ORIGINAL RESEARCH article

Front. Cell. Infect. Microbiol.

Sec. Clinical Microbiology

Volume 15 - 2025 | doi: 10.3389/fcimb.2025.1589277

This article is part of the Research TopicAdvances in Vaginal Microbiome and Metabolite Research: Genetics, Evolution, and Clinical PerspectivesView all 7 articles

Distinct Cervical Microbiome and Metabolite Profiles Before and After Menopause: Implications for Cervical Cancer Progression

Provisionally accepted
Takuma  FujiiTakuma Fujii1*Rie  KawasakiRie Kawasaki1Iwao  KukimotoIwao Kukimoto2Eiji  NishioEiji Nishio1Sayaka  OtaniSayaka Otani1Haruki  NishizawaHaruki Nishizawa1Aya  IwataAya Iwata1Yasuhiro  MaedeaYasuhiro Maedea1
  • 1Fujita Health University, Toyoake, Japan
  • 2National Institute of Infectious Diseases (NIID), Tokyo, Tôkyô, Japan

The final, formatted version of the article will be published soon.

Introduction: Cervical cancer is the fourth most common malignancy in women and is primarily caused by persistent infection with high-risk human papillomavirus (HPV). In addition, host immune responses, genetic factors, and lifestyle habits also have etiological roles. The cervicovaginal microbiome undergoes dynamic changes during menopause, which may be involved in the progression of cervical neoplasia. We aimed to elucidate the association between cervical microenvironmental changes and the progression of cervical neoplasia before and after menopause by integrating analyses of the cervical microbiome, related metabolites, cytokines, and microRNAs. Methods: A total of 248 HPV-positive women with cervical neoplasia, including 17 with cervical intraepithelial neoplasia (CIN1), 80 with CIN2, 82 with CIN3, and 69 with squamous cell carcinoma (SCC), were enrolled. As normal controls, 48 HPV-negative healthy women were included. Each group was stratified based on the mean menopausal age of 50 years. Cervical mucus was analyzed according to the methods outlined below. The microbiota was profiled by 16S rRNA gene sequencing, metabolites were analyzed by ultra-HPLC-tandem mass spectrometry, RT-qPCR was used for miRNA expression analysis, and RANTES levels were quantified by multiplex bead array. Data analysis was performed using MicrobiomeAnalyst and MetaboAnalyst.Results: In the SCC group, Prevotella and Atopobium were the key bacterial genera among the younger group, while Peptoniphilus, Fusobacterium, and Porphyromonas were more prevalent in elderly group (LDA score > 4.5). We observed a consistent positive correlation between Atopobium and xanthine in younger groups with CIN2 or worse (p < 0.0001). However, no such correlations were detected in elderly women. In addition, Atopobium, Adlercreutzia, and Gardnerella showed significant positive correlation with nicotinic acid in younger women with SCC compared to the elderly women (p < 0.0001). In the younger SCC women, several metabolites were significantly elevated in groups with high expression levels of RANTES, miR-20b-5p, and miR-155-5p.The cervical microbiome undergoes changes during menopause, and may influence disease progression by interacting with metabolites, cytokines, and miRNAs. These results highlight the potential for personalized medicine for cervical cancer that is tailored to different age groups.

Keywords: cervical cancer, Cervical Intraepithelial Neoplasia, microbiome, Metabolites, microRNA, Cytokines, Menopause

Received: 07 Mar 2025; Accepted: 27 May 2025.

Copyright: © 2025 Fujii, Kawasaki, Kukimoto, Nishio, Otani, Nishizawa, Iwata and Maedea. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Takuma Fujii, Fujita Health University, Toyoake, Japan

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