Novel systems analysis elucidates the influence of personalized variation in microbiome composition on metronidazole efficacy in bacterial vaginosis

Abstract Bacterial vaginosis (BV) is a syndrome of the female reproductive tract associated with adverse reproductive outcomes and characterized by a shift from a Lactobacillus (LB)-dominant vaginal microbiota to a polymicrobial, anaerobic microbiota, consistently colonized by strains of Gardnerella vaginalis (Gv). The first-line treatment for BV is metronidazole (MNZ); however, treatment failure and recurrence rates remain high. To gain insight into complex interactions between target species (Gv) and non-target Lactobacillus species (Lactobacillus iners (Li)) with MNZ and understand their respective roles in efficacy, we developed an ordinary differential equation model that predicts bacterial growth as a function of drug uptake, metabolism, proliferation, and MNZ sensitivity. Model findings revealed a critical factor in MNZ efficacy may be Li sequestration of MNZ, and that efficacy decreases when the relative abundance of Li is higher pre-treatment. These results were validated in Gv and Li co-cultures (p < 0.001), and in two clinical cohorts, finding women with recurrent BV had significantly lower pre-treatment levels of BV-associated bacteria relative to Lactobacillus spp. (p = 0.0366; p = 0.0484). Overall, model results support a mechanism where non-target Lactobacillus species sequester MNZ from BV-associated target species, such as Gv, promoting BV recurrence by reducing MNZ bioavailability.

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Quantitative modeling predicts mechanistic links between pre-treatment microbiome composition and metronidazole efficacy in bacterial vaginosis

Nature Communications ◽

10.1038/s41467-020-19880-w ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Christina Y. Lee ◽

Ryan K. Cheu ◽

Melissa M. Lemke ◽

Andrew T. Gustin ◽

Michael T. France ◽

...

Keyword(s):

Bacterial Vaginosis ◽

Critical Factor ◽

Equation Model ◽

Gardnerella Vaginalis ◽

Recurrence Rates ◽

Associated Bacteria ◽

Microbiome Composition ◽

Complex Interactions ◽

Pre Treatment ◽

Antibiotic Efficacy

AbstractBacterial vaginosis is a condition associated with adverse reproductive outcomes and characterized by a shift from a Lactobacillus-dominant vaginal microbiota to a polymicrobial microbiota, consistently colonized by strains of Gardnerella vaginalis. Metronidazole is the first-line treatment; however, treatment failure and recurrence rates remain high. To understand complex interactions between Gardnerella vaginalis and Lactobacillus involved in efficacy, here we develop an ordinary differential equation model that predicts bacterial growth as a function of metronidazole uptake, sensitivity, and metabolism. The model shows that a critical factor in efficacy is Lactobacillus sequestration of metronidazole, and efficacy decreases when the relative abundance of Lactobacillus is higher pre-treatment. We validate results in Gardnerella and Lactobacillus co-cultures, and in two clinical cohorts, finding women with recurrence have significantly higher pre-treatment levels of Lactobacillus relative to bacterial vaginosis–associated bacteria. Overall results provide mechanistic insight into how personalized differences in microbial communities influence vaginal antibiotic efficacy.

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

Antibiotics ◽

10.3390/antibiotics10060719 ◽

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.

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Gardnerella Vaginalis Associated Bacterial Vaginosis: A Review Article

Archives of Health Science ◽

10.31829/2641-7456/ahs2021-5(1)-011 ◽

2021 ◽

pp. 1-8

Keyword(s):

