The Role of the Microbiome and Notch Signaling in Esophageal Adenocarcinoma

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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.