Pathobionts in the Vaginal Microbiota: Individual Participant Data Meta-Analysis of Three Sequencing Studies

Sequencing studies have shown that optimal vaginal microbiota (VMB) are lactobacilli-dominated and that anaerobes associated with bacterial vaginosis (BV-anaerobes) are commonly present. However, they overlooked a less prevalent but more pathogenic group of vaginal bacteria: the pathobionts that cause maternal and neonatal infections and pelvic inflammatory disease. We conducted an individual participant data meta-analysis of three VMB sequencing studies that included diverse groups of women in Rwanda, South Africa, and the Netherlands (2,044 samples from 1,163 women in total). We identified 40 pathobiont taxa but only six were non-minority taxa (at least 1% relative abundance in at least one sample) in all studies: Streptococcus (54% of pathobionts reads), Staphylococcus, Enterococcus, Escherichia/Shigella, Haemophilus, and Campylobacter. When all pathobionts were combined into one bacterial group, the VMB of 17% of women contained a relative abundance of at least 1%. We found a significant negative correlation between relative abundances (ρ = -0.9234), but not estimated concentrations (r = 0.0031), of lactobacilli and BV-anaerobes; and a significant positive correlation between estimated concentrations of pathobionts and BV-anaerobes (r = 0.1938) but not between pathobionts and lactobacilli (r = 0.0436; although lactobacilli declined non-significantly with increasing pathobionts proportions). VMB sequencing data were also classified into mutually exclusive VMB types. The overall mean bacterial load of the ≥20% pathobionts VMB type (5.85 log₁₀ cells/μl) was similar to those of the three lactobacilli-dominated VMB types (means 5.13-5.83 log₁₀ cells/μl) but lower than those of the four anaerobic dysbiosis VMB types (means 6.11-6.87 log₁₀ cells/μl). These results suggest that pathobionts co-occur with both lactobacilli and BV-anaerobes and do not expand as much as BV-anaerobes do in a dysbiotic situation. Pathobionts detection/levels were increased in samples with a Nugent score of 4-6 in both studies that conducted Nugent-scoring. Having pathobionts was positively associated with young age, non-Dutch origin, hormonal contraceptive use, smoking, antibiotic use in the 14 days prior to sampling, HIV status, and the presence of sexually transmitted pathogens, in at least one but not all studies; inconsistently associated with sexual risk-taking and unusual vaginal discharge reporting; and not associated with vaginal yeasts detection by microscopy. We recommend that future VMB studies quantify common vaginal pathobiont genera.