Human vaginal microbiome in cervical dysplasia and healthy controls. Vamigyn: dysplasia and controls

Shotgun metagenomic sequencing was used to taxonomically and functionally characterize the vaginal microbiota of women with and without cervical dysplasia. Study participants were recruited between June 2017 and January 2020. Women with histologically verified dysplasia and cancer (n = 177; low grade dysplasia (LSIL) n=81, high-grade dysplasia (HSIL) n= 94, cancer n=2) were recruited at the gynaecological out-patient clinic at Uppsala University hospital, Sweden. Healthy controls were recruited by sending invitations by regular mail to all women invited to the organized cervical screening programme in Uppsala County, Sweden (VaMiGyn study). Women were selected as controls from the VaMiGyn study based on having two consecutive normal screening tests, and no abnormal cervical pathology, including histology, cytology and HPV, during the full duration of the study period (n= 177). Women with dysplasia had a higher vaginal microbial diversity, and higher abundances of Gardnerella vaginalis, Aerococcus christensenii, Peptoniphilus lacrimalis and Fannyhessea vaginae, while healthy controls had higher relative abundance of Lactobacillus crispatus. Genes involved in e.g. nucleotide biosynthesis and peptidoglycan biosynthesis were more abundant in women with dysplasia. Healthy controls showed higher abundance of genes important for e.g. amino acid biosynthesis, (especially L-lysine) and sugar degradation. These findings suggest that the microbiota may have a role in creating a pro-oncogenic environment in women with dysplasia. Its role and potential interactions with other components in the microenvironment deserve further exploration.

本研究采用霰弹枪宏基因组测序（shotgun metagenomic sequencing），对伴或不伴宫颈发育异常（cervical dysplasia）女性的阴道微生物群（vaginal microbiota）进行分类学与功能学表征。研究参与者的招募时间为2017年6月至2020年1月。经组织学证实的宫颈发育异常及癌症患者（总例数n=177；其中低级别发育异常LSIL n=81、高级别发育异常HSIL n=94、癌症n=2）在瑞典乌普萨拉大学医院妇科门诊招募。健康对照组通过常规邮寄邀请函的方式，招募自瑞典乌普萨拉县所有受邀参与官方宫颈筛查项目的女性（VaMiGyn研究）。对照组从VaMiGyn研究队列中筛选，筛选标准为在整个研究周期内连续两次宫颈筛查结果均正常，且无包括组织学、细胞学及HPV检测在内的各类宫颈异常病变，共纳入177例。宫颈发育异常患者的阴道微生物多样性更高，加德纳菌（Gardnerella vaginalis）、克里斯滕森气球菌（Aerococcus christensenii）、泪液消化链球菌（Peptoniphilus lacrimalis）及阴道范尼菌（Fannyhessea vaginae）的相对丰度也显著升高；而健康对照组的卷曲乳酸杆菌（Lactobacillus crispatus）相对丰度更高。与健康对照组相比，核苷酸生物合成、肽聚糖生物合成等相关功能基因在宫颈发育异常患者中丰度更高。健康对照组则在氨基酸生物合成（尤其是L-赖氨酸）及糖类降解相关的关键功能基因上呈现更高丰度。上述研究结果提示，阴道微生物群可能在宫颈发育异常女性的促癌微环境形成过程中发挥作用，其具体功能及与微环境其他组分的潜在相互作用仍有待进一步探索。