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Gestational diabetes augments group B Streptococcus infection by disrupting maternal immunity and the vaginal microbiota.

ABSTRACT: Group B Streptococcus (GBS) is a pervasive perinatal pathogen, yet factors driving GBS dissemination in utero are poorly defined. Gestational diabetes mellitus (GDM), a complication marked by dysregulated immunity and maternal microbial dysbiosis, increases risk for GBS perinatal disease. Using a murine GDM model of GBS colonization and perinatal transmission, we find that GDM mice display greater GBS in utero dissemination and subsequently worse neonatal outcomes. Dual-RNA sequencing reveals differential GBS adaptation to the GDM reproductive tract, including a putative glycosyltransferase (yfhO), and altered host responses. GDM immune disruptions include reduced uterine natural killer cell activation, impaired recruitment to placentae, and altered maternofetal cytokines. Lastly, we observe distinct vaginal microbial taxa associated with GDM status and GBS invasive disease status. Here, we show a model of GBS dissemination in GDM hosts that recapitulates several clinical aspects and identifies multiple host and bacterial drivers of GBS perinatal disease.

SUBMITTER: Mercado-Evans V

PROVIDER: S-EPMC10838280 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Gestational diabetes augments group B Streptococcus infection by disrupting maternal immunity and the vaginal microbiota.

Mercado-Evans Vicki V Mejia Marlyd E ME Zulk Jacob J JJ Ottinger Samantha S Hameed Zainab A ZA Serchejian Camille C Marunde Madelynn G MG Robertson Clare M CM Ballard Mallory B MB Ruano Simone H SH Korotkova Natalia N Flores Anthony R AR Pennington Kathleen A KA Patras Kathryn A KA

Nature communications 20240203 1

Group B Streptococcus (GBS) is a pervasive perinatal pathogen, yet factors driving GBS dissemination in utero are poorly defined. Gestational diabetes mellitus (GDM), a complication marked by dysregulated immunity and maternal microbial dysbiosis, increases risk for GBS perinatal disease. Using a murine GDM model of GBS colonization and perinatal transmission, we find that GDM mice display greater GBS in utero dissemination and subsequently worse neonatal outcomes. Dual-RNA sequencing reveals di ...[more]

PMID: 38310089

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Project description:The composition of the vaginal microbiota is heavily influenced by pregnancy and may factor into pregnancy complications, including spontaneous preterm birth. However, results among studies have been inconsistent due, in part, to variation in sample sizes and ethnicity. Thus, an association between the vaginal microbiota and preterm labor continues to be debated. Yet, before assessing associations between the composition of the vaginal microbiota and preterm labor, a robust and in-depth characterization of the vaginal microbiota throughout pregnancy in the specific study population under investigation is required. Here, we report a large longitudinal study (n = 474 women, 1,862 vaginal samples) of a predominantly African-American cohort-a population that experiences a relatively high rate of pregnancy complications-evaluating associations between individual identity, gestational age, and other maternal characteristics with the composition of the vaginal microbiota throughout gestation resulting in term delivery. The principal factors influencing the composition of the vaginal microbiota in pregnancy are individual identity and gestational age at sampling. Other factors are maternal age, parity, obesity, and self-reported Cannabis use. The general pattern across gestation is for the vaginal microbiota to remain or transition to a state of Lactobacillus dominance. This pattern can be modified by maternal parity and obesity. Regardless, network analyses reveal dynamic associations among specific bacterial taxa within the vaginal ecosystem, which shift throughout the course of pregnancy. This study provides a robust foundational understanding of the vaginal microbiota in pregnancy and sets the stage for further investigation of this microbiota in obstetrical disease. IMPORTANCE There is debate regarding links between the vaginal microbiota and pregnancy complications, especially spontaneous preterm birth. Inconsistencies in results among studies are likely due to differences in sample sizes and cohort ethnicity. Ethnicity is a complicating factor because, although all bacterial taxa commonly inhabiting the vagina are present among all ethnicities, the frequencies of these taxa vary among ethnicities. Therefore, an in-depth characterization of the vaginal microbiota throughout pregnancy in the specific study population under investigation is required prior to evaluating associations between the vaginal microbiota and obstetrical disease. This initial investigation is a large longitudinal study of the vaginal microbiota throughout gestation resulting in a term delivery in a predominantly African-American cohort, a population that experiences disproportionally negative maternal-fetal health outcomes. It establishes the magnitude of associations between maternal characteristics, such as age, parity, body mass index, and self-reported Cannabis use, on the vaginal microbiota in pregnancy.

