The Role of the Microbiome and Notch Signaling in Esophageal Adenocarcinoma

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.