Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Apr 2;25(1):189.
doi: 10.1186/s12866-025-03922-8.

The inferred modulation of correlated vaginal microbiota and metabolome by cervical differentially expressed genes across distinct CIN grades

Wenkui Dai #  1   2   3 , Yu Liu #  4   5   6 , Xin Jiang #  4   5   6 , Ruinan Xu #  4   5   6 , Chunlei Guo  4   5   6 , Jun Hou  4   5   6 , Di Wu  4   5   6 , Changzhong Li  4   5   6 , Hui Du  7   8   9 , Ruifang Wu  10   11   12
Affiliations

The inferred modulation of correlated vaginal microbiota and metabolome by cervical differentially expressed genes across distinct CIN grades

Wenkui Dai et al. BMC Microbiol. .

Abstract

Background: In vitro studies have demonstrated the modulation of vaginal microbiota (VM) by cervical peptides which levels varied with the status of HPV infection and cervical intraepithelial neoplasia (CIN) grades. However, there is a deficiency in population-based studies investigating the modulation of VM compositions and metabolome by cervical differentially expressed genes (DEGs) across different grades of CIN.

Methods: This study included 43 HPV-positive women, classified into low-grade (CIN1, n = 23) and high-grade (CIN2 + , n = 20) groups. Vaginal swabs were collected for both microbiota and metabolome analysis. Cervical exfoliated cells were collected for RNA-Seq analysis.

Results: We identified 258 differentially expressed genes (DEGs), among which 176 CIN1-enriched genes were linked to immune responses, cell chemotaxis, negative regulation of cell migration, and B cell differentiation, activation, and proliferation. Eighty-two genes upregulated in CIN2 + cohorts were associated with epidermis development and keratinization. Then, we identified 5,686 paired correlations between DEGs, VM, and metabolome, with 2,320 involving Lactobacillus. Further analysis revealed Lactobacillus as the primary determinant of metabolic profiles, followed by Gardnerella, Faecalibacterium, Aerococcus and Streptococcus, such as the notable positive correlation between Lactobacillus with D-lactic acid and DL-indole-3-lactic acid. Applying mediation analysis, we found that Lactobacillus mediated the association of 14 CIN1-enriched DEGs, such as COL4A2, CCBE1 and SPON1, with the production of 57 metabolites, including D-lactic acid, oleic acid and various amino acids. Additional analysis indicated significant mediation effects of 79 metabolites on the association of DEGs with the growth of Lactobacillus, Gardnerella, Fannyhessea and Aerococcus.

Conclusions: Our findings provide valuable population-based evidence for the inferred modulation of correlated VM and metabolome by cervical DEGs across different CIN stages.

Keywords: Cervical intraepithelial neoplasia; Host gene expression; Human papillomavirus; Vaginal metabolome; Vaginal microbiota.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of Peking University Shenzhen Hospital (registration number: 2021–006). All participants were fully informed and then provided signed consents. We declare that our study adhered to the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Study design and DEGs between CIN1 and CIN2 + cohort. A Study pipeline. B This plot displays 258 genes with significant variation (FDR < 0.1) between CIN1 and CIN2 + cohorts, emphasizing the magnitude and statistical significance of expression changes. C The heatmap depicts the normalized expression levels of 258 DEGs (FDR < 0.1), alongside functional enrichments associated with these genes, offering a comprehensive view of their biological relevance. D Functional enrichment of DEGs upregulated in CIN1 cohort
Fig. 2
Fig. 2
Correlations between VM and metabolome. A Explained variance(R2) for variations of metabolic profiles. * represents FDR < 0.1. B The O2PLS analysis indicates the loading value of genera in the correlation with metabolic profiles. C Being assessed by spearman rho coefficient, there are notable correlations (FDR < 0.1) between five genera with metabolites
Fig. 3
Fig. 3
Paired correlations between DEGs, VM and metabolome and DEGs (FDR < 0.1). Red and blue lines signify positive and negative correlations, respectively
Fig. 4
Fig. 4
Being assessed by mediation effects, the inferred modulation of DEGs on correlated VM and metabolome. A This analysis explores the mediation effects of VM in the influence of DEGs on metabolites. B This analysis explores the mediation effects of metabolites in the influence of DEGs on VM
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Łaniewski P, Ilhan ZE, Herbst-Kralovetz MM. The microbiome and gynaecological cancer development, prevention and therapy. Nat Rev Urol. 2020;17:232–50. 10.1038/s41585-020-0286-z. - PMC - PubMed
    1. de Sanjosé S, Brotons M, Pavón MA. The natural history of human papillomavirus infection. Best Pract Res Clin Obstet Gynaecol. 2018;47:2–13. 10.1016/j.bpobgyn.2017.08.015. - PubMed
    1. Delgado-Diaz DJ, Jesaveluk B, Hayward JA, Tyssen D, Alisoltani A, Potgieter M, Bell L, Ross E, Iranzadeh A, Allali I, Dabee S, Barnabas S, Gamieldien H, Blackburn JM, Mulder N, Smith SB, Edwards VL, Burgener AD, Bekker LG, Ravel J, Passmore JS, Masson L, Hearps AC, Tachedjian G. Lactic acid from vaginal microbiota enhances cervicovaginal epithelial barrier integrity by promoting tight junction protein expression. Microbiome. 2022;10(1):141. 10.1186/s40168-022-01337-5. - PMC - PubMed
    1. Berard AR, Brubaker DK, Birse K, Lamont A, Mackelprang RD, Noël-Romas L, Perner M, Hou X, Irungu E, Mugo N, Knodel S, Muwonge TR, Katabira E, Hughes SM, Levy C, Calienes FL, Lauffenburger DA, Baeten JM, Celum C, Hladik F, Lingappa J, Burgener AD. Vaginal epithelial dysfunction is mediated by the microbiome, metabolome, and mTOR signaling. Cell Rep. 2023;42(5):112474. 10.1016/j.celrep.2023.112474. - PMC - PubMed
    1. Nicolò S, Antonelli A, Tanturli M, Baccani I, Bonaiuto C, Castronovo G, Rossolini GM, Mattiuz G, Torcia MG. Bacterial species from vaginal microbiota differently affect the production of the E6 and E7 oncoproteins and of p53 and p-Rb oncosuppressors in HPV16-infected cells. Int J Mol Sci. 2023;24(8):7173. 10.3390/ijms24087173. - PMC - PubMed

MeSH terms