Altered Vaginal Microbiota Composition Correlates With Human Papillomavirus and Mucosal Immune Responses in Women With Symptomatic Cervical Ectopy

Abstract

Cervical ectopy is a benign condition of the lower genital tract that is frequently detected in women of reproductive age. Although cervical ectopy is regarded as a physiological condition, some women experience symptoms such as leucorrhoea, persistent bleeding and recurrent vaginal infections that require medical intervention. Cervical ectopy has not been linked to cervical cancer, but it is thought to facilitate the acquisition of sexually transmitted diseases (STDs), like Human Papillomavirus (HPV) infection, as it provides a favorable microenvironment for virus infection and dissemination. We and others have described the presence of oncogenic HPV types in women with symptomatic cervical ectopy. The relevance of this finding and the impact of symptomatic cervical ectopy on the cervicovaginal microenvironment (vaginal microbiota, immune and inflammatory responses) are currently unknown. To shed some light into the interplay between HPV, the vaginal microbiota and mucosal immune and inflammatory responses in the context of this condition, we enrolled 156 women with symptomatic cervical ectopy and determined the presence of HPV using a type-specific multiplex genotyping assay. Overall, HPV was detected in 54.48% women, oncogenic HPV types were found in more than 90% of HPV-positive cases. The most prevalent HPV types were HPV16 (29.4%), HPV31 (21.17%) and HPV18 (15.29%). Next, we evaluated the vaginal microbial composition and diversity by 16S rDNA sequencing, and quantified levels of cytokines and chemokines by flow cytometry using bead-based multiplex assays in a sub-cohort of 63 women. IL-21 and CXCL9 were significantly upregulated in HPV-positive women (p=0.0002 and p=0.013, respectively). Women with symptomatic cervical ectopy and HPV infection had increased diversity (p<0.001), and their vaginal microbiota was enriched in bacterial vaginosis-associated anaerobes (Sneathia, Shuttleworthia, Prevotella, and Atopobium) and depleted in Lactobacillus spp. Furthermore, the vaginal microbiota of women with symptomatic cervical ectopy and HPV infection correlated with vaginal inflammation (IL-1β, rho=0.56, p=0.0004) and increased mucosal homeostatic response (IL-22, rho=0.60, p=0.0001). Taken together, our results suggest that HPV infection and dysbiotic vaginal communities could favor a vaginal microenvironment that might delay the recovery of the cervical epithelium in women with symptomatic cervical ectopy and favor STDs acquisition.

High risk HPV-positive women cervicovaginal microbial profiles in a Greek cohort: a retrospective analysis of the GRECOSELF study

“…Although several reports mention an increased microbial diversity and richness of the vaginal flora in the context of HPV infections (Usyk et al, 2020;López-Filloy et al, 2022), we did not observe any significant differences in microbial diversity between groups of women infected by different hrHPV types, including women with precancerous cervical lesions. However, significant differences in the vaginal microbial diversity were observed depending on the age of HPV infected women.…”

Torquetenovirus in pregnancy: Correlation with vaginal microbiome, metabolome and pro-inflammatory cytokines

“…In fact, genital inflammation can be linked to specific BV-related microorganisms, including Sneathia (Kaelin et al, 2022). As reported by Lopez-Filloy et al, women with HPV infection are characterized by a significant increase in anaerobes, such as Sneathia and Shuttleworthia, their presence being in turn associated to a higher level of cervico-vaginal inflammation and a higher risk of BV recurrence (López-Filloy et al, 2022).…”

Temporal composition of the cervicovaginal microbiome associates with hrHPV infection outcomes in a longitudinal study

“…5 ). P. timonensis interacts with vaginal dendritic cells, which are involved in mucosal inflammation [ 53 , 54 ], and both species have been associated with viral persistence, slower regression of SIL, and cervical cancer [ 46 , 55 ]. Sneathia and Prevotella species also express several homologous genes that are enriched in CST IV and that allow them to consume glycogen and mucins from cervical cells [ 56 ].…”