Cervical Microbiota Associated with Higher Grade Cervical Intraepithelial Neoplasia in Women Infected with High-Risk Human Papillomaviruses

It is increasingly recognized that microbes that reside in and on human body sites play major roles in modifying the pathogenesis of several diseases, including cancer. However, specific microbes or microbial communities that can be mechanistically linked to cervical carcinogenesis remain largely unexplored. The purpose of the study was to examine the association between cervical microbiota and high-grade cervical intraepithelial neoplasia (CIN 2+) in women infected with high-risk (HR) human papillomaviruses (HPV) and to assess whether the cervical microbiota are associated with oxidative DNA damage as indicated by the presence of cervical cells positive for 8-hydroxy-2'-deoxyguanosine. The study included 340 women diagnosed with CIN 2+ (cases) and 90 diagnosed with CIN 1 (non-cases). Microbiota composition was determined by Illumina sequencing of the 16S rRNA gene amplified from DNA extracted from cervical mucus samples. Measures of alpha/beta-diversity were not associated with either CIN severity or oxidative DNA damage. However, a cervical mucosal community type (CT) dominated by L. iners and unclassified Lactobacillus spp. was associated with CIN 2+ (OR = 3.48; 95% CI, 1.27–9.55). Sequence reads mapping to Lactobacillaceae, Lactobacillus, L. reuteri, and several sub–genus level Lactobacillus operational taxonomic units were also associated with CIN 2+ when examined independently (effect size >2.0; P < 0.05). Our 16S rRNA sequencing results need confirmation in independent studies using whole-genome shotgun sequencing and that would allow sharpening the suggested associations at finer taxonomic levels. Our results provide little evidence that DNA oxidative damage mediates the effect of the microbiome on the natural history of HPV infection and CIN severity. Cancer Prev Res; 9(5); 357–66. ©2016 AACR.

越来越多的研究证实，寄居在人体各部位的微生物在调控包括癌症在内的多种疾病的发病机制中发挥关键作用。然而，目前在机制层面与宫颈癌发生相关的特定微生物或菌群仍未得到充分探索。本研究旨在探究高危型人乳头瘤病毒（high-risk human papillomavirus, HR-HPV）感染女性的宫颈菌群与高级别宫颈上皮内瘤变（high-grade cervical intraepithelial neoplasia, CIN 2+）之间的关联，并评估宫颈菌群是否与以宫颈细胞8-羟基-2'-脱氧鸟苷（8-hydroxy-2'-deoxyguanosine）阳性为标志的DNA氧化损伤存在关联。本研究共纳入340名确诊为CIN 2+的受试者（病例组）以及90名确诊为CIN 1的受试者（非病例组）。通过对宫颈黏液样本提取的DNA扩增得到的16S rRNA基因进行Illumina测序（Illumina sequencing），以此确定菌群组成。α/β多样性分析结果显示，其与CIN严重程度及DNA氧化损伤均无关联。然而，以惰性乳杆菌（Lactobacillus iners, L. iners）和未分类乳杆菌属（Lactobacillus spp.）为主的宫颈黏膜群落型（community type, CT）与CIN 2+存在显著关联（比值比（odds ratio, OR）=3.48；95%置信区间（confidence interval, CI）：1.27~9.55）。单独分析时，匹配乳杆菌科（Lactobacillaceae）、乳杆菌属（Lactobacillus）、罗伊氏乳杆菌（Lactobacillus reuteri, L. reuteri）以及数个乳杆菌属亚属级操作分类单元（operational taxonomic units, OTU）的序列读长同样与CIN 2+存在关联（效应量>2.0；P<0.05）。本研究的16S rRNA测序结果尚需在独立研究中通过全基因组鸟枪测序（whole-genome shotgun sequencing）进行验证，以便在更精细的分类学层面明确上述关联。本研究结果未发现足够证据表明DNA氧化损伤可介导菌群对HPV感染自然进程及CIN严重程度的影响。《癌症预防研究（Cancer Prev Res）》；9卷第5期；357~366页。©2016 美国癌症研究协会（AACR）。