Predictive functional analysis reveals inferred features unique to cervicovaginal microbiota of African women with bacterial vaginosis and high-risk human papillomavirus infection

Abstract

Mounting evidence suggests that Lactobacillus species may not necessarily be the sine qua non of healthy cervicovaginal microbiota (CVM), especially among reproductive-age African women. A majority of African women have high-diversity non-Lactobacillus-dominated CVM whose bacterial functions remain poorly characterized. Functional profiling of the CVM is vital for investigating human host-microbiota interactions in health and disease. Here, we investigated the functional potential of L. iners-dominated and high-diversity non-Lactobacillus-dominated CVM of 75 African women with and without bacterial vaginosis (BV) and high-risk human papillomavirus (HR-HPV) infection. Functional contents were predicted using PICRUSt. Microbial taxonomic diversity, BV, and HR-HPV infection statuses were correlated with the inferred functional composition of the CVM. Differentially abundant inferred functional categories were identified using linear discriminant analysis (LDA) effect size (LEfSe) (p-value <0.05 and logarithmic LDA score >2.0). Of the 75 women, 56 (74.7%), 35 (46.7%), and 29 (38.7%) had high-diversity non-Lactobacillus-dominated CVM, BV, and HR-HPV infection, respectively. Alpha diversity of the inferred functional contents (as measured by Shannon diversity index) was significantly higher in women with high-diversity non-Lactobacillus-dominated CVM and BV than their respective counterparts (H statistic ≥11.5, q-value <0.001). Ordination of the predicted functional metagenome content (using Bray-Curtis distances) showed that the samples segregated according to the extent of microbial taxonomic diversity and BV (pseudo-F statistic ≥19.6, q-value = 0.001) but not HR-HPV status (pseudo-F statistic = 1.7, q-value = 0.159). LEfSe analysis of the inferred functional categories revealed that transport systems (including ABC transporters) and transcription factors were enriched in high-diversity CVM. Interestingly, transcription factors and sporulation functional categories were uniquely associated with high-diversity CVM, BV, and HR-HPV infection. Our predictive functional analysis reveals features unique to high-diversity CVM, BV and HR-HPV infections. Such features may represent important biomarkers of BV and HR-HPV infection. Our findings require proof-of-concept functional studies to examine the relevance of these potential biomarkers in women’s reproductive health and disease.

Role of Immunity and Vaginal Microbiome in Clearance and Persistence of Human Papillomavirus Infection

“…A high relative abundance of Gardnerella and Atopobium vaginae were associated with CIN (Godoy-Vitorino et al, 2018;Berggrund et al, 2020). Increased abundance of Sneathia, Atopobium, and Gardnerella is associated with incident high-risk HPV infection (Onywera et al, 2021). A study by Lee et al (2013) showed that HPV-infected women had lower Lactobacillus species and increased Fusobacteria and Sneathia compared to HPV-uninfected women (Lee et al, 2013).…”

Preliminary Identification of the Aerobic Cervicovaginal Microbiota in Mexican Women With Cervical Cancer as the First Step Towards Metagenomic Studies

“…Several studies have already exposed the link of cervicovaginal bacterial microbiota and CC during the natural history of the disease, where it is shown that from HPV infection and up to the presence of a cervical intraepithelial lesion, there is an association between cervical dysbiosis and disease (Mitra et al, 2015;Usyk et al, 2020;Onywera et al, 2021). The most studied entity is bacterial vaginosis, in which a higher diversity of strict anaerobic species and a considerable decrease in lactobacilli are observed (Sodhani et al, 2017;Brusselaers et al, 2019;Kovachev, 2020).…”

HPV‐related cervical diseases: Alteration of vaginal microbiotas and promising potential for diagnosis

“…Since Lactobacillus is the most abundant genus, it is no doubt that the enrichment of carbohydrate metabolism, including glycolysis/gluconeogenesis, fructose and mannose metabolism, and galactose metabolism, is in healthy controls. Another one of the most significantly enriched microbial function in healthy controls is the ABC transporter, a pathway involved in many basic biological functions, which also includes antibiotic resistance, 51 while some strains associated with this pathway may also be involved in high‐risk HPV infection and CIN 52 . Another enriched pathway in healthy controls, the phosphotransferase system, is positively associated with high‐risk HPV infection and bacterial vaginosis 52 .…”

“…52 Another enriched pathway in healthy controls, the phosphotransferase system, is positively associated with high-risk HPV infection and bacterial vaginosis. 52 Although it is difficult for us to figure out the correlation between vaginal microbial community functions and the occurrence of HRCD currently, alterations in these functions may imply the importance of vaginal microbiota in the pathogenesis of HRCD.…”