Modeling the temporal dynamics of cervicovaginal microbiota identifies targets that may promote reproductive health

Munoz, Alexander; Hayward, Matthew R.; Bloom, Seth M.; Rocafort, Muntsa; Ngcapu, Sinaye; Mafunda, Nomfuneko A.; Xu, Jiawu; Xulu, Nondumiso; Dong, Mary; Dong, Krista; Ndung’u, Thumbi; Ghebermichael, Musie S.; Kwon, Douglas S.

doi:10.1186/s40168-021-01096-9

Cited by 31 publications

(34 citation statements)

References 42 publications

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“…By contrast, FGT bacterial communities dominated by Lactobacillus crispatus and most other Lactobacillus species are generally considered optimal for health 9 . One notable exception involves communities dominated by Lactobacillus iners, the most prevalent and abundant FGT species worldwide 11 , which are associated with many of the same unfavorable outcomes as BV 1,7,12 and have higher risk of transitioning to BV and BV-like communities 3,[13][14][15][16][17] . However factors influencing the balance between L. iners and more health-associated lactobacilli are incompletely understood 16,18 .…”

Section: Main Textmentioning

confidence: 99%

Cysteine dependence of Lactobacillus iners is a potential therapeutic target for vaginal microbiota modulation

et al. 2022

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Vaginal microbiota composition affects many facets of reproductive health. Lactobacillus inersdominant microbial communities are associated with poorer outcomes, including higher risk of bacterial vaginosis (BV), compared with vaginal microbiota rich in Lactobacillus crispatus.Unfortunately, standard-of-care metronidazole therapy for BV typically results in dominance of L. iners, likely contributing to post-treatment relapse. Here we generate an L. iners isolate collection comprising 34 previously unreported isolates from 14 South African with and without BV and 4 previously unreported isolates from 3 US women and we report an associated genome catalog comprising 1,218 vaginal Lactobacillus isolate genomes and metagenome-assembled genomes (MAGs) from >300 women across four continents. We show that, unlike L. crispatus, L. iners growth is dependent on L-cysteine in vitro and we trace this phenotype to the absence of canonical cysteine biosynthesis pathways and a restricted repertoire of cysteine-related transport mechanisms. We further show cysteine concentrations in cervicovaginal lavage samples correlate with Lactobacillus abundance in vivo and that cystine uptake inhibitors selectively inhibit L. iners growth in vitro. Combining an inhibitor with metronidazole promotes L. crispatus dominance of defined BV-like communities in vitro by suppressing L. iners growth. Our findings enable a better understanding of L. iners biology and suggest candidate treatments to modulate the vaginal microbiota to improve reproductive health for women globally.

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Section: Main Textmentioning

confidence: 99%

Cysteine dependence of Lactobacillus iners is a potential therapeutic target for vaginal microbiota modulation

et al. 2022

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“…We selected samples from a subset of 30 participants for paired transcriptome-microbiome analysis to ensure distribution of participants across the four vaginal microbiota community types as determined by bacterial 16S rRNA gene sequencing ( Figure 1 and Table 1 ). We have previously established a classification system that divides the FGT microbial communities into four cervicotypes (CTs) ( Gosmann et al., 2017 ; Munoz et al., 2021 ). CT1 is dominated by Lactobacillus crispatus and CT2 is dominated by Lactobacillus iners .…”

Section: Resultsmentioning

confidence: 99%

Antigen Presenting Cells Link the Female Genital Tract Microbiome to Mucosal Inflammation, With Hormonal Contraception as an Additional Modulator of Inflammatory Signatures

Byrne

Fărcăşanu

Bloom

et al. 2021

Front. Cell. Infect. Microbiol.