Project description:Group B Streptococcus (GBS) colonizes the vaginal mucosa of a significant percentage of healthy women and is a leading cause of neonatal bacterial infections. Currently, pregnant women are screened in the last month of pregnancy, and GBS-positive women are given antibiotics during parturition to prevent bacterial transmission to the neonate. Recently, human milk oligosaccharides (HMOs) isolated from breastmilk were found to inhibit GBS growth and biofilm formation in vitro, and women that make certain HMOs are less likely to be vaginally colonized with GBS. Using in vitro human vaginal epithelial cells and a murine vaginal colonization model, we tested the impact of HMO treatment on GBS burdens and the composition of the endogenous microbiota by 16S rRNA amplicon sequencing. HMO treatment reduced GBS vaginal burdens in vivo with minimal alterations to the vaginal microbiota. HMOs displayed potent inhibitory activity against GBS in vitro, but HMO pretreatment did not alter adherence of GBS or the probiotic Lactobacillus rhamnosus to human vaginal epithelial cells. In addition, disruption of a putative GBS glycosyltransferase (Δsan_0913) rendered the bacterium largely resistant to HMO inhibition in vitro and in vivo but did not compromise its adherence, colonization, or biofilm formation in the absence of HMOs. We conclude that HMOs are a promising therapeutic bioactive to limit GBS vaginal colonization with minimal impacts on the vaginal microenvironment. IMPORTANCE During pregnancy, GBS ascension into the uterus can cause fetal infection or preterm birth. In addition, GBS exposure during labor creates a risk of serious disease in the vulnerable newborn and mother postpartum. Current recommended prophylaxis consists of administering broad-spectrum antibiotics to GBS-positive mothers during labor. Although antibiotics have significantly reduced GBS neonatal disease, there are several unintended consequences, including altered neonatal gut bacteria and increased risk for other types of infection. Innovative preventions displaying more targeted antimicrobial activity, while leaving the maternal microbiota intact, are thus appealing. Using a mouse model, we found that human milk oligosaccharides (HMOs) reduce GBS burdens without perturbing the vaginal microbiota. We conclude that HMOs are a promising alternative to antibiotics to reduce GBS neonatal disease.

Project description:BackgroundMaternal Group B Streptococcus (GBS) colonization is influenced by many factors but results are inconsistent. Consideration of antenatal risk factors may help inform decision making on GBS microbiological culture screening where universal screening is not standard of care. We sought to identify independent predictors of GBS colonization at 34-37 weeks gestation incorporating vaginal symptoms, perineal hygiene measures, sexual activity, and a potential novel factor, constipation.MethodsIn this prospective cross-sectional study, 573 women at 34-37 weeks gestation had an ano-vaginal swab taken and sent for selective culture for GBS. Women were asked about vaginal bleeding, discharge, irritation and candidiasis, antibiotic use during pregnancy, ano-vaginal hygiene practices such as douching and perineal cleansing after toileting, sexual intercourse related activities, and a potential novel factor for GBS carriage, constipation. Maternal basic demographics and obstetric-related characteristics were also collected. Bivariate analyses were performed to identify associates of GBS colonization. All variables with p < 0.05 found on bivariate analysis were then included into a model for multivariable binary logistic regression analysis to identify independent risk factors for GBS colonization.ResultsGBS colonization was found in 235/573 (41.0%) of participants. Twenty six independent variables were considered for bivariate analysis. Eight were found to have p < 0.05. Following adjusted analysis, six independent predictors of GBS colonization were identified: ethnicity, previous neonatal GBS prophylaxis, antenatal vaginal irritation, antibiotic use, recent panty liner use, and frequency of sexual intercourse. Vaginal discharge and perineal cleansing were not associated after adjustment. Recent douching and constipation were not associated on bivariate analysis.ConclusionThe identification of independent predictors of GBS colonization in late pregnancy may inform the woman and care provider in their shared decision making for microbiological screening at 35-38 weeks gestation in locations where universal GBS screening is not standard of care.Ethics oversightThis study was approved by the Medical Ethics Committee of University Malaya Medical Centre (UMMC) on August 9, 2022, reference number 2022328-11120.

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Gestational diabetes augments group B Streptococcus infection by disrupting maternal immunity and the vaginal microbiota.

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Gestational diabetes augments group B Streptococcus infection by disrupting maternal immunity and the vaginal microbiota.

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