Temporal Changes in Vaginal Microbiota and Genital Tract Cytokines Among South African Women Treated for Bacterial Vaginosis.

Andile Mtshali,Jo-Ann S Passmore,Quarraisha Abdool Karim,Jennifer Giandhari,Lenine J P Liebenberg,Jacques Ravel,Gugulethu Mzobe,Khanyisile Mngomezulu,Anne Rompalo,Tulio De Oliveira,James Emmanuel San,Salim S Abdool Karim,Christina Balle,Harris Onywera,Nigel Garrett,Adrian Mindel,Farzana Osman,Heather B Jaspan,Sinaye Ngcapu

doi:10.3389/fimmu.2021.730986

Abstract

The standard treatment for bacterial vaginosis (BV) with oral metronidazole is often ineffective, and recurrence rates are high among African women. BV-associated anaerobes are closely associated with genital inflammation and HIV risk, which underscores the importance of understanding the interplay between vaginal microbiota and genital inflammation in response to treatment. In this cohort study, we therefore investigated the effects of metronidazole treatment on the vaginal microbiota and genital cytokines among symptomatic South African women with BV [defined as Nugent score (NS) ≥4] using 16S rRNA gene sequencing and multiplex bead arrays. Among 56 BV-positive women, we observed short-term BV clearance (NS <4) in a proportion of women six weeks after metronidazole treatment, with more than half of these experiencing recurrence by 12 weeks post-treatment. BV treatment temporarily reduced the relative abundance of BV-associated anaerobes (particularly Gardnerella vaginalis and Atopobium vaginae) and increased lactobacilli species (mainly L. iners), resulting in significantly altered mucosal immune milieu over time. In a linear mixed model, the median concentrations of pro-inflammatory cytokines and chemokines were significantly reduced in women who cleared BV compared to pre-treatment. BV persistence and recurrence were strongly associated with mucosal cytokine profiles that may increase the risk of HIV acquisition. Concentrations of these cytokines were differentially regulated by changes in the relative abundance of BVAB1 and G. vaginalis. We conclude that metronidazole for the treatment of BV induced short-term shifts in the vaginal microbiota and mucosal cytokines, while treatment failures promoted persistent elevation of pro-inflammatory cytokine concentrations in the genital tract. These data suggest the need to improve clinical management of BV to minimize BV related reproductive risk factors.

Highlights

Vaginal microbiota dominated by Lactobacillus species are considered optimal for the female genital tract (FGT), because they regulate host immunity and inhibit pathogen colonization by producing antimicrobial substances, like lactic acid and bacteriocins [1, 2]
Of the 101 HIV-negative women enrolled in the CAPRISA 083 cohort, 56 women with median age of 24 years [interquartile range (IQR) 21-27 years] had symptomatic intermediate bacterial vaginosis (BV) or BV by Nugent score (NS) (Nugent-BV defined as NS ≥4) at baseline, who attended all three visits, and had genital specimen stored to conduct the longitudinal microbiota and cytokine analysis were used for this sub-analysis (Figure 1)
We identified three CSTs based on the composition and relative abundance of bacterial species by VALENCIA (Figure 2 and Supplementary Figure 1)

Summary

Introduction

Vaginal microbiota dominated by Lactobacillus species are considered optimal for the female genital tract (FGT), because they regulate host immunity and inhibit pathogen colonization by producing antimicrobial substances, like lactic acid and bacteriocins [1, 2]. This paradigm of an optimal vaginal microbiota may not apply as clearly to women of African descent, because high proportions of nonLactobacillus-dominant microbiota have frequently been found in asymptomatic women [3]. In vitro studies have further shown that the relative abundance of Prevotella bivia was closely associated with increased levels of vaginal pro-inflammatory cytokines and chemokines [4, 10]

Methods

Results

Conclusion