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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Cooperative Agreement Phase II (UH3)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IDM-A (52))
Program Officer
Howcroft, Thomas K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Xu, Weisheng; Yang, Liying; Lee, Peng et al. (2014) Mini-review: perspective of the microbiome in the pathogenesis of urothelial carcinoma. Am J Clin Exp Urol 2:57-61
Baghdadi, Jonathan; Chaudhary, Noami; Pei, Zhiheng et al. (2014) Microbiome, innate immunity, and esophageal adenocarcinoma. Clin Lab Med 34:721-32
Yang, Liying; Chaudhary, Noami; Baghdadi, Jonathan et al. (2014) Microbiome in reflux disorders and esophageal adenocarcinoma. Cancer J 20:207-10
Ma, Yingfei; Madupu, Ramana; Karaoz, Ulas et al. (2014) Human papillomavirus community in healthy persons, defined by metagenomics analysis of human microbiome project shotgun sequencing data sets. J Virol 88:4786-97
Cho, Margaret; Carter, Janell; Harari, Saul et al. (2014) The interrelationships of the gut microbiome and inflammation in colorectal carcinogenesis. Clin Lab Med 34:699-710
Hale, Christopher S; Huang, Hongying; Melamed, Jonathan et al. (2013) Urethral adenocarcinoma associated with intestinal-type metaplasia, case report and literature review. Int J Clin Exp Pathol 6:1665-70
Yang, Youngik; Yooseph, Shibu (2013) SPA: a short peptide assembler for metagenomic data. Nucleic Acids Res 41:e91
Werner, Jeffrey J; Koren, Omry; Hugenholtz, Philip et al. (2012) Impact of training sets on classification of high-throughput bacterial 16s rRNA gene surveys. ISME J 6:94-103
Saxena, Deepak; Li, Yihong; Yang, Liying et al. (2012) Human microbiome and HIV/AIDS. Curr HIV/AIDS Rep 9:44-51
Yang, Liying; Francois, Fritz; Pei, Zhiheng (2012) Molecular pathways: pathogenesis and clinical implications of microbiome alteration in esophagitis and Barrett esophagus. Clin Cancer Res 18:2138-44

Showing the most recent 10 out of 11 publications