The Role of the Microbiome and Notch Signaling in Esophageal Adenocarcinoma

项目概要 过去半个世纪以来，食管腺癌 (EAC) 的发病率上升了 10 倍， 仍然有令人沮丧的预后。已知的可改变的 EAC 风险因素并不能充分解释这些 发病趋势； EAC 病例的增加早于两种胃肠道疾病患病率增加的十年 食管反流病和肥胖。 20世纪中期以来幽门螺杆菌感染率直线下降 世纪以来，幽门螺杆菌的缺失与巴雷特食管 (BE) 的风险增加约 2 倍相关。 EAC 前体病变以及 EAC 本身的病变。幽门螺杆菌的丧失与胃向胃的深刻转变有关 微生物组组成。因此，西方人群上消化道微生物组的巨大变化可能 BE 和随后的 EAC 发病率开始上升的同时发生。虽然之前的工作有 显示微生物组、BE 和 EAC 之间的相关性，但在机制方面存在关键的知识差距 细菌通过这种方式与上皮相互作用并可能促进癌症。覆盖在上面的粘液层 肠道上皮对于维持宿主细菌稳态至关重要。我们假设增加的水平 胃食管反流液中的胆汁酸、脱氧胆酸导致 Notch 活性增加，进而 抑制杯状细胞分化并减少粘液产生。这可能会导致粘液层变薄， 促进生物膜的形成并导致细菌-上皮相互作用增加和慢性 炎症，促进食管腺癌（EAC）的发展。在目标 1 中，我们将进行 对患有和不患有 BE、发育不良或 EAC 的患者进行病例对照研究。我们将重点关注脱氧胆酸 胃食管反流及其与 Notch 信号传导和细菌组成的关系。在目标 2 中，我们 重点关注Notch信号传导与肠杆菌科细菌之间的关系，这种信号在患有以下疾病的患者中增加 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类器官的实验 测试 BE 中 Notch、脱氧胆酸和细菌之间的相互关系。微生物组代表 BE 和 EAC 发展的一个新的、潜在可改变的风险因素。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，将导致后续试验 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.