Vaginal microbiota composition in untreated high-grade cervical intraepithelial neoplasia

Background: Emerging evidence describe associations among the vaginal microbiota (VMB) composition, HPV infection, and cervical intra-epithelial neoplasia (CIN), however causal inference remains uncertain. The use of longitudinal cohorts can enable temporal assessment of the relationship between VMB and the natural history of CIN.Aim: To assess whether VMB composition affects rates of progression, persistence or clearance in a longitudinal cohort of young women with histologically confirmed untreated CIN2 lesions. Materials & Methods: Population: Non-pregnant young women (16-26y) with histologically-proven CIN2 that was managed conservatively in Northern California, USA over a 24-month period.Experiment: DNA was extracted from serially collected liquid-based cytology samples and V1-V2 amplicons of the bacterial 16S rRNA gene were sequenced using the Illumina MiSeq platform.Analysis: Hierarchical clustering of sequence data was used to examine bacterial species classification data. Multinomial logistical regression and Markov modelling was used to identify associations between VMB composition and disease status throughout the study.Results: Of the 87 women included in the cohort, 48.3% had regressed by 12 months (42/87), 72.4% (63/87) by 24 months. High-diversity, Lactobacillus spp. deplete VMB composition at time of CIN2 diagnosis was associated with higher rates of disease persistence at 12 months, compared to those with Lactobacillus spp. dominance at baseline. Relative abundances of anaerobic taxa including Megasphaera spp. (p=0.0004), Prevotella timonensis (p=0.015) and Gardnerella vaginalis (p=0.036) were higher in women with persistent disease at 12 months compared to those who regressed. A similar trend was seen by 24-month follow-up but was not statistically significant. Rate of CIN2 regression was slower in women with Lactobacillus spp. depletion at baseline.Conclusions: Our findings suggest paucity of Lactobacillus and presence of specific anaerobic taxa are associated with CIN2 persistence and slower regression. Further research in the impact of VMB on the natural history of CIN may help identify VMB compositions and specific taxa associated with increased risk of progression and thus offer rational targets for the development of new prevention and treatment strategies.