The Role of the Microbiome and Notch Signaling in Esophageal Adenocarcinoma

微生物组和 Notch 信号传导在食管腺癌中的作用

• 批准号: 10543870
• 负责人: Julian Abrams
• 金额: $ 52.39万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543870
• 关键词: Acceleration; Acids; Antibiotics; Area; Automobile Driving; Bacteria; Barrett Esophagus; Bile Acids; Case/Control Studies; Cell Differentiation process; Cessation of life; Chronic; Clinical; Collaborations; Colon; Colon Carcinoma; Data; Deoxycholic Acid; Development; Dysplasia; Enrollment; Enterobacteriaceae; Epithelium; Esophageal Adenocarcinoma; Esophageal Neoplasms; Esophageal Tissue; Esophagus; Feedback; Future; Gastroesophageal reflux disease; Goals; Goblet Cells; Helicobacter Infections; Helicobacter pylori; High grade dysplasia; Homeostasis; Incidence; Inflammation; Intervention; Intestines; Knowledge; Lesion; Logistic Regressions; Malignant Neoplasms; Malignant neoplasm of esophagus; Microbial Biofilms; Minority; Modeling; Mucins; Mucous body substance; Mutagens; NF-kappa B; Neoplasms; Obesity; Organoids; Pathway interactions; Patients; Population; Prevalence; Probiotics; Production; Prognosis; Prospective cohort; Public Health; Research; Risk; Risk Factors; Role; Sampling; Series; Signal Transduction; Stomach; Study models; Testing; Thinness; Time; Tissue Sample; Translating; Upper digestive tract structure; Work; aspirate; carcinogenesis; carcinogenicity; cohort; experimental study; gastric microbiome; gastrointestinal epithelium; gut microbiome; high risk; infection rate; microbiome; microbiome alteration; microbiome composition; modifiable risk; mouse model; notch protein; novel; prevent; prospective; trend

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.

项目摘要 食管腺癌（EAC）的发生率在过去半个世纪中增长了10倍，并且 继续有一个令人沮丧的提示。 EAC的已知可修改风险因素不能充分解释这些 发生率趋势； EAC病例的上升开始了十年，直到两种胃的流行率的增加 食管反射疾病和肥胖。自20世纪中旬以来，幽门螺杆菌的幽门螺杆菌感染率暴跌 世纪，幽门螺杆菌的缺失与巴雷特食管（BE）的风险增加了约2倍 EAC前体病变和EAC本身。幽门螺杆菌的丧失与向胃的深刻转变有关 微生物组组成。这是西方人群中胃肠地上微生物组的急剧变化 发生在同一时间，随后EAC开始发生事件。虽然先前的工作 显示了微生物组，BE和EAC之间的相关性，机制存在关键的知识差距 细菌与上皮相互作用并可能促进癌症。覆盖的粘液层 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 胃酸脱氧胆酸在胃道食道中反映导致缺口活性增加 抑制杯状细胞分化并降低粘液产生。这可能会导致粘液层变薄， 促进生物膜的发展并导致细菌 - 上皮相互作用增加和慢性 炎症，促进食管腺癌（EAC）的发展。在AIM 1中，我们将携带 进行病例对照研究，对有或没有BE，发育不良或EAC的患者。我们将专注于脱氧胆酸 在胃食管反射氧化物及其与Notch信号传导和细菌组成的关联中。在AIM 2中，我们 关注Notch信号传导和肠杆菌科之间的关系，这在患者中有所增加 高级发育不良和早期EAC。最后，在AIM 3中，我们将执行一系列基于器官的实验 测试BE中的Notch，脱氧胆酸和细菌之间的相关性。微生物组代表 BE和EAC开发的一种新颖且潜在的可修改风险因素。阐明微生物组 促进肿瘤的特征和机制是一个关键步骤，将导致随后的试验 针对改变微生物组的抗生素，益生菌和其他干预措施，目的是降低 这种高度致命的恶性肿瘤的风险。