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Vaginal microbiota composition affects many facets of reproductive health. Lactobacillus iners -dominated microbial communities are associated with poorer outcomes, including higher risk of bacterial vaginosis (BV), compared with vaginal microbiota rich in L. crispatus . Unfortunately, standard-of-care metronidazole therapy for BV typically results in dominance of L. iners , probably contributing to post-treatment relapse. Here we generate an L. iners isolate collection comprising 34 previously unreported isolates from 14 South African women with and without BV and 4 previously unreported isolates from 3 US women. We also report an associated genome catalogue comprising 1,218 vaginal Lactobacillus isolate genomes and metagenome-assembled genomes from >300 women across 4 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 that 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. l -cysteine is required for the growth of Lactobacillus iners , a vaginal microbiome species typically associated with adverse outcomes that lacks cysteine biosynthesis pathways and key uptake mechanisms present in other lactobacilli. Cystine uptake inhibitors can be used to suppress L. iners abundance in vitro in favour of L. crispatus , a species associated with favourable outcomes.

Bacterial vaginosis (BV), the overgrowth of diverse anaerobic bacteria in the vagina, is the most common cause of vaginal symptoms worldwide. BV frequently recurs after antibiotic therapy, and the best probiotic treatments only result in transient changes from BV-associated states to “optimal” communities dominated by a single species of Lactobacillus . Therefore, additional treatment strategies are needed to durably alter vaginal microbiota composition for patients with BV. Vaginal microbiota transplantation (VMT), the transfer of vaginal fluid from a healthy person with an optimal vaginal microbiota to a recipient with BV, has been proposed as one such alternative. However, VMT carries potential risks, necessitating strict safety precautions. Here, we present an FDA-approved donor screening protocol and detailed methodology for donation collection, storage, screening, and analysis of VMT material. We find that Lactobacillus viability is maintained for over six months in donated material stored at − 80 °C without glycerol or other cryoprotectants. We further show that species-specific quantitative PCR for L. crispatus and L. iners can be used as a rapid initial screening strategy to identify potential donors with optimal vaginal microbiomes. Together, this work lays the foundation for designing safe, reproducible trials of VMT as a treatment for BV.

HIV-associated changes in intestinal microbiota are believed to be important drivers of disease progression. However, the majority of studies have focused on populations in high-income countries rather than in developing regions where HIV burden is greatest. To better understand the impact of HIV on fecal microbiota globally, we compare the fecal microbial community of individuals in the U.S., Uganda, and Botswana. We identify significant bacterial taxa alterations with both treated and untreated HIV infection with a high degree of uniqueness in each cohort. HIV-associated taxa alterations are also significantly different between populations that report men who have sex with men (MSM) behavior and non-MSM populations. Additionally, while we find that HIV infection is consistently associated with higher soluble markers of immune activation, most specific bacterial taxa associated with these markers in each region are not shared and none are shared across all three geographic locations in our study. Our findings demonstrate that HIV-associated changes in fecal microbiota are overall distinct among geographical locations and sexual behavior groups, although a small number of taxa shared between pairs of geographic locations warrant further investigation, highlighting the importance of considering host context to fully assess the impact of the gut microbiome on human health and disease. Here, the authors compare the fecal microbial community of individuals in the U.S., Uganda, and Botswana, and identify significant bacterial taxa alterations with both treated and untreated HIV infection although with a high degree of uniqueness in each cohort, and also significant differences between populations that report men who have sex with men (MSM) behavior and non-MSM populations.

Identifying the origin of a biological invasion has important applications to the effective control of the invaders. This is more critical for invasive agricultural pests that cause severe economic losses. The brown marmorated stink bug, Halyomorpha halys , originally from East Asia, has become a principal agricultural pest in the US since its first detection in Pennsylvania in 1996. This species is responsible for crop failures on many mid-Atlantic farms and current control efforts rely on heavy insecticide applications because no other options are available. To examine the genetic diversity and identify the source region of the US introductions, we sequenced portions of the mitochondrial cytochrome c oxidase subunit II gene, 12S ribosomal RNA gene and control region in populations from the US, China, South Korea and Japan. We detected high genetic divergence among native populations and traced the origin of US H. halys to the Beijing area in China. We observed much lower genetic diversity in exotic compared to native populations—two mitochondrial haplotypes in 55 US specimens versus 43 haplotypes in 77 native specimens. A single introduction of small propagule size matches the invasion history in the US. For the effective control of the US population, we suggest that surveys on egg parasitoids and insecticide resistance in natives should focus on the Beijing area in China.

Many studies investigating the human microbiome-cancer interface have focused on the gut microbiome and gastrointestinal cancers. Outside of human papillomavirus driving cervical cancer, little is known about the relationship between the vaginal microbiome and other gynecological cancers, such as ovarian cancer. In this retrospective study, we investigated the relationship between ovarian cancer, platinum-free interval (PFI) length, and vaginal and gut microbiomes. We observed that Lactobacillus -dominated vaginal communities were less common in women with ovarian cancer, as compared to existing datasets of similarly aged women without cancer. Primary platinum-resistance (PPR) disease is strongly associated with survivability under one year, and we found over one-third of patients with PPR (PFI < 6 months, n = 17) to have a vaginal microbiome dominated by Escherichia (>20% relative abundance), while only one platinum super-sensitive (PFI > 24 months, n = 23) patient had an Escherichia -dominated microbiome. Additionally, L. iners was associated with little, or no, gross residual disease, while other Lactobacillus species were dominant in women with >1 cm gross residual disease. In the gut microbiome, we found patients with PPR disease to have lower phylogenetic diversity than platinum-sensitive patients. The trends we observe in women with ovarian cancer and PPR disease, such as the absence of Lactobacillus and presence of Escherichia in the vaginal microbiome as well as low gut microbiome phylogenetic diversity have all been linked to other diseases and/or pro-inflammatory states, including bacterial vaginosis and autoimmune disorders. Future prospective studies are necessary to explore the translational potential and underlying mechanisms driving these associations.