Bacterial Vaginosis ◽

Reproductive Tract ◽

Sexual Experience ◽

Bacterial Species ◽

Anaerobic Bacteria ◽

Clinical Syndrome ◽

Sexual Contact ◽

Sexual Partners ◽

Female Reproductive Tract ◽

Gardnerella Vaginalis

Introduction: Gardnerella vaginalis is associated with bacterial vaginosis. Bacterial vaginosis (bacterial vaginosis = BV) is a clinical syndrome due to replacement of Lactobacillus spp. producing hydrogen peroxidase (H2O2) in normal vagina with high concentrations of anaerobic bacteria (eg Bacteroides spp., Mobiluncus spp.), this clinical syndrome also has other names, namely Haemophilus vaginalis vaginitis, nonspecific vaginitis or Gardnerella vaginalis vaginitis. Because the cause of BV is bacteria which are normal vaginal flora, BV is referred to as an endogenous infection in the female reproductive tract. Previous published research on BV has shown disagreements about transmission through sexual contact. Post-puberty women without sexual experience experience BV less frequently than those who have sexual experience. However, longitudinal cohort studies provide evidence that women who have new sexual partners or have multiple sexual partners have an increased incidence of BV.The likelihood that a woman has BV has a 20-fold increase in risk if her partner has BV. This raises the suggestion that it is possible that BV can be transmitted through sexual contact. However, there was no association between the incidence of BV with smoking habits, a history of abnormal Pap smears, menstruation, and menarche. Aim of this article is to review gardnerella vaginalis infection in bacterial vaginosis. Discussion: The presence of sexually transmitted diseases can also increase the risk of bacterial vaginosis. The normal vaginal ecosystem is a complex aspect. Lactobacillius is the dominant bacterial species (normal flora) in the vagina of women of childbearing age, but there are also other bacteria, namely aerobic and anaerobic bacteria. At the time BV appears, there is an overgrowth of some bacterial species which are normally present in low concentrations. Therefore, BV is categorized as an endogenous infection of the female reproductive tract.. Women with positive G. vaginalis cultures do not need routine therapy, unless they have BV symptomatically. All women with symptomatic BV require treatment, including pregnant women. Treatment of BV in pregnant women is to relieve signs and symptoms of vaginal infection, reduce the risk of infectious complications that accompany BV during pregnancy, and decrease other risk factors. Several studies using placebo have shown that treatment of sexual partners of women with BV does not improve clinical outcome of BV or decrease recurrence. Conclusion: BV has a favorable prognosis, and spontaneous improvement is reported in over one-third of cases. With the treatment of metronidazole and clindamycin gave a high cure rate (84 - 96%).Prevention needs to be done to minimize the actions that can be taken to prevent bacterial vaginosis.

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Efficacy and safety of a novel vaginal medical device in recurrent bacterial vaginosis: an international multicentre clinical trial

10.1101/674705 ◽

2019 ◽

Author(s):

Filippo Murina ◽

Ciprian Crişan ◽

Marius Biriş ◽

Daniela Sîrbu ◽

Dionisio Franco Barattini ◽

...

Keyword(s):

Bacterial Vaginosis ◽

Medical Device ◽

Recurrence Rate ◽

Vaginal Flora ◽

Gardnerella Vaginalis ◽

Lactobacillus Species ◽

Published Data ◽

Childbearing Age ◽

Open Label ◽

Adverse Pregnancy

ABSTRACTSeveral risk factors have been identified but the etiology and pathogenesis of Bacterial vaginosis (BV) are still not completely understood, and the recurrence rate of BV remains high despite adequate chemotherapy treatment.The primary objective of the study was to assess the effectiveness of a new vaginal medical device, which contains polycarbophil, 0.04 % lauryl glucoside, and glycerides (Polybactum®– Effik Italia), in reducing BV recurrence rate.This was a multicenter, open label, not comparative study performed in Italy and Romania. Female subjects over 18-years-old affected by recurrent BV were included. The latest episode was diagnosed by Amsel criteria 6-9 days before the start of the study and treated with vaginal metronidazole (gel 0.75% mg for 5 days or ovules 500 mg for 7 days). The recurrence was defined by at least 2 episodes in the previous 12 months. Polybactum®vaginal ovules, day 1-4-7, were started within the 12th and the 24th hr after the end of metronidazole therapy and repeated monthly for 3 cycles.The first 41 patients enrolled were evaluated for an interim analysis 6 months after the study started; 2 patients interrupted the trial, leaving 39 evaluable subjects. The recurrence rate was significantly reduced compared to previous published data (10.26% vs 40% p<0.001). In 35 patients without recurrence, the assessment of Lactobacillus vaginal flora performed by phase contrast microscopy evidenced a significant improvement form baseline (p=0.022) The Investigator global assessment of tolerability was excellent in 38 out of 39 cases.IMPORTANCEBacterial vaginosis (BV) is the most common vaginal disorder in women of childbearing age. In BV, Lactobacillus species, which are predominant in a healthy vaginal flora, are replaced by anaerobes, mainly Gardnerella vaginalis. BV is responsible for more than 60% of vulvovaginal infections and has been linked to serious, potentially life-threatening conditions, including: pelvic inflammatory disease, postoperative infections, acquisition and transmission of the human immunodeficiency virus, preterm birth, and several adverse pregnancy outcomes. Our research showed that 3 monthly cycles of Polybactum®ovules administered after one course of metronidazole vaginal therapy can reduce the rate of Bacterial vaginosis recurrence and improve the vaginal milieu, favouring the growth of vaginal lactobacillus species. Taken together our results confirm that Polibactum®is a safe and effective treatment to reduce BV recurrence rate after a first line therapy with metronidazole.

