title: Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity.
abstract: Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary for cervical carcinogenesis. Although evidence suggests that the vaginal microbiome plays a functional role in the persistence or regression of HPV infections, this has yet to be described in women with cervical intra-epithelial neoplasia (CIN). We hypothesised that increasing microbiome diversity is associated with increasing CIN severity. llumina MiSeq sequencing of 16S rRNA gene amplicons was used to characterise the vaginal microbiota of women with low-grade squamous intra-epithelial lesions (LSIL; n = 52), high-grade (HSIL; n = 92), invasive cervical cancer (ICC; n = 5) and healthy controls (n = 20). Hierarchical clustering analysis revealed an increased prevalence of microbiomes characterised by high-diversity and low levels of Lactobacillus spp. (community state type-CST IV) with increasing disease severity, irrespective of HPV status (Normal = 2/20,10%; LSIL = 11/52,21%; HSIL = 25/92,27%; ICC = 2/5,40%). Increasing disease severity was associated with decreasing relative abundance of Lactobacillus spp. The vaginal microbiome in HSIL was characterised by higher levels of Sneathia sanguinegens (P < 0.01), Anaerococcus tetradius (P < 0.05) and Peptostreptococcus anaerobius (P < 0.05) and lower levels of Lactobacillus jensenii (P < 0.01) compared to LSIL. Our results suggest advancing CIN disease severity is associated with increasing vaginal microbiota diversity and may be involved in regulating viral persistence and disease progression.
authors.affiliation: Institute of Reproductive and Developmental Biology, Department of Surgery &Cancer, Imperial College, London, UK.|Department of Obstetrics and Gynaecology, Queen Charlotte's &Chelsea - Hammersmith Hospital, Imperial Healthcare NHS Trust, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Mitra
authors.affiliation: Institute of Reproductive and Developmental Biology, Department of Surgery &Cancer, Imperial College, London, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: MacIntyre
authors.affiliation: Institute of Reproductive and Developmental Biology, Department of Surgery &Cancer, Imperial College, London, UK.
authors.forename: Y S
authors.initials: YS
authors.lastname: Lee
authors.affiliation: School of Biosciences, Cardiff University, CF10 3AX, UK.
authors.forename: A
authors.initials: A
authors.lastname: Smith
authors.affiliation: School of Biosciences, Cardiff University, CF10 3AX, UK.|Section of Biomolecular Medicine, Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Marchesi
authors.affiliation: Department of Epidemiology &Biostatistics, Medicine, Imperial College London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Lehne
authors.affiliation: HPV Research Group, Division of Pathology, University of Edinburgh, UK.
authors.forename: R
authors.initials: R
authors.lastname: Bhatia
authors.affiliation: Department of Obstetrics and Gynaecology, St Mary's Hospital, Imperial Healthcare NHS Trust, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Lyons
authors.affiliation: Department of Obstetrics and Gynaecology, University Hospital of Ioannina, Ioannina, Greece.
authors.forename: E
authors.initials: E
authors.lastname: Paraskevaidis
authors.affiliation: Section of Biomolecular Medicine, Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, UK.
authors.forename: J V
authors.initials: JV
authors.lastname: Li
authors.affiliation: Section of Biomolecular Medicine, Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Holmes
authors.affiliation: Section of Biomolecular Medicine, Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, UK.
authors.forename: J K
authors.initials: JK
authors.lastname: Nicholson
authors.affiliation: Institute of Reproductive and Developmental Biology, Department of Surgery &Cancer, Imperial College, London, UK.|Department of Obstetrics and Gynaecology, Queen Charlotte's &Chelsea - Hammersmith Hospital, Imperial Healthcare NHS Trust, London, UK.
authors.forename: P R
authors.initials: PR
authors.lastname: Bennett
authors.affiliation: Institute of Reproductive and Developmental Biology, Department of Surgery &Cancer, Imperial College, London, UK.|Department of Obstetrics and Gynaecology, Queen Charlotte's &Chelsea - Hammersmith Hospital, Imperial Healthcare NHS Trust, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Kyrgiou
mesh_terms: D000328:Adult; D044822:Biodiversity; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D007778:Lactobacillus / Q000235:genetics / Q000302:isolation & purification; D064307:Microbiota; D008875:Middle Aged; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification; D010462:Peptostreptococcus / Q000235:genetics / Q000302:isolation & purification; D012336:RNA, Ribosomal, 16S / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D002583:Uterine Cervical Neoplasms / Q000382:microbiology* / Q000473:pathology* / Q000821:virology; D014621:Vagina / Q000382:microbiology* / Q000821:virology; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000382:microbiology* / Q000473:pathology* / Q000821:virology
chemical_list: D015415:Biomarkers; D004279:DNA, Viral; D012336:RNA, Ribosomal, 16S