Esophageal adenocarcinoma (EA), the type of cancer linked to heartburn due to gastroesophageal reflux diseases (GERD), has increased six fold in the past 30 years, which can not be explained by the usual environmental or host factors. EA is the end result of a sequence of GERD-related diseases, preceded by reflux esophagitis (RE) and Barrett's esophagus (BE). Our preliminary study in elderly male veterans found two types of microbiotas in the esophagus. Patients who carry the type II microbiota are >15 fold likely to have esophagitis and BE than those harboring the type I microbiota. In a small scale study, we also found that 3 of 3 cases of EA harbored the type II biota. The findings have opened a new approach to understanding the recent surge in the incidence of EA. Our long-term goal is to identify the cause of GERD sequence. The hypothesis to be tested is that changes in the foregut microbiome are associated with EA and its precursors, RE and BE in GERD sequence. We will examine whether the finding in elderly male subjects also applies to younger as well as female subjects. 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, by two specific aims.
Aim 1 is to conduct a comprehensive population survey of the foregut microbiome and demonstrate its association with GERD sequence. Furthermore, spatial relationship between the esophageal microbiota and upstream (mouth) and downstream (stomach) foregut microbiotas as well as temporal stability of the microbiome-disease association will also be examined.
Aim 2 is to define the distal esophageal metagenome and demonstrate its association with GERD sequence. Detailed analyses will include pathway-disease and gene-disease associations. Archaea, fungi and viruses, if identified, also will be correlated with the diseases. A significant association between the foregut microbiome and GERD sequence, if demonstrated, will be the first step for eventually testing whether an abnormal microbiome is required for the development of the sequence of phenotypic changes toward EA. If EA and its precursors represent a microecological disease, treating the cause of GERD might become possible, for example, by normalizing the microbiota through use of antibiotics, probiotics, or prebiotics. Causative therapy of GERD could prevent its progression and reverse the current trend of increasing incidence of EA.

Public Health Relevance

Esophageal adenocarcinoma, the type of cancer linked to heartburn due to gastroesophageal reflux diseases (GERD), has jumped six folds in the past 30 years, which can not be explained by the usual environmental or host factors. We intend to characterize the change in the esophageal microbiome (the native bacterial population of the esophagus), in patients at various stages in GERD. If GERD represents a microbiome-related disease, it could be possible to design new antibiotic or probiotic treatment strategies to prevent GERD and reverse the current trend of increasing rate of esophageal adenocarcinoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Cooperative Agreement Phase II (UH3)
Project #
5UH3CA140233-04
Application #
8310069
Study Section
Special Emphasis Panel (ZRG1-IDM-A (52))
Program Officer
Howcroft, Thomas K
Project Start
2009-05-08
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$1,377,812
Indirect Cost
$512,518
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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