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

Pathogens ◽

10.3390/pathogens8040205 ◽

2019 ◽

Vol 8 (4) ◽

pp. 205 ◽

Cited By ~ 4

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.

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Transkingdom Analysis of the Female Reproductive Tract Reveals Bacteriophages Form Communities

10.1101/2021.10.12.464088 ◽

2021 ◽

Author(s):

Ferralita S Madere ◽

Michael Sohn ◽

Angelina Winbush ◽

Breona Barr ◽

Alex Grier ◽

...

Keyword(s):

Bacterial Vaginosis ◽

South African ◽

Reproductive Tract ◽

Alpha Diversity ◽

Female Reproductive Tract ◽

African Women ◽

Complex Interactions ◽

Vaginal Health ◽

South African Women ◽

Community Clustering

The female reproductive tract (FRT) microbiome plays an important role in maintaining vaginal health. Viruses play a key role in regulating other microbial ecosystems, but little is known about how the FRT viruses (virome), particularly bacteriophages, impacts FRT health and dysbiosis. We hypothesize that bacterial vaginosis is associated with alterations in the FRT virome, and these changes correlate with bacteriome shifts. We conducted a retrospective, longitudinal analysis of vaginal swabs collected from 54 bacterial vaginosis (BV)-positive and 46 BV-negative South African women. Bacteriome analysis revealed samples clustered into five distinct bacterial community groups (CG). Bacterial alpha diversity was significantly associated with BV. Virome analysis on a subset of baseline samples showed FRT bacteriophages clustering into novel viral state types (VSTs), a viral community clustering system based on virome composition and abundance. Distinct BV bacteriophage signatures included increased alpha diversity along with Bacillus, Burkholderia and Escherichia bacteriophages. Discriminate bacteriophage-bacteria transkingdom associations were also identified between Bacillus and Burkholderia viruses and BV-associated bacteria, providing key insight for future studies elucidating transkingdom interactions driving BV-associated microbiome perturbations. In this cohort, bacteriophage-bacterial associations suggest complex interactions which may play a role in the establishment and maintenance of BV.

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P–196 Bacterial influence on oocyte quality - the secret of a successful fertilization

Human Reproduction ◽

10.1093/humrep/deab130.195 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

M Schenk ◽

E Voroshilina ◽

M Boldyreva ◽

M Koranda ◽

N Reinschissler ◽

...

Keyword(s):

