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， 仍然有着令人沮丧的预后。已知的EAC可改变的风险因素不能充分解释这些 发病趋势；EAC病例的上升早于胃肠道疾病患病率增加的十年。 食道反流病和肥胖。幽门螺杆菌感染率自20世纪中期以来直线下降 而幽门螺杆菌的缺失与患巴雷特食道(BE)的风险增加~2倍相关。 EAC前驱病变和EAC本身。幽门螺杆菌的缺失与胃的深刻转移有关 微生物群组成。因此，西方人群的上消化道微生物群可能会发生戏剧性的变化 与BE同时发生，随后EAC的发病率开始上升。虽然之前的工作已经 显示出微生物组、BE和EAC之间的相关性，在机制上存在严重的知识差距 细菌通过这种方式与上皮细胞相互作用，并有可能促进癌症。覆盖在皮肤表面的粘液层 肠道上皮细胞是维持宿主细菌动态平衡的关键。我们假设，增加的水平 胃-食道反流中的胆汁酸脱氧胆酸导致Notch活性增加，进而 抑制杯状细胞分化，减少粘液产生。这可能导致粘液层变薄， 促进生物膜的发展，增加细菌-上皮相互作用和慢性 炎症，促进食管腺癌的发展。在目标1中，我们将携带 对患有和不患有BE、异型增生或EAC的患者进行病例对照研究。我们将重点介绍脱氧胆酸 胃-食道反流及其与Notch信号和细菌组成的关系。在目标2中，我们 关注Notch信号与肠杆菌科细菌的关系，肠杆菌科细菌在慢性阻塞性肺疾病患者中增加 高度不典型增生和早期EAC。最后，在目标3中，我们将进行一系列基于有机化合物的实验 测试Notch、脱氧胆酸和BE中细菌之间的相互关系。微生物群代表着 BE和EAC发生的一个新的和潜在的可改变的危险因素。微生物组的阐明 促进肿瘤形成的特征和机制是导致后续试验的关键一步 抗生素、益生菌和其他旨在改变微生物组的干预措施，目的是降低 这种高度致命的恶性肿瘤的风险。

PROJECT SUMMARY The incidence of esophageal adenocarcinoma (EAC) has risen 10-fold over the past half century and continues to have a dismal prognosis. Known modifiable risk factors for EAC do not adequately explain these incidence trends; the rise in EAC cases began a decade before increases in the prevalence of both gastro- esophageal reflux disease and obesity. Helicobacter pylori infection rates have plummeted since the mid-20th century, and absence of H. pylori is associated with a ~2-fold increased risk of Barrett’s esophagus (BE), the EAC precursor lesion, and of EAC itself. Loss of H. pylori is associated with profound shifts to gastric microbiome composition. Thus, dramatic changes in the upper GI microbiome in western populations likely occurred at the same time that BE and subsequently EAC began to rise in incidence. While prior work has shown correlations between the microbiome, BE, and EAC, there is a critical knowledge gap on mechanisms by which bacteria interact with the epithelium and potentially promote cancer. The mucus layer that overlies the gut epithelium is critical to maintaining host-bacteria homeostasis. We hypothesize that increased levels of the bile acid deoxycholic acid in gastro-esophageal refluxate results in increased Notch activity, which in turn inhibits goblet cell differentiation and decreases mucus production. This may lead to mucus layer thinning, facilitating the development of biofilms and leading to increased bacterial-epithelial interaction and chronic inflammation, which promotes the development of esophageal adenocarcinoma (EAC). In Aim 1, we will carry out a case-control study of patients with and without BE, dysplasia, or EAC. We will focus on deoxycholic acid in gastro-esophageal refluxate and its association with Notch signaling and bacterial composition. In Aim 2, we focus on the relationship between Notch signaling and Enterobacteriaceae, which is increased in patients with high grade dysplasia and early EAC. Finally, in Aim 3, we will perform a series of organoid-based experiments to test the inter-relatedness between Notch, deoxycholic acid, and bacteria in BE. The microbiome represents a novel and potentially modifiable risk factor for the development of BE and EAC. Elucidation of microbiome features and mechanisms that promote neoplasia is a critical step that will lead to subsequent trials of antibiotics, probiotics, and other interventions targeted to altering the microbiome, with the goal of lowering the risk of this highly lethal malignancy.