The Role of the Microbiome and Notch Signaling in Esophageal Adenocarcinoma

项目摘要 食管腺癌（EAC）的发病率在过去的半个世纪中上升了10倍，并且仍在继续 预后很差模型研究表明，只有少数EAC病例可归因于肥胖 或胃食管反流。自世纪中期以来，幽门螺杆菌感染率直线下降， 没有H。pylori与EAC前体巴雷特食管（BE）的风险增加约两倍相关 以及EAC本身的病变。西方人群的上消化道微生物组可能发生了巨大变化 而BE和随后EAC的发病率开始上升。我们小组先前的研究发现 微生物组BE和EAC之间的关系。在BE中，我们描述了组织相关微生物组的改变， 进展为EAC，肠杆菌科和链球菌显著增加。口腔微生物组改变 与将来患EAC的风险有关，我们先前也描述了口服 一小群BE患者的微生物组。口腔微生物组的改变也与 在最近的一项分析中，口腔健康不良本身与EAC风险增加有关。在本提案中，我们 试图阐明口腔微生物组和代谢物的改变如何推动食管肿瘤的进展。 特别是，我们试图了解特定的口腔社区成员是如何丰富或减少异常 状态可能改变代谢产物的产生，并导致上消化道的促癌变化 环境我们假设口腔微生物组的特定改变可以促进 EAC，细菌的促肿瘤作用部分是由于代谢产物的产生。这一假设将 通过以下相互关联的具体目标来实现：1）评估口腔微生物群落结构 通过鉴定关键的细菌分类群，与从BE到EAC的进展相关，和2）分离唾液微生物 与从BE进展至EAC相关的代谢物，同时描述 口腔微生物组比以往任何工作都更深入。父母补助金解决了脱氧胆酸 胃食管反流液中的DCA诱导BE中的Notch信号传导，降低杯状细胞分化 和粘液的产生。然而，亲本R01没有解决关键细菌之间的关系， 代谢物及其与Notch信号传导和肿瘤进展至EAC的关系。该提案涉及 这个关键的差距。

PROJECT SUMMARY The incidence of esophageal adenocarcinoma (EAC) has risen 10-fold over the past half century and continues to have a dismal prognosis. Modeling studies suggest that only a minority of EAC cases are attributable to obesity or gastric esophageal reflux. Helicobacter pylori infection rates have plummeted since the mid-20th century, and absence of H. pylori is associated with ~two-fold increased risk of Barrett’s esophagus (BE), the EAC precursor lesion, and of EAC itself. Dramatic changes in the upper GI microbiome in western populations likely occurred while BE and subsequently EAC began to rise in incidence. Our group’s prior work has discovered correlations between the microbiome, BE, and EAC. In BE, we’ve described tissue-associated microbiome alterations with progression to EAC, with notably increased Enterobacteriaceae and Streptococcus. Oral microbiome alterations have been associated with future risk of EAC, and we also previously described differences in the oral microbiome of a small group of BE patients. Alterations in the oral microbiome have also been associated with poor oral health, which was itself associated with increased risk of EAC in a recent analysis. In this proposal we seek to clarify how oral microbiome and metabolite alterations may drive progression of esophageal neoplasia. In particular, we seek to understand how specific oral community members enriched or depleted in abnormal states may shift metabolite production and lead to pro-carcinogenic changes in the upper gastrointestinal environment. We hypothesize that specific alterations of the oral microbiome can promote the development of EAC, and that the pro-neoplastic effects of bacteria are due in part to metabolite production. This hypothesis will be pursued through the following inter-related specific aims: 1) To assess the oral microbial community structure associated with progression from BE to EAC by identifying key bacterial taxa, and 2) To isolate salivary microbial metabolites associated with progression from BE to EAC, while describing the totality of metabolites within the oral microbiome more deeply than any prior work. The parent grant addresses the hypothesis that deoxycholic acid (DCA) in gastro-esophageal refluxate induces Notch signaling in BE, decreasing goblet cell differentiation and mucus production. However, the parent R01 does not address the relationship between key bacterial metabolites and their relationship to Notch signaling and neoplastic progression to EAC. This proposal addresses this critical gap.