Follicular Fluid ◽

Genital Tract ◽

Reproductive Tract ◽

Female Reproductive Tract ◽

Lactobacillus Species ◽

Bacterial Composition ◽

Vitro Fertilization ◽

Dna Technology ◽

Follicular Fluids

Abstract Study question Is there a difference in bacterial composition of follicular fluid between oocytes developing a good quality blastocyst and oocytes that fail fertilization? Summary answer Follicular fluids of oocytes failing fertilization show a different bacterial profile compared to follicular fluids of oocytes that were successfully fertilized. What is known already The presence of pathogens in the female reproductive tract has been intensively investigated. Lactobacillus species are mainly associated with a healthy genital tract and good prognosis for a successful pregnancy. Studies of the bacterial composition of follicular fluids have been mainly undertaken in women participating in reproductive medicine treatment because of the nature to obtain the specimen. In most studies follicular fluids have been pooled for analysis. Information on separately collected follicular fluids is still rare. We hypothesized that the composition of bacteria within follicular fluids is responsible for the success of the fertilization process. Study design, size, duration The study was designed and conducted at the Kinderwunsch Institut Schenk GmbH (Dobl, Austria) together with DNA-Technology. Follicular fluids from 46 patients undergoing IVF (in vitro fertilization) and ICSI (intracytoplasmic sperm injection) treatment were included and analyzed. Participants/materials, setting, methods Follicular fluids from 46 patients were collected separately. 2 follicular fluids from each patient were screened for common bacteria of the genital tract. One from an oocyte developing a good quality blastocyst and one displaying fertilization failures. Samples were analyzed for bacterial composition using the Femoflor16 (DNA-Technology). Main results and the role of chance Quantitative analysis revealed a higher total bacteria mass in follicles from oocytes that failed fertilization. Furthermore, Lactobacillus were not present in those follicles compared to good blastocyst follicles. In addition, Chlamydia trachomatis was found mainly in follicular fluid of not fertilized oocytes together with Eubacterium, Gardnarella and Trichomonas species. Interestingly, a trend of elevated levels of Ureaplasma species in follicular fluids of oocytes developing good quality blastocysts was observed. Limitations, reasons for caution Contamination of follicular fluids due to the procedure of oocyte pick up and follicular fluid retrieval cannot be completely excluded. Results should be confirmed with a higher sample size. Wider implications of the findings: We assume that different bacterial compositions in follicular fluids are responsible for the destiny of the oocyte. It is tempting to speculate that bacterial analysis of follicular fluids may be beneficial to select to best oocytes in future IVF/ICSI treatments. Trial registration number Not applicable

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

The Journal of Infectious Diseases ◽

10.1093/infdis/jiy704 ◽

2019 ◽

Vol 220 (7) ◽

pp. 1099-1108 ◽

Cited By ~ 13

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.

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

npj Biofilms and Microbiomes ◽

10.1038/s41522-021-00259-8 ◽

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.

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Matrix Metalloproteinases Expressed in Response to Bacterial Vaginosis Disrupt the Endocervical Epithelium, Increasing Transmigration of HIV

Infection and Immunity ◽

10.1128/iai.00041-20 ◽

2020 ◽

Vol 88 (4) ◽

Author(s):

Michelle D. Cherne ◽

Amy L. Cole ◽

Lisa Newberry ◽

Mary Schmidt-Owens ◽

Michael Deichen ◽

...

Keyword(s):

Matrix Metalloproteinases ◽

Hiv Infection ◽

Bacterial Vaginosis ◽

Reproductive Tract ◽

Female Reproductive Tract ◽

Target Cells ◽

Barrier Dysfunction ◽

Host Matrix ◽

Mmp Inhibitor ◽

Hiv 1

ABSTRACT Bacterial vaginosis (BV), a disorder of the female reproductive tract (FRT) in which a healthy Lactobacillus-dominant microflora is replaced by BV-associated bacteria (BVAB), can significantly increase the incidence of human immunodeficiency virus (HIV) acquisition. Discerning the effect of BV on the mucosal epithelium of the FRT may yield novel preventatives and therapeutics for HIV infection. Here, we investigated barrier dysfunction of the endocervix by host-derived factors, secreted in response to BV, as a potential cause of HIV infection. Using a polarized endocervical cell culture system, we determined that conditioned media (CM) from endocervical cells cocultured with BVAB (endocervical+BVAB CM), as well as cervicovaginal fluid (CVF) from women with BV, disrupted epithelial polarization. We assessed host matrix metalloproteinases (MMPs) as the BV-associated secreted factors which disrupt the endocervical epithelium. MMPs were overexpressed in endocervical+BVAB CM and CVF from women with BV and were capable of disrupting endocervical epithelial polarization. When we cocultured polarized endocervical cells with HIV-1-infected lymphocyte-derived cells, we discovered endocervical+BVAB CM and MMPs significantly increased the transmigration of virus through the epithelium, and treatment with an MMP inhibitor decreased these effects. When we examined the effect of CVF on HIV-1 transmigration through endocervical epithelium, we demonstrated that CVF samples with greater concentrations of BV-associated MMPs increased viral transmigration. Our results suggest MMPs increase HIV-1 infection by disrupting the endocervical epithelium, permitting transmigration of virus through the epithelium to infect underlying target cells.

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