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: 10747759
• 负责人: Julian Abrams
• 金额: $ 7.08万
• 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/10747759
• 关键词: Acceleration; Acids; Address; Area; Bacteria; Barrett Esophagus; Bile Acids; Cell Differentiation process; Clinical; Collaborations; Colon; Colon Carcinoma; Communities; Data; Deoxycholic Acid; Development; Dysplasia; Enrollment; Enterobacteriaceae; Environment; Epithelium; Esophageal Adenocarcinoma; Esophageal Neoplasms; Esophageal Tissue; Feedback; Future; Gastroesophageal reflux disease; Goblet Cells; Helicobacter Infections; Helicobacter pylori; Homeostasis; Incidence; Inflammation; Intestines; Knowledge; Lesion; Logistic Regressions; Microbial Biofilms; Minority; Modeling; Mucins; Mucous body substance; Mutagens; NF-kappa B; Neoplasms; Obesity; Oral; Oral health; Organoids; Parents; Pathway interactions; Patients; Population; Prevalence; Production; Prognosis; Prospective cohort; Research; Risk; Risk Factors; Role; Salivary; Sampling; Series; Signal Transduction; Stomach; Streptococcus; Structure; Study models; Testing; Thinness; Time; Tissue Sample; Tissues; Upper digestive tract structure; Work; aspirate; carcinogenesis; carcinogenicity; cohort; experimental study; gastric microbiome; gastrointestinal; gastrointestinal epithelium; gut microbiome; infection rate; member; microbial; microbiome; microbiome alteration; microbiome composition; modifiable risk; mouse model; neoplastic; notch protein; oral microbial community; oral microbiome; parent grant; prospective; trend; tumor progression

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.

项目概要 食管腺癌 (EAC) 的发病率在过去半个世纪中上升了 10 倍，并且持续上升 预后不佳。模型研究表明，只有少数 EAC 病例可归因于肥胖 或胃食管反流。自20世纪中叶以来，幽门螺杆菌感染率直线下降， 幽门螺杆菌的缺失与 Barrett 食管 (BE)（EAC 前体）的风险增加约两倍相关 病变以及 EAC 本身。西方人群上消化道微生物群可能发生巨大变化 而BE和随后的EAC发病率开始上升。我们小组之前的工作已经发现了相关性 微生物组、BE 和 EAC 之间。在 BE 中，我们描述了与组织相关的微生物组的改变 进展为 EAC，肠杆菌科和链球菌显着增加。口腔微生物群的改变 与未来的 EAC 风险相关，我们之前也描述了口腔中的差异 一小群 BE 患者的微生物组。口腔微生物组的改变也与 口腔健康状况不佳，最近的一项分析显示，口腔健康状况不佳本身与 EAC 风险增加有关。在这个提案中我们 试图阐明口腔微生物组和代谢物的改变如何驱动食管肿瘤的进展。 特别是，我们试图了解特定的口腔社区成员如何在异常中丰富或减少 状态可能会改变代谢物的产生并导致上消化道的致癌变化 环境。我们假设口腔微生物组的特定改变可以促进口腔微生物的发展 EAC，并且细菌的促肿瘤作用部分归因于代谢产物的产生。这个假设将 通过以下相互关联的具体目标来实现： 1) 评估口腔微生物群落结构 通过识别关键细菌分类群与从 BE 到 EAC 的进展相关，以及 2) 分离唾液微生物 与从 BE 到 EAC 的进展相关的代谢物，同时描述了代谢物的总量 口腔微生物组比之前的任何工作都更加深入。家长资助提出了脱氧胆酸的假设 胃食管反流液中的 DCA 会诱导 BE 中的 Notch 信号传导，从而减少杯状细胞分化 和粘液的产生。然而，母版 R01 并未解决关键细菌之间的关系 代谢物及其与 Notch 信号传导和 EAC 肿瘤进展的关系。该提案解决了 这个关键差距。