Foregut Microbiome in the Development of Esophageal Adenocarcinoma

The distal esophagus is an important anatomical area where gastric acid reflux can cause reflux esophagitis (RE), Barrett’s esophagus (BE) (intestinal metaplasia), and esophageal adenocarcinoma (EA). The incidence of EA has increased 6-fold in the U.S. since the 1970s, parallel to a significant increase in the prevalence of gastroesophageal reflux diseases (GERD). Although specific host factors might predispose one to disease risk, such a rapid increase in incidence must be predominantly environmental. The cause remains unknown.
Our hypothesis is that changes in the foregut microbiome are associated with EA and its precursors, RE and BE in the GERD sequence.

We will conduct a case control study to demonstrate the microbiome-disease association in every stage of GERD sequence as well as analyze the trend in changes in the microbiome along disease progression toward EA.

Specific aim 1:

To conduct a comprehensive population survey of the foregut microbiome and demonstrate its association with GERD sequence. We will analyze samples of the foregut microbiome at the mouth, distal esophagus, and gastric corpus and correlate their changes along disease progression toward EA.

Specific aim 2:

To define distal esophageal metagenome and demonstrate its association with GERD sequence. We will analyze pathway-disease and gene-disease associations. DNA from viruses and fungi, if identified, also will be correlated with the GERD phenotypes.

A significant association between the foregut microbiome and GERD sequence, if demonstrated, will be the first step for eventually testing the causal hypothesis that an abnormal microbiome is required for the development of the sequence of phenotypic changes toward EA. If EA and its precursors represent a microbial ecological disease, treating the cause of GERD might become possible, for example, by normalizing the microbiome through use of antibiotics, probiotics, or prebiotics. Causative therapy for GERD could prevent its progression and reverse the current trend of increasing incidence of EA