Bacterial Composition of the Human Upper Gastrointestinal Tract Microbiome Is Dynamic and Associated with Genomic Instability in a Barrett’s Esophagus Cohort

BackgroundThe incidence of esophageal adenocarcinoma (EAC) has increased nearly five-fold over the last four decades in the United States. Barrett’s esophagus, the replacement of the normal squamous epithelial lining with a mucus-secreting columnar epithelium, is the only known precursor to EAC. Like other parts of the gastrointestinal (GI) tract, the esophagus hosts a variety of bacteria and comparisons among published studies suggest bacterial communities in the stomach and esophagus differ. Chronic infection with Helicobacter pylori in the stomach has been inversely associated with development of EAC, but the mechanisms underlying this association remain unclear.MethodologyThe bacterial composition in the upper GI tract was characterized in a subset of participants (n=12) of the Seattle Barrett’s Esophagus Research cohort using broad-range 16S PCR and pyrosequencing of biopsy and brush samples collected from squamous esophagus, Barrett’s esophagus, stomach corpus and stomach antrum. Three of the individuals were sampled at two separate time points. Prevalence of H. pylori infection and subsequent development of aneuploidy (n=339) and EAC (n=433) was examined in a larger subset of this cohort.Results/SignificanceWithin individuals, bacterial communities of the stomach and esophagus showed overlapping community membership. Despite closer proximity, the stomach antrum and corpus communities were less similar than the antrum and esophageal samples. Re-sampling of study participants revealed similar upper GI community membership in two of three cases. In this Barrett’s esophagus cohort, Streptococcus and Prevotella species dominate the upper GI and the ratio of these two species is associated with waist-to-hip ratio and hiatal hernia length, two known EAC risk factors in Barrett’s esophagus. H. pylori-positive individuals had a significantly decreased incidence of aneuploidy and a non-significant trend toward lower incidence of EAC.

背景
食管腺癌（esophageal adenocarcinoma, EAC）的发病率在过去四十年间在美国增长了近五倍。巴雷特食管（Barrett’s esophagus）指正常鳞状上皮内衬被分泌黏液的柱状上皮所取代，是目前已知的唯一一种食管腺癌的癌前病变。与胃肠道（gastrointestinal tract, GI）的其他部位类似，食管定植有多种细菌；对已发表研究的对比分析显示，胃与食管内的细菌群落存在差异。胃内幽门螺杆菌（Helicobacter pylori）慢性感染与食管腺癌的发生呈负相关，但该关联的具体分子机制仍未阐明。

研究方法
本研究针对西雅图巴雷特食管研究队列的12名受试者亚群，采用广谱16S聚合酶链反应（broad-range 16S PCR）及焦磷酸测序（pyrosequencing）技术，对取自鳞状上皮食管、巴雷特食管、胃体及胃窦的活检与刷取样本进行分析，以解析上胃肠道的细菌组成。其中3名受试者在两个独立时间点接受了重复采样。本研究在该队列的更大规模亚群中，分析了幽门螺杆菌感染的患病率，以及339名受试者后续发生非整倍体（aneuploidy）、433名受试者后续罹患食管腺癌的情况。

结果与意义
在同一受试者体内，胃与食管的细菌群落具有重叠的类群组成。尽管胃窦与胃体的空间距离更近，但二者的细菌群落相似性低于胃窦与食管样本的相似性。对受试者的二次采样结果显示，3名受试者中有2名的上胃肠道细菌群落组成相似。在本巴雷特食管队列中，上胃肠道的优势细菌类群为链球菌属（Streptococcus）与普雷沃菌属（Prevotella），二者的丰度比值与腰臀比及食管裂孔疝（hiatal hernia）长度相关——这两者均为巴雷特食管患者已知的食管腺癌危险因素。幽门螺杆菌阳性受试者的非整倍体发生率显著降低，而食管腺癌发生率虽呈降低趋势但未达到统计学显著性。