The direct and indirect association of cervical microbiota with the risk of cervical intraepithelial neoplasia.

Cervical microbiota composition is associated with cervical HPV infection and CIN severity. Previous studies only assessed the total association between cervical microbiota and HPV infections or CINs, and yet no study reported the direct and indirect associations between cervical microbiota and CINs mediated by HPV infection, respectively. The aim of this study was to investigate the direct and indirect associations between microbiotas and CIN severity. Cervical microbiota of 126 women with CIN 1- (normal cytology and CIN 1) and 40 with CIN 2+ (CIN 2 and CIN 3) were analyzed using Illumina sequencing based on the 16S rRNA gene. HPV was detected using a highly sensitive PCR primer set (SPF1/GP6+). Indirect effects of Pseudomonas stutzeri, Bacteroides fragilis, Lactobacillus delbrueckii, Atopobium vaginae, and Streptococcus agalactiae mediated by HPV infection on CIN status were observed. The directions of the direct and the indirect associations between CIN status and Ps. stutzeri were opposite. The directions of the direct and the indirect associations between CIN status and A. vaginae were the same. B. fragilis, L. delbrueckii, and S. agalactiae only had indirect association with CIN status. In summary, our study provided suggestive evidence that some microbial populations could have direct or indirect effects mediated by affecting HPV infection on CIN progression. Besides HPV infection, microbial community composition possibly plays a role in cervical carcinogenesis.