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， 仍然前景黯淡已知的可改变的EAC风险因素不能充分解释这些 发病率趋势; EAC病例的增加开始于胃- 食管反流病和肥胖症。幽门螺杆菌感染率自20世纪中期以来大幅下降 世纪，H.幽门螺杆菌与巴雷特食管（BE）的风险增加约2倍相关， EAC前驱病变和EAC本身。失去H。幽门螺杆菌与胃肠道 微生物组组成。因此，西方人群中上消化道微生物组的巨大变化可能 与BE和随后EAC的发病率开始上升同时发生。虽然之前的工作 显示微生物组，BE和EAC之间的相关性，在机制上存在关键的知识差距 细菌通过这种方式与上皮细胞相互作用并潜在地促进癌症。覆盖在皮肤上的粘液层 肠上皮对于维持宿主细菌的体内平衡是至关重要的。我们假设， 胃食管反流液中的胆汁酸脱氧胆酸导致Notch活性增加， 抑制杯状细胞分化并减少粘液产生。这可能导致粘液层变薄， 促进生物膜的形成并导致细菌-上皮相互作用和慢性炎症的增加。 炎症，促进食管腺癌（EAC）的发展。在目标1中，我们将携带 对有或无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 及其与Notch信号传导和细菌组成的关系。在目标2中， 关注Notch信号传导与肠杆菌科之间的关系， 高度异型增生和早期EAC。最后，在目标3中，我们将进行一系列基于类器官的实验 检测Notch、脱氧胆酸和BE中细菌之间的相互关系。微生物组代表了 BE和EAC发展的一种新的和潜在的可改变的风险因素。微生物组的阐明 促进肿瘤形成的特征和机制是关键的一步，这将导致随后的试验， 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.