The vulvar microbiome in lichen sclerosus and high-grade intraepithelial lesions

Lisa Pagan; Bertine W Huisman; Michelle van der Wurff; Rosanne G C Naafs; Frank H J Schuren; Ingrid M J G Sanders; Wiep Klaas Smits; Romy D Zwittink; Jacobus Burggraaf; Robert Rissmann; Jurgen M J Piek; Jannie G E Henderickx; Mariëtte I E van Poelgeest

doi:10.3389/fmicb.2023.1264768

The vulvar microbiome in lichen sclerosus and high-grade intraepithelial lesions

Front Microbiol. 2023 Nov 29:14:1264768. doi: 10.3389/fmicb.2023.1264768. eCollection 2023.

Authors

Lisa Pagan^{1

2}, Bertine W Huisman^{1

2}, Michelle van der Wurff³, Rosanne G C Naafs¹, Frank H J Schuren³, Ingrid M J G Sanders⁴, Wiep Klaas Smits^{4

5}, Romy D Zwittink^{4

5}, Jacobus Burggraaf^{1

6}, Robert Rissmann^{1

6

7}, Jurgen M J Piek⁸, Jannie G E Henderickx^#^{4

5}, Mariëtte I E van Poelgeest^#^{1

2}

Affiliations

¹ Centre for Human Drug Research, Leiden, Netherlands.
² Department of Gynaecology and Obstetrics, Leiden University Medical Center, Leiden, Netherlands.
³ Netherlands Organisation for Applied Scientific Research (TNO), Zeist, Netherlands.
⁴ Department of Medical Microbiology, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, Leiden, Netherlands.
⁵ Department of Medical Microbiology, Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, Netherlands.
⁶ Leiden Amsterdam Center for Drug Research, Leiden University, Leiden, Netherlands.
⁷ Department of Dermatology, Leiden University Medical Center, Leiden, Netherlands.
⁸ Department of Obstetrics and Gynaecology, Catharina Cancer Institute, Eindhoven, Netherlands.

^# Contributed equally.

Abstract

Background: The role of the vulvar microbiome in the development of (pre)malignant vulvar disease is scarcely investigated. The aim of this exploratory study was to analyze vulvar microbiome composition in lichen sclerosus (LS) and vulvar high-grade squamous intraepithelial lesions (HSIL) compared to healthy controls.

Methods: Women with vulvar lichen sclerosus (n = 10), HSIL (n = 5) and healthy controls (n = 10) were included. Swabs were collected from the vulva, vagina and anal region for microbiome characterization by metagenomic shotgun sequencing. Both lesional and non-lesional sites were examined. Biophysical assessments included trans-epidermal water loss for evaluation of the vulvar skin barrier function and vulvar and vaginal pH measurements.

Results: Healthy vulvar skin resembled vaginal, anal and skin-like microbiome composition, including the genera Prevotella, Lactobacillus, Gardnerella, Staphylococcus, Cutibacterium, and Corynebacterium. Significant differences were observed in diversity between vulvar skin of healthy controls and LS patients. Compared to the healthy vulvar skin, vulvar microbiome composition of both LS and vulvar HSIL patients was characterized by significantly higher proportions of, respectively, Papillomaviridae (p = 0.045) and Alphapapillomavirus (p = 0.002). In contrast, the Prevotella genus (p = 0.031) and Bacteroidales orders (p = 0.038) were significantly less abundant in LS, as was the Actinobacteria class (p = 0.040) in vulvar HSIL. While bacteria and viruses were most abundant, fungal and archaeal taxa were scarcely observed. Trans-epidermal water loss was higher in vulvar HSIL compared to healthy vulvar skin (p = 0.043).

Conclusion: This study is the first to examine the vulvar microbiome through metagenomic shotgun sequencing in LS and HSIL patients. Diseased vulvar skin presents a distinct signature compared to healthy vulvar skin with respect to bacterial and viral fractions of the microbiome. Key findings include the presence of papillomaviruses in LS as well as in vulvar HSIL, although LS is generally considered an HPV-independent risk factor for vulvar dysplasia. This exploratory study provides clues to the etiology of vulvar premalignancies and may act as a steppingstone for expanding the knowledge on potential drivers of disease progression.

Keywords: HPV; lichen sclerosus; vaginal microbiome; vulvar HSIL; vulvar cancer; vulvar microbiome.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This project was funded by the Research and Development fund of the Centre for Human Drug Research, in addition to financial contributions from the Bontiusstichting (project 8222-32146) of the Leiden University Medical Centre and individual donors of the Catharinaziekenhuis Onderzoeksfonds.