The Role of the Microbiome and Notch Signaling in Esophageal Adenocarcinoma

项目总结 食管腺癌(EAC)的发病率在过去的半个世纪里上升了10倍，而且还在继续 有一个悲观的预后。建模研究表明，只有少数EAC病例可归因于肥胖 或者胃食道反流。自20世纪中叶以来，幽门螺杆菌的感染率直线下降， 幽门螺杆菌的缺失与EAC的前驱--巴雷特食道(BE)的风险增加两倍相关 病变，以及EAC本身。西方人群的上消化道微生物群可能发生了戏剧性的变化 而BE和随后的EAC的发病率开始上升。我们小组之前的工作发现了 在微生物群、BE和EAC之间。在BE中，我们描述了与组织相关的微生物群变化 进展为EAC，肠杆菌科和链球菌显著增加。口腔微生物群改变 都与未来的EAC风险有关，我们之前也描述了口腔中的差异 一小部分BE患者的微生物组。口腔微生物群的改变也与 口腔健康差，在最近的一项分析中，这本身与EAC风险增加有关。在这份提案中，我们 试图阐明口腔微生物群和代谢物的改变如何可能推动食道肿瘤的进展。 特别是，我们试图了解特定的口腔社区成员如何在异常情况下丰富或耗尽 各州可能会改变代谢物的产生，并导致上胃肠道的致癌变化 环境。我们推测，口腔微生物群的特定变化可以促进牙周炎的发生 EAC，细菌的促肿瘤作用部分是由于代谢物的产生。这一假说将 通过下列相互关联的具体目标来实现：1)评估口腔微生物群落结构 通过确定关键的细菌分类群与从BE到EAC的进展相关，以及2)分离唾液微生物 与从BE到EAC进展相关的代谢物，同时描述了 口腔微生物组比以前的任何工作都要深入。家长拨款解决了脱氧胆碱的假设 胃-食道反流中的酸(DCA)诱导BE中的Notch信号，减少杯状细胞的分化 和粘液的产生。然而，亲本R01没有解决关键细菌之间的关系 代谢产物及其与Notch信号和肿瘤进展到EAC的关系。这项提案涉及 这一关键差距。

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.