099-1108 ◽  
Author(s):  
Nicole M Gilbert ◽  
Warren G Lewis ◽  
Guocai Li ◽  
Dorothy K Sojka ◽  
Jean Bernard Lubin ◽  
...  
Keyword(s):  
Bacterial Vaginosis ◽  
Reproductive Tract ◽  
Adverse Outcomes ◽  
Gardnerella Vaginalis ◽  
Sialidase Activity ◽  
Ascending Infection ◽  
Prevotella Bivia ◽  
Increased Risk ◽  
Adverse Pregnancy ◽  
Tract Infections

AbstractBackgroundBacterial vaginosis (BV) is a common imbalance of the vaginal microbiota characterized by overgrowth of diverse Actinobacteria, Firmicutes, and Gram-negative anaerobes. Women with BV are at increased risk of secondary reproductive tract infections and adverse pregnancy outcomes. However, which specific bacteria cause clinical features of BV is unclear.MethodsWe previously demonstrated that Gardnerella vaginalis could elicit many BV features in mice. In this study, we established a BV model in which we coinfected mice with G. vaginalis and another species commonly found in women with BV: Prevotella bivia.ResultsThis coinfection model recapitulates several aspects of human BV, including vaginal sialidase activity (a diagnostic BV feature independently associated with adverse outcomes), epithelial exfoliation, and ascending infection. It is notable that G. vaginalis facilitated uterine infection by P. bivia.ConclusionsTaken together, our model provides a framework for advancing our understanding of the role of individual or combinations of BV-associated bacteria in BV pathogenesis.

scholarly journals Interleukin-36γ Is Elevated in Cervicovaginal Epithelial Cells in Women With Bacterial Vaginosis and In Vitro After Infection With Microbes Associated With Bacterial Vaginosis

2019 ◽  
Vol 221 (6) ◽  
pp. 983-988 ◽  
Author(s):  
Jameson K Gardner ◽  
Paweł Łaniewski ◽  
Anna Knight ◽  
Lisa B Haddad ◽  
Alison Swaims-Kohlmeier ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Bacterial Vaginosis ◽  
Host Response ◽  
Cell Model ◽  
Bacterial Species ◽  
Clinical Samples ◽  
Sexually Transmitted ◽  
3 Dimensional

Abstract In recent studies, the interleukin (IL)-36 cytokines were shown to be elevated in women with non-Lactobacillus-dominated vaginal microbiomes. In this study, we evaluated IL36G expression in clinical samples from women with and without bacterial vaginosis (BV) and a human 3-dimensional cervical epithelial cell model. IL36G expression was significantly elevated in cervicovaginal epithelial cells isolated from BV-positive women and corresponded with increased neutrophil counts relative to BV-negative women. In addition, specific BV-associated bacterial species as well as a polymicrobial cocktail significantly induced IL36G expression in vitro. These findings suggest that IL-36γ may exhibit an important function in the host response to BV and other sexually transmitted infections.

scholarly journals Veillonellaceae family members uniquely alter the cervical metabolic microenvironment in a human three-dimensional epithelial model

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Mary E. Salliss ◽  
Jason D. Maarsingh ◽  
Camryn Garza ◽  
Paweł Łaniewski ◽  
Melissa M. Herbst-Kralovetz
Keyword(s):  
Epithelial Cell ◽  
Reproductive Health ◽  
Cell Membrane ◽  
Bacterial Vaginosis ◽  
Inflammatory Mediators ◽  
Membrane Lipids ◽  
Cell Model ◽  
Three Dimensional ◽  
Cell Cytotoxicity ◽  
Significant Elevation

AbstractBacterial vaginosis (BV) is a gynecologic disorder characterized by a shift in cervicovaginal microbiota from Lactobacillus spp. dominance to a polymicrobial biofilm composed of diverse anaerobes. We utilized a well-characterized human three-dimensional cervical epithelial cell model in conjunction with untargeted metabolomics and immunoproteomics analyses to determine the immunometabolic contribution of three members of the Veillonellaceae family: Veillonella atypica, Veillonella montpellierensis and Megasphaera micronuciformis at this site. We found that Veillonella spp. infections induced significant elevation of polyamines. M. micronuciformis infections significantly increased soluble inflammatory mediators, induced moderate levels of cell cytotoxicity, and accumulation of cell membrane lipids relative to Veillonella spp. Notably, both V. atypica and V. montpellierensis infections resulted in consumption of lactate, a key metabolite linked to gynecologic and reproductive health. Collectively our approach and data provide unique insights into the specific contributions of Veillonellaceae members to the pathogenesis of BV and women’s health.

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