Background Cervicovaginal bacterial communities composed of diverse anaerobes with low Lactobacillus abundance are associated with poor reproductive outcomes such as preterm birth, infertility, cervicitis, and risk of sexually transmitted infections (STIs), including human immunodeficiency virus (HIV). Women in sub-Saharan Africa have a higher prevalence of these high-risk bacterial communities when compared to Western populations. However, the transition of cervicovaginal communities between high- and low-risk community states over time is not well described in African populations. Results We profiled the bacterial composition of 316 cervicovaginal swabs collected at 3-month intervals from 88 healthy young Black South African women with a median follow-up of 9 months per participant and developed a Markov-based model of transition dynamics that accurately predicted bacterial composition within a broader cross-sectional cohort. We found that Lactobacillus iners -dominant, but not Lactobacillus crispatus -dominant, communities have a high probability of transitioning to high-risk states. Simulating clinical interventions by manipulating the underlying transition probabilities, our model predicts that the population prevalence of low-risk microbial communities could most effectively be increased by manipulating the movement between L. iners - and L. crispatus -dominant communities. Conclusions The Markov model we present here indicates that L. iners -dominant communities have a high probability of transitioning to higher-risk states. We additionally identify transitions to target to increase the prevalence of L. crispatus -dominant communities. These findings may help guide future intervention strategies targeted at reducing bacteria-associated adverse reproductive outcomes among women living in sub-Saharan Africa. 1LauPY4wMZcfM5CbQRn5pv Video Abstract

Vaginal microbiota have been shown to be a modifier of protection offered by topical tenofovir in preventing HIV infection in women, an effect not observed with oral tenofovir-based pre-exposure prophylaxis (PrEP). It remains unclear whether PrEP can influence the vaginal microbiota composition. This study investigated the impact of daily oral tenofovir disoproxil fumarate in combination with emtricitabine for PrEP on the vaginal microbiota in South African women. At baseline, Lactobacillus iners or Gardnerella vaginalis dominant vaginal communities were observed in the majority of participants. In cross sectional analysis, vaginal microbiota were not affected by the initiation and use of PrEP. Longitudinal analysis revealed that Lactobacillus crispatus -dominant “cervicotypes 1 (CT1)” communities had high probability of remaining stable in PrEP group, but had a higher probability of transitioning to L. iners -dominant CT2 communities in non-PrEP group. L. iners -dominant communities were more likely to transition to communities associated with bacterial vaginosis (BV), irrespective of PrEP or antibiotic use. As expected, BV-linked CTs had a higher probability of transitioning to L. iners than L. crispatus dominant CTs and this shift was not associated with PrEP use.

Humans are the only species with a commensal Lactobacillus -dominant vaginal microbiota. Reproductive tract microbes have been linked to fertility outcomes, as has intrauterine inflammation, suggesting immune response may mediate adverse outcomes. In this pilot study, we compared vaginal microbiota composition and immune marker concentrations between patients with unexplained or male factor infertility (MFI), as a control. We applied a supervised machine learning algorithm that integrated microbiome and inflammation data to predict pregnancy outcomes. Twenty-eight participants provided vaginal swabs at three IVF cycle time points; 18 achieved pregnancy. Pregnant participants had lower microbial diversity and inflammation. Among them, MFI cases had higher diversity but lower inflammation than those with unexplained infertility. Our model showed the highest prediction accuracy at time point 2 of the IVF cycle. These findings suggest that vaginal microbiota and inflammation jointly impact fertility and can inform predictive tools in reproductive medicine.

Background The majority of studies characterizing female genital tract microbiota have focused on luminal organisms, while the presence and impact of tissue-adherent ectocervical microbiota remain incompletely understood. Studies of luminal and tissue-associated bacteria in the gastrointestinal tract suggest that these communities may have distinct roles in health and disease. Here, we performed a multi-omics characterization of paired luminal and tissue samples collected from a cohort of Kenyan female sex workers. Results We identified a tissue-adherent bacterial microbiome, with a higher alpha diversity than the luminal microbiome, in which dominant genera overall included Gardnerella and Lactobacillus , followed by Prevotella , Atopobium , and Sneathia . About half of the L. iners- dominated luminal samples had a corresponding Gardnerella- dominated tissue microbiome. Broadly, the tissue-adherent microbiome was associated with fewer differentially expressed host genes than the luminal microbiome. Gene set enrichment analysis revealed that L. crispatus- dominated tissue-adherent communities were associated with protein translation and antimicrobial activity, whereas a highly diverse microbial community was associated with epithelial remodeling and pro-inflammatory pathways. Tissue-adherent communities dominated by L. iners and Gardnerella were associated with lower host transcriptional activity. Tissue-adherent microbiomes dominated by Lactobacillus and Gardnerella correlated with host protein profiles associated with epithelial barrier stability, although with a more pro-inflammatory profile for the Gardnerella -dominated microbiome group. Tissue samples with a highly diverse composition had a protein profile representing cell proliferation and pro-inflammatory activity. Conclusion We identified ectocervical tissue-adherent bacterial communities in all study participants of a female sex worker cohort. These communities were distinct from cervicovaginal luminal microbiota in a significant proportion of individuals. We further revealed that bacterial communities at both sites correlated with distinct host gene expression and protein levels. The tissue-adherent bacterial community could possibly act as a reservoir that seed the lumen with less optimal, non- Lactobacillus , bacteria. 1vNfGdLTcr4_vB6d-MCta- Video Abstract

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.