Human Papillomavirus Infections and the Role Played by Cervical and Cervico-Vaginal Microbiota-Evidence from Next-Generation Sequencing Studies

Abstract

This comprehensive review encompasses studies examining changes in the cervical and cervico-vaginal microbiota (CM and CVM) in relation to human papillomavirus (HPV) using next-generation sequencing (NGS) technology. HPV infection remains a prominent global health concern, with a spectrum of manifestations, from benign lesions to life-threatening cervical cancers. The CM and CVM, a unique collection of microorganisms inhabiting the cervix/vagina, has emerged as a critical player in cervical health. Recent research has indicated that disruptions in the CM and CVM, characterized by a decrease in Lactobacillus and the overgrowth of other bacteria, might increase the risk of HPV persistence and the progression of cervical abnormalities. This alteration in the CM or CVM has been linked to a higher likelihood of HPV infection and cervical dysplasia. NGS technology has revolutionized the study of the cervical microbiome, providing insights into microbial diversity, dynamics, and taxonomic classifications. Bacterial 16S rRNA gene sequencing, has proven invaluable in characterizing the cervical microbiome, shedding light on its role in HPV infections and paving the way for more tailored strategies to combat cervical diseases. NGS-based studies offer personalized insights into an individual's cervical microbiome. This knowledge holds promise for the development of novel diagnostic tools, targeted therapies, and preventive interventions for cervix-related conditions, including cervical cancer.

Keywords: 16S rRNA gene; cervical intraepithelial neoplasia (CIN); cervical microbiota; cervico-vaginal microbiota; human papillomavirus (HPV) infections; next-generation sequencing (NGS) technology; squamous intraepithelial lesion (SIL).

Figure 1

Relationship between cervical and cervico-vaginal microbiota and high-risk HPV infections. The composition of cervical microbiota can impact vulnerability to high-risk (hr) HPV infections and the subsequent development of cervical lesions or cancer. Disturbances in the normal cervical microbiota, a reduction in Lactobacillus species, or an overgrowth of other bacteria are linked to an elevated risk of persistent HPV infection and the advancement of cervical abnormalities. Bacterial vaginosis (BV) is a shift from the dominance of Lactobacillus to a more diverse microbiome characterized by increased levels of anaerobic bacteria like Gardnerella vaginalis, Peptostreptococcus anaerobius, and Porphyromonas uenoni. BV is associated with an increased susceptibility to HPV-related cervical intraepithelial neoplasia (CIN) and cervical cancer. Decreased abundance of Lactobacillus species and increased presence of Gardnerella vaginalis correlate with an altered cervical and cervico-vaginal microbiome (CM/CVM) and higher risk of HPV infection and cervical dysplasia. Certain bacteria within the CM and CVM can activate immune cells and regulate inflammation, potentially affecting the clearance or persistence of HPV. As the lesions progress, an upward trend in species diversity is noted. Progression from CIN to cancer requires persistent HPV infection. Created with BioRender.com (accessed on 10 December 2023).

Figure 2

The impact of microbiota on the progression of cervical cancer: examining immune reactions and potential therapeutic avenues. (A) In healthy women, the gut and vaginal microbiota are protected by a multi-layered barrier system comprising a mucus layer, immune mediators, and an intact epithelium. Failure of this barrier can lead to the translocation of pathogenic bacteria, causing chronic inflammation and cancer. Prevotella-rich environments stimulate dendritic cells via TLR 2, releasing cytokines and promoting immune responses that may be linked to cervical cancer (CC) risk. CC patients show a decrease in butyrate-producing bacteria, essential for controlling inflammation and maintaining intestinal health. Butyrate microbial metabolites also stimulate cells to produce anti-inflammatory compounds, contributing to intestinal homeostasis. The reduction in Ruminococcus and Clostridium may impact overall intestinal health, thereby influencing vaginal health. (B) The use of prebiotics and probiotics has shown promise in preventing HPV-induced cervical malignancy. Results indicated increased rates of HPV clearance, cytological and colposcopic clearance of abnormalities, and improved histological outcomes following treatment. These supplements, known for their positive effects on digestive system function and immune processes, contribute to overall health and may play a role in managing HPV-related cervical lesions. Created with BioRender.com (accessed on 13 January 2024).