The Role of the Cervicovaginal Microbiome on the Genesis and as a Biomarker of Premalignant Cervical Intraepithelial Neoplasia and Invasive Cervical Cancer

Abstract

The microbiome is able to modulate immune responses, alter the physiology of the human organism, and increase the risk of viral infections and development of diseases such as cancer. In this review, we address changes in the cervical microbiota as potential biomarkers to identify the risk of cervical intraepithelial neoplasia (CIN) development and invasive cervical cancer in the context of human papillomavirus (HPV) infection. Current approaches for clinical diagnostics and the manipulation of microbiota with the use of probiotics and through microbiota transplantation are also discussed.

Keywords: cervical intraepithelial neoplasia; cervical lesion; cervical microbiota; invasive cervical cancer.

Figure 1

The impact of microbiota dysbiosis in carcinogenesis. Dysbiotic microbiota (blue and pink rods and circles) may drive carcinogenesis either by modulation of host mechanisms, such as promoting immune response alterations and DNA damage, or by directly eliciting tissue damage, thus facilitating infection by oncoviruses.

Figure 2

Bacterial bioproducts modulate cervical microenvironment. Bacterial cervical communities named CSTs (community state types) are displayed on the top of the Figure (A,B) in roman numerals (I, II, III, IV). (A) CST I, II, and V contain dominant Lactobacillus (non-iners) species (dark blue rods) and produce high level of lactic acid, hydrogen peroxide, and bacterial bioproducts (bacteriocins and biosurfactants). (B) CST III shows the Lactobacillus iners-dominant community (pink rods) and CST IV displays bacterial high diversity (light blue rods and circles) with increased frequency of anaerobic species. They both produce less lactic acid and exhibit inerolysin, sialidase, and butyric acid production. In addition, CST III and IV modulate immune responses by induction of proinflammatory cytokine production and recruitment of CD4+CCR5+ lymphocytes to the cervical region.

Figure 3

Bacterial diversity distribution in intraepithelial neoplasia progression. The scheme displays the progression of the cervical epithelium from normal to invasive cervical cancer, as well as the bacterial diversity (alpha-diversity) and the species abundance in the cervical microenvironment at each cytological stage. The normal cytology is commonly associated with CSTs I, II, or V, which are Lactobacillus species (non-iners)-dominant (light green rods). However, following the cervical disease progression, the relative abundance of Lactobacillus non-iners species start to decrease. Concomitant to that, alpha-diversity increases and the microbiota is changed to CST III (pink rods and circles) or IV (light blue and pink shapes). Some bacterial species were found, in different studies, associated with cervical disease progression. They are also displayed in this figure in a representative graph of relative abundance (lower panel).