Cervical microbiota dysbiosis associated with high-risk Human Papillomavirus infection

High-risk Human Papillomavirus (HR-HPV) genotypes, specifically HPV16 and HPV18, pose a significant risk for the development of cervical intraepithelial neoplasia and cervical cancer. In the multifaceted cervical microenvironment, consisting of immune cells and diverse microbiota, Lactobacillus emerges as a pivotal factor, wielding significant influence in both stabilizing and disrupting the microbiome of the reproductive tract. To analyze the distinction between the cervical microbiota and Lactobacillus-dominant/non-dominant status of HR-HPV and non-infected healthy women, sixty-nine cervical swab samples were analyzed, included 44 with HR-HPV infection and healthy controls. All samples were recruited from Human Papillomavirus-based cervical cancer screening program and subjected to 16s rRNA sequencing analysis. Alpha and beta diversity analyses reveal no significant differences in the cervical microbiota of HR-HPV-infected women, including 16 and 18 HPV genotypes, and those with squamous intraepithelial lesion (SIL), compared to a control group. In this study we identified significantly lower abundance of Lactobacillus mucosae in women with HR-HPV infection compared to the control group. Furthermore, changes in bacterial diversity were noted in Lactobacillus non-dominant (LND) samples compared to Lactobacillus-dominant (LD) in both HR-HPV-infected and control groups. LND samples in HR-HPV-infected women exhibited a cervical dysbiotic state, characterized by Lactobacillus deficiency. In turn, the LD HR-HPV group showed an overrepresentation of Lactobacillus helveticus. In summary, our study highlighted the distinctive roles of L. mucosae and L. helveticus in HR-HPV infections, signaling a need for further research to demonstrate potential clinical implications of cervical microbiota dysbiosis.

[1]  M. Dąbrowska,et al.  Human Papillomavirus Infections and the Role Played by Cervical and Cervico-Vaginal Microbiota—Evidence from Next-Generation Sequencing Studies , 2024, Cancers.

[2]  G. Campisi,et al.  Orogenital Human Papillomavirus Infection and Vaccines: A Survey of High- and Low-Risk Genotypes Not Included in Vaccines , 2023, Vaccines.

[3]  L. Forney,et al.  The cervical microbiota of Hispanics living in Puerto Rico is nonoptimal regardless of HPV status , 2023, mSystems.

[4]  Lokesh Kumar,et al.  The Female Reproductive Tract Microbiota: Friends and Foe , 2023, Life.

[5]  S. Boussios,et al.  HPV and Cervical Cancer: A Review of Epidemiology and Screening Uptake in the UK , 2023, Pathogens.

[6]  Xin Li,et al.  Roles of vaginal flora in human papillomavirus infection, virus persistence and clearance , 2023, Frontiers in Cellular and Infection Microbiology.

[7]  Yuanyue Li,et al.  The diversity of vaginal microbiome in women infected with single HPV and multiple genotype HPV infections in China , 2022, Frontiers in Cellular and Infection Microbiology.

[8]  P. Gajer,et al.  Lactobacillus-dominance and rapid stabilization of vaginal microbiota in combined oral contraceptive pill users examined through a longitudinal cohort study with frequent vaginal sampling over two years , 2022, EBioMedicine.

[9]  Eun Chae Moon,et al.  Lactobacillus helveticus HY7801 ameliorates bacterial vaginosis by inhibiting biofilm formation and epithelial cell adhesion of Gardnerella vaginalis , 2022, Food Science and Biotechnology.

[10]  B. Nedjai,et al.  2022-RA-1195-ESGO Longitudinal study of vaginal microbiome pre- and post-treatment identifies biomarkers for cervical intraepithelial neoplasia 3 (CIN3) , 2022, Translational research/biomarkers.

[11]  M. Huynen,et al.  In-depth insights into cervicovaginal microbial communities and hrHPV infections using high-resolution microbiome profiling , 2022, npj Biofilms and Microbiomes.

[12]  A. Nowakowski,et al.  Increased diversity of a cervical microbiome associates with cervical cancer , 2022, Frontiers in Oncology.

[13]  J. M. Wessels,et al.  The female reproductive tract microbiotas, inflammation, and gynecological conditions , 2022, Frontiers in Reproductive Health.

[14]  Shuaicheng Li,et al.  Cervicovaginal microbiota significantly changed for HPV-positive women with high-grade squamous intraepithelial lesion , 2022, Frontiers in Cellular and Infection Microbiology.

[15]  G. Ingravallo,et al.  Association between Cervical Microbiota and HPV: Could This Be the Key to Complete Cervical Cancer Eradication? , 2022, Biology.

[16]  Zhen-bo Zhang,et al.  Changes in the cervicovaginal microbiota composition of HPV16‐infected patients after clinical treatment , 2022, Cancer medicine.

[17]  T. Mizutani,et al.  Role of Microbiota in Viral Infections and Pathological Progression , 2022, Viruses.

[18]  Bin Zhang,et al.  Dysbiosis of Cervical and Vaginal Microbiota Associated With Cervical Intraepithelial Neoplasia , 2022, Frontiers in Cellular and Infection Microbiology.

[19]  Dominika Jurášková,et al.  Exopolysaccharides Produced by Lactic Acid Bacteria: From Biosynthesis to Health-Promoting Properties , 2022, Foods.

[20]  R. Su,et al.  The Microbiome as a Key Regulator of Female Genital Tract Barrier Function , 2021, Frontiers in Cellular and Infection Microbiology.

[21]  Y. Meng,et al.  Characteristics of the Cervicovaginal Microenvironment in Childbearing-Age Women with Different Degrees of Cervical Lesions and HR-HPV Positivity , 2021, Polish journal of microbiology.

[22]  M. Huynen,et al.  Novel high-resolution targeted sequencing of the cervicovaginal microbiome , 2021, BMC biology.

[23]  Yutao Diao,et al.  Reproductive tract microbiota of women in childbearing age shifts upon gynecological infections and menstrual cycle , 2021, BMC microbiology.

[24]  P. Di Carlo,et al.  Socio-Demographic Characteristics and Sexual Behavioral Factors of Patients with Sexually Transmitted Infections Attending a Hospital in Southern Italy , 2021, International journal of environmental research and public health.

[25]  Xianyang Zhang,et al.  LinDA: linear models for differential abundance analysis of microbiome compositional data , 2021, Genome Biology.

[26]  Justin C. Fay,et al.  The structure and diversity of strain-level variation in vaginal bacteria , 2021, Microbial genomics.

[27]  T. Tsukamoto,et al.  Changes to the cervicovaginal microbiota and cervical cytokine profile following surgery for cervical intraepithelial neoplasia , 2021, Scientific Reports.

[28]  T. Jin,et al.  Epidemiology and Burden of Human Papillomavirus and Related Diseases, Molecular Pathogenesis, and Vaccine Evaluation , 2021, Frontiers in Public Health.

[29]  J. Huber,et al.  Human papillomavirus persistence or clearance after infection in reproductive age. What is the status? Review of the literature and new data of a vaginal gel containing silicate dioxide, citric acid, and selenite , 2021, Women's health.

[30]  M. L. Sallas,et al.  Microbiome and Cervical Cancer , 2020, Pathobiology.

[31]  L. Than,et al.  Vaginal microbiota and the potential of Lactobacillus derivatives in maintaining vaginal health , 2020, Microbial Cell Factories.

[32]  C. Adebamowo,et al.  Vaginal microbiota diversity and paucity of Lactobacillus species are associated with persistent hrHPV infection in HIV negative but not in HIV positive women , 2020, Scientific Reports.

[33]  V. Gouyer,et al.  The Cervicovaginal Mucus Barrier , 2020, International journal of molecular sciences.

[34]  Stefan Enroth,et al.  Temporal changes in the vaginal microbiota in self-samples and its association with persistent HPV16 infection and CIN2+ , 2020, Virology journal.

[35]  T. de Oliveira,et al.  Determinants of Vaginal Microbiota Composition , 2020, Frontiers in Cellular and Infection Microbiology.

[36]  V. Chiantera,et al.  ‘Secondary prevention’ against female HPV infection: literature review of the role of carrageenan , 2020, Expert review of anti-infective therapy.

[37]  Charles Nkufi Tango,et al.  Taxonomic and Functional Differences in Cervical Microbiome Associated with Cervical Cancer Development , 2020, Scientific Reports.

[38]  Wenjing Wang,et al.  Human papillomavirus infection and cervical intraepithelial neoplasia progression are associated with increased vaginal microbiome diversity in a Chinese cohort , 2020, BMC Infectious Diseases.

[39]  P. Castle,et al.  Cervicovaginal microbiome and natural history of HPV in a longitudinal study , 2020, PLoS pathogens.

[40]  P. Gajer,et al.  VALENCIA: a nearest centroid classification method for vaginal microbial communities based on composition , 2020, Microbiome.

[41]  Z. Ilhan,et al.  The microbiome and gynaecological cancer development, prevention and therapy , 2020, Nature Reviews Urology.

[42]  K. Pal,et al.  Contrasting diversity of vaginal lactobacilli among the females of Northeast India , 2019, BMC Microbiology.

[43]  Hua Gao,et al.  Association between the vaginal microbiome and high-risk human papillomavirus infection in pregnant Chinese women , 2019, BMC Infectious Diseases.

[44]  J. H. van de Wijgert,et al.  Vaginal dysbiosis and the risk of human papillomavirus and cervical cancer: systematic review and meta-analysis. , 2019, American journal of obstetrics and gynecology.

[45]  J. Ravel,et al.  The vaginal microbiota and its association with human papillomavirus, Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium infections: a systematic review and meta-analysis. , 2019, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[46]  J. Ravel,et al.  Cervicovaginal microbiota, women's health, and reproductive outcomes. , 2018, Fertility and sterility.

[47]  S. Graham The human papillomavirus replication cycle, and its links to cancer progression: a comprehensive review. , 2017, Clinical science.

[48]  D. Cavalieri,et al.  Characterization of cervico-vaginal microbiota in women developing persistent high-risk Human Papillomavirus infection , 2017, Scientific Reports.

[49]  A. Firenze,et al.  Potential impact of a nonavalent HPV vaccine on HPV related low-and high-grade cervical intraepithelial lesions: A referral hospital-based study in Sicily , 2017, Human vaccines & immunotherapeutics.

[50]  P. Gajer,et al.  Association of HPV infection and clearance with cervicovaginal immunology and the vaginal microbiota , 2016, Mucosal Immunology.

[51]  R. Dunn,et al.  Lactobacilli Dominance and Vaginal pH: Why Is the Human Vaginal Microbiome Unique? , 2016, Front. Microbiol..

[52]  Mardge H. Cohen,et al.  The Cervicovaginal Microbiota and Its Associations With Human Papillomavirus Detection in HIV-Infected and HIV-Uninfected Women. , 2016, The Journal of infectious diseases.

[53]  J. Marrazzo,et al.  The Vaginal Microbiome: Current Understanding and Future Directions. , 2016, The Journal of infectious diseases.

[54]  J. K. Nicholson,et al.  Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity , 2015, Scientific Reports.

[55]  S. Seo,et al.  The association of uterine cervical microbiota with an increased risk for cervical intraepithelial neoplasia in Korea. , 2015, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[56]  Seon-Ho Kim,et al.  Effect of Lactobacillus mucosae on In vitro Rumen Fermentation Characteristics of Dried Brewers Grain, Methane Production and Bacterial Diversity , 2014, Asian-Australasian journal of animal sciences.

[57]  Jennifer M. Fettweis,et al.  Differences in vaginal microbiome in African American women versus women of European ancestry. , 2014, Microbiology.

[58]  D. Kang,et al.  In vitro evaluation of the mucin‐adhesion ability and probiotic potential of Lactobacillus mucosae LM1 , 2014, Journal of applied microbiology.

[59]  J. Klausner,et al.  Characterization of culturable vaginal Lactobacillus species among women with and without bacterial vaginosis from the United States and India: a cross-sectional study. , 2014, Journal of medical microbiology.

[60]  A. Horii,et al.  An Adhesin-Like Protein, Lam29, from Lactobacillus mucosae ME-340 Binds to Histone H3 and Blood Group Antigens in Human Colonic Mucus , 2012, Bioscience, biotechnology, and biochemistry.

[61]  P. Gajer,et al.  Vaginal microbiome of reproductive-age women , 2010, Proceedings of the National Academy of Sciences.

[62]  David J Van Horn,et al.  Introducing mothur: Open-Source, Platform-Independent, Community-Supported Software for Describing and Comparing Microbial Communities , 2009, Applied and Environmental Microbiology.

[63]  D. Brassart,et al.  In vitro antibacterial activity of Lactobacillus helveticus strain KS300 against diarrhoeagenic, uropathogenic and vaginosis‐associated bacteria , 2006, Journal of applied microbiology.

[64]  Eoin L. Brodie,et al.  Greengenes, a Chimera-Checked 16S rRNA Gene Database and Workbench Compatible with ARB , 2006, Applied and Environmental Microbiology.

[65]  J. A. Plascak,et al.  Wang-Landau Monte Carlo simulation of the Blume-Capel model. , 2006, Physical review. E, Statistical, nonlinear, and soft matter physics.

[66]  Ben Nichols,et al.  Distributed under Creative Commons Cc-by 4.0 Vsearch: a Versatile Open Source Tool for Metagenomics , 2022 .