The Microbiome, Bile Acids, and Notch in Barrett's Esophagus (BE)

The Role of the Microbiome and Notch Signaling in Esophageal Adenocarcinoma

The purpose of this study is to prospectively collect and analyze clinical data and biospecimens from a cohort of 100 patients without BE (20), with non-dysplastic BE (40), or with BE and high grade dysplasia (HGD) or EAC (40). The investigators will enroll 80 patients scheduled for upper endoscopy for clinical purposes, with a history of histologically confirmed BE (2 cm length); 40 with no history of dysplasia, and 40 with HGD or EAC. The investigators will also enroll 20 non-BE controls undergoing endoscopy for any indication who are on stable dose proton-pump inhibitors (PPI) for the past month. PPI therapy is standard of care for BE patients.

Study Overview

• Status: Recruiting
• Conditions: Barrett Esophagus; Esophageal Adenocarcinoma
• Intervention / Treatment: Other: Sample Collection; Other: Endoscopy results; Other: Dietary questionnaire

Detailed Description

The incidence of esophageal adenocarcinoma (EAC) has risen 10-fold over the past half century and continues to have a dismal prognosis. Known 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. Over the past 50+ years, dramatic changes in the bacterial composition (or microbiome) of the upper gastrointestinal tract have also occurred. 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 esophagus and potentially promote cancer. The investigators hypothesize that increased levels of the certain bile acids in gastroesophageal reflux fluid cause changes that lead to increased interaction between bacteria and the esophagus, which may promote the development of esophageal adenocarcinoma (EAC). The investigators will carry out a case-control study of patients with and without BE, dysplasia, or EAC. The investigators will focus on deoxycholic acid in gastro-esophageal refluxate and its association with Notch signaling in tissue and bacterial composition. 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 the development of EAC 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.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Julian Abrams, MD; Phone Number: 2128059541; Email: ja660@cumc.columbia.edu
• Study Contact Backup: Name: Katharine Boyce, RN; Email: kb3217@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
      • Contact: Julian Abrams, MD; Phone Number: 212-305-1909; Email: ja660@cumc.columbia.edu
    • New York, New York, United States, 10065
      • Recruiting
      • Weill Cornell Medical Center
      • Contact: Felice Schnoll-Sussman, MD; Phone Number: 646-962-4463; Email: fhs2001@med.cornell.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Study population will be based on the population of BE and EAC as well as the demographics of those who undergo upper endoscopy for other indications (the control population) at Columbia and Cornell, together with data drawn from numerous prior studies in our BE population.

Description

Inclusion Criteria:

All subjects:

• Scheduled for an upper endoscopy
• Taking stable dose of a proton pump inhibitor at least once daily for 1 months prior to enrollment
• Eighteen years of age or older
• Able to give informed consent

Barrett's esophagus subjects only:

• Histologically confirmed BE (defined as endoscopically- suspected BE with intestinal metaplasia with goblet cells on esophageal biopsies)
• Maximal BE length ≥ 2 cm (Prague criteria: any C, M≥2)

Exclusion Criteria:

All subjects:

• History of head and neck cancer or esophageal or gastric cancer (except esophageal intramucosal adenocarcinoma)
• History of esophageal or gastric surgery
• Use of antibiotics or immunosuppressants within 1 month prior to endoscopy

Barrett's esophagus subjects only:

• History of prior endoscopic therapy for BE, except a history of prior endoscopic mucosal resection (EMR) of focal lesions withoutsubsequent ablative therapy is permitted

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Control; Non-BE controls undergoing endoscopy for any indication who are on stable dose Proton Pump Inhibitors for the past month.	Other: Sample Collection; Saliva, gastric aspirate, and esophageal brushings and biopsies.; Other: Endoscopy results; Results from standard of care endoscopy (scheduled separate of study); Other: Dietary questionnaire; Diet History Questionnaire (II)
Barrett's Esophagus; Patients scheduled for upper endoscopy for clinical purposes, with a history of histologically confirmed Barrett's esophagus (2 cm length); 40 with no history of dysplasia, and 40 with high grade dysplasia or esophageal adenocarcinoma.	Other: Sample Collection; Saliva, gastric aspirate, and esophageal brushings and biopsies.; Other: Endoscopy results; Results from standard of care endoscopy (scheduled separate of study); Other: Dietary questionnaire; Diet History Questionnaire (II)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of Deoxycholic Acid (DCA)	To determine whether refluxate deoxycholic acid (DCA) is associated with increased Notch signaling in the development of esophageal adenocarcinoma (EAC), the investigators will calculate Pearson's correlation coefficients to assess within individual correlations between DCA and NOTCH3 