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The microbiome of the female genital tract (FGT) is closely linked to reproductive health outcomes. Diverse, anaerobe-dominated communities with low Lactobacillus abundance are associated with a number of adverse reproductive outcomes, such as preterm birth, cervical dysplasia, and sexually transmitted infections (STIs), including HIV. Vaginal dysbiosis is associated with local mucosal inflammation, which likely serves as a biological mediator of poor reproductive outcomes. Yet the precise mechanisms of this FGT inflammation remain unclear. Studies in humans have been complicated by confounding demographic, behavioral, and clinical variables. Specifically, hormonal contraception is associated both with changes in the vaginal microbiome and with mucosal inflammation. In this study, we examined the transcriptional landscape of cervical cell populations in a cohort of South African women with differing vaginal microbial community types. We also investigate effects of reproductive hormones on the transcriptional profiles of cervical cells, focusing on the contraceptive depot medroxyprogesterone acetate (DMPA), the most common form of contraception in sub-Saharan Africa. We found that antigen presenting cells (APCs) are key mediators of microbiome associated FGT inflammation. We also found that DMPA is associated with significant transcriptional changes across multiple cell lineages, with some shared and some distinct pathways compared to the inflammatory signature seen with dysbiosis. These results highlight the importance of an integrated, systems-level approach to understanding host-microbe interactions, with an appreciation for important variables, such as reproductive hormones, in the complex system of the FGT mucosa.

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“…A paucity of Lactobacillus and a diverse array of strict and facultative anaerobes, however, are associated with negative health outcomes such as preterm birth (4,5) and susceptibility to sexually transmitted infections (6)(7)(8)(9), including HIV (10)(11)(12). Some Lactobacillus species, such as L. crispatus or L. gasseri, are more robustly resistant to invasion or replacement by non-Lactobacillus species and create greater vaginal ecosystem stability during and outside of pregnancy (13)(14)(15). Other Lactobacillus species, such as L. iners, are more frequently associated with non-optimal communities (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

“…Some Lactobacillus species, such as L. crispatus or L. gasseri, are more robustly resistant to invasion or replacement by non-Lactobacillus species and create greater vaginal ecosystem stability during and outside of pregnancy (13)(14)(15). Other Lactobacillus species, such as L. iners, are more frequently associated with non-optimal communities (13)(14)(15). In some individuals, the vaginal microbiota structure may change several times over the course of a few months or even a few days (4,13,14,16).…”

Section: Introductionmentioning

confidence: 99%

Sub-communities of the vaginal microbiota in pregnant and non-pregnant women

Symul

Jeganathan

Costello

et al. 2021

Preprint

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Diverse and non-Lactobacillus-dominated vaginal microbial communities are associated with adverse health outcomes such as preterm birth and acquisition of sexually transmitted infections. Despite the importance of recognizing and understanding the key risk-associated features of these communities, their heterogeneous structure and properties remain ill-defined. Clustering approaches have been commonly used to characterize vaginal communities, but they lack sensitivity and robustness in resolving community substructures and revealing transitions between potential sub-communities. We used a more highly resolved approach based on mixed membership topic models with multi-domain longitudinal data from cohorts of pregnant and non-pregnant subjects to identify several non-Lactobacillus-dominated sub-communities common to women regardless of reproductive status. These sub-communities correlated with clusters of metabolites. In non-pregnant subjects, we identified a few sub-communities that were more common during menses but did not predict an increased likelihood of non-Lactobacillus-dominated communities during the rest of the menstrual cycle. The menstrual cycle was a strong driver of transitions between sub-communities and was correlated with changes in levels of cytokines, for example, elevated TNF-α concentrations at the time of ovulation, and metabolites, for example, elevated kynurenine concentrations during menses. In pregnant women, some metabolite clusters were predictive of changes in vaginal microbiota structure. Overall, our results show that the vaginal community substructure is shaped by the menstrual cycle and that specific sets of metabolites are associated with community instability during pregnancy.

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Modeling the temporal dynamics of cervicovaginal microbiota identifies targets that may promote reproductive health

Cited by 31 publications

References 42 publications

Cysteine dependence of Lactobacillus iners is a potential therapeutic target for vaginal microbiota modulation

Cysteine dependence of Lactobacillus iners is a potential therapeutic target for vaginal microbiota modulation

Antigen Presenting Cells Link the Female Genital Tract Microbiome to Mucosal Inflammation, With Hormonal Contraception as an Additional Modulator of Inflammatory Signatures

Sub-communities of the vaginal microbiota in pregnant and non-pregnant women

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