Association of the Vaginal Microbiota with Human Papillomavirus Infection in a Korean Twin Cohort

Human papillomavirus (HPV) is the most important causative agent of cervical cancers worldwide. However, our understanding of how the vaginal microbiota might be associated with HPV infection is limited. In addition, the influence of human genetic and physiological factors on the vaginal microbiota is unclear. Studies on twins and their families provide the ideal settings to investigate the complicated nature of human microbiota. This study investigated the vaginal microbiota of 68 HPV-infected or uninfected female twins and their families using 454-pyrosequencing analysis targeting the variable region (V2–V3) of the bacterial 16S rRNA gene. Analysis of the vaginal microbiota from both premenopausal women and HPV-discordant twins indicated that HPV-positive women had significantly higher microbial diversity with a lower proportion of Lactobacillus spp. than HPV-negative women. Fusobacteria, including Sneathia spp., were identified as a possible microbiological marker associated with HPV infection. The vaginal microbiotas of twin pairs were significantly more similar to each other than to those from unrelated individuals. In addition, there were marked significant differences from those of their mother, possibly due to differences in menopausal status. Postmenopausal women had a lower proportion of Lactobacillus spp. and a significantly higher microbiota diversity. This study indicated that HPV infection was associated with the composition of the vaginal microbiota, which is influenced by multiple host factors such as genetics and menopause. The potential biological markers identified in this study could provide insight into HPV pathogenesis and may represent biological targets for diagnostics.

[1]  K. Anastos,et al.  Risk of cervical precancer and cancer among HIV-infected women with normal cervical cytology and no evidence of oncogenic HPV infection. , 2012, JAMA.

[2]  Joelle M. Brown,et al.  HPV Type Distribution and Cervical Cytology among HIV-Positive Tanzanian and South African Women , 2012, ISRN obstetrics and gynecology.

[3]  G. Reid,et al.  PCR‐based identification of eight lactobacillus species and 18 hr‐HPV genotypes in fixed cervical samples of south african women at risk of HIV and BV , 2012, Diagnostic cytopathology.

[4]  B. Birren,et al.  Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. , 2012, Genome research.

[5]  Rob Knight,et al.  Selection of primers for optimal taxonomic classification of environmental 16S rRNA gene sequences , 2012, The ISME Journal.

[6]  M. Schiffman,et al.  Evaluation of Any or Type-Specific Persistence of High-Risk Human Papillomavirus for Detecting Cervical Precancer , 2011, Journal of Clinical Microbiology.

[7]  Jean M. Macklaim,et al.  Vaginal Microbiome and Epithelial Gene Array in Post-Menopausal Women with Moderate to Severe Dryness , 2011, PloS one.

[8]  Tarah Lynch,et al.  Invasive potential of gut mucosa‐derived fusobacterium nucleatum positively correlates with IBD status of the host , 2011, Inflammatory bowel diseases.

[9]  C. Huttenhower,et al.  Metagenomic biomarker discovery and explanation , 2011, Genome Biology.

[10]  B. Haas,et al.  Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons. , 2011, Genome research.

[11]  Joris Meys,et al.  Bacterial vaginosis is associated with uterine cervical human papillomavirus infection: a meta-analysis , 2011, BMC infectious diseases.

[12]  J. H. van de Wijgert,et al.  Factors affecting transmission of mucosal human papillomavirus. , 2010, The Lancet. Infectious diseases.

[13]  Yuzhen Ye,et al.  Identification and quantification of abundant species from pyrosequences of 16S rRNA by consensus alignment , 2010, 2010 IEEE International Conference on Bioinformatics and Biomedicine (BIBM).

[14]  Fang Liu,et al.  Molecular analysis of the diversity of vaginal microbiota associated with bacterial vaginosis , 2010, BMC Genomics.

[15]  Gregory B. Gloor,et al.  Deep Sequencing of the Vaginal Microbiota of Women with HIV , 2010, PloS one.

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

[17]  Yun-Mi Song,et al.  Validity of the Zygosity Questionnaire and Characteristics of Zygosity-Misdiagnosed Twin Pairs in the Healthy Twin Study of Korea , 2010, Twin Research and Human Genetics.

[18]  William A. Walters,et al.  QIIME allows analysis of high-throughput community sequencing data , 2010, Nature Methods.

[19]  J. H. van de Wijgert,et al.  Prevalence, distribution and correlates of endocervical human papillomavirus types in Brazilian women , 2010, International journal of STD & AIDS.

[20]  Martin Hartmann,et al.  Introducing mothur: Open-Source, Platform-Independent, Community-Supported Software for Describing and Comparing Microbial Communities , 2009, Applied and Environmental Microbiology.

[21]  C. Quince,et al.  Accurate determination of microbial diversity from 454 pyrosequencing data , 2009, Nature Methods.

[22]  T. Hope,et al.  Human Immunodeficiency Virus Type 1 Is Trapped by Acidic but Not by Neutralized Human Cervicovaginal Mucus , 2009, Journal of Virology.

[23]  Sandra Doria Xavier,et al.  Detecção de HPV na mucosa oral e genital pela técnica PCR em mulheres com diagnóstico histopatológico positivo para HPV genital , 2009 .

[24]  S. Xavier,et al.  HPV detection in the oral and genital mucosa of women with positive histopathological exam for genital HPV, by means of the PCR , 2009, Brazilian journal of otorhinolaryngology.

[25]  Chris J. Williams,et al.  Bacterial populations in the vaginas of healthy adolescent women. , 2009, Journal of pediatric and adolescent gynecology.

[26]  James R. Cole,et al.  The Ribosomal Database Project: improved alignments and new tools for rRNA analysis , 2008, Nucleic Acids Res..

[27]  B. Roe,et al.  A core gut microbiome in obese and lean twins , 2008, Nature.

[28]  Masoumeh Sikaroodi,et al.  Comparison of the diversity of the vaginal microbiota in HIV-infected and HIV-uninfected women with or without bacterial vaginosis. , 2008, The Journal of infectious diseases.

[29]  J. Peipert,et al.  Viral Sexually Transmitted Infections and Bacterial Vaginosis: 2001–2004 National Health and Nutrition Examination Survey Data , 2008, Sexually transmitted diseases.

[30]  B. Ziola,et al.  Real-time PCR detection of bacteria belonging to the Firmicutes Phylum. , 2008, International journal of food microbiology.

[31]  Michael Wilson,et al.  Bacteriology of Humans: An Ecological Perspective , 2008 .

[32]  D. Relman,et al.  An ecological and evolutionary perspective on human–microbe mutualism and disease , 2007, Nature.

[33]  Sung-il Cho,et al.  Healthy Twin: a twin-family study of Korea--protocols and current status. , 2006, Twin research and human genetics : the official journal of the International Society for Twin Studies.

[34]  Rob Knight,et al.  UniFrac – An online tool for comparing microbial community diversity in a phylogenetic context , 2006, BMC Bioinformatics.

[35]  Philip Hugenholtz,et al.  NAST: a multiple sequence alignment server for comparative analysis of 16S rRNA genes , 2006, Nucleic Acids Res..

[36]  A. Dennison,et al.  Role of Inflammation in Pancreatic Carcinogenesis and the Implications for Future Therapy , 2005, Pancreatology.

[37]  G. Freund,et al.  Test performance comparison of inform HPV and hybrid capture 2 high-risk HPV DNA tests using the SurePath liquid-based Pap test as the collection method. , 2005, American journal of clinical pathology.

[38]  E. Weiss,et al.  Fluorescence based measurements of Fusobacterium nucleatum coaggregation and of fusobacterial attachment to mammalian cells. , 2005, FEMS microbiology letters.

[39]  J. Palefsky,et al.  Effects of bacterial vaginosis and other genital infections on the natural history of human papillomavirus infection in HIV-1-infected and high-risk HIV-1-uninfected women. , 2005, The Journal of infectious diseases.

[40]  Qiang Wu,et al.  Fusobacterium nucleatum Increases Collagenase 3 Production and Migration of Epithelial Cells , 2005, Infection and Immunity.

[41]  M. Vaneechoutte,et al.  Cloning of 16S rRNA genes amplified from normal and disturbed vaginal microflora suggests a strong association between Atopobium vaginae, Gardnerella vaginalis and bacterial vaginosis , 2004, BMC Microbiology.

[42]  E. Boyko,et al.  Prevalence and determinants of vaginal flora alterations in postmenopausal women. , 2003, The Journal of infectious diseases.

[43]  L. Meyn,et al.  Association between acquisition of herpes simplex virus type 2 in women and bacterial vaginosis. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[44]  Alexandra Kaider,et al.  Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. , 2003, American journal of obstetrics and gynecology.

[45]  M. Krohn,et al.  Bacterial vaginosis is a strong predictor of Neisseria gonorrhoeae and Chlamydia trachomatis infection. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[46]  A I Saeed,et al.  TM4: a free, open-source system for microarray data management and analysis. , 2003, BioTechniques.

[47]  C. Woodworth.  HPV innate immunity. , 2002, Frontiers in bioscience : a journal and virtual library.

[48]  R. Genco,et al.  Interactions between Periodontal Bacteria and Human Oral Epithelial Cells: Fusobacterium nucleatum Adheres to and Invades Epithelial Cells , 2000, Infection and Immunity.

[49]  A. Moscicki,et al.  Th1 Cytokine Patterns in Cervical Human Papillomavirus Infection , 1999, Clinical Diagnostic Laboratory Immunology.

[50]  A. Rutherford,et al.  Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study , 1999, BMJ.

[51]  A. Stapleton,et al.  Inverse association of H2O2-producing lactobacilli and vaginal Escherichia coli colonization in women with recurrent urinary tract infections. , 1998, The Journal of infectious diseases.

[52]  S. Hillier,et al.  Vaginal microflora in postmenopausal women who have not received estrogen replacement therapy. , 1997, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[53]  R. Burk,et al.  PCR detection of human papillomavirus: comparison between MY09/MY11 and GP5+/GP6+ primer systems , 1997, Journal of clinical microbiology.

[54]  K. Holmes,et al.  Hydrogen peroxide-producing lactobacilli and acquisition of vaginal infections. , 1996, The Journal of infectious diseases.

[55]  D. McCance,et al.  The E5 oncoprotein of human papillomavirus type 16 inhibits the acidification of endosomes in human keratinocytes , 1995, Journal of virology.

[56]  M. Van Ranst,et al.  Analysis of short novel human papillomavirus sequences. , 1994, Biochemical and biophysical research communications.

[57]  W E Moore,et al.  The bacteria of periodontal diseases. , 1994, Periodontology 2000.

[58]  A. Eley,et al.  Fusobacteria: new taxonomy and related diseases. , 1993, Journal of medical microbiology.

[59]  C. Mathers,et al.  GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer , 2013 .

[60]  E. Somers.  International Agency for Research on Cancer. , 1985, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[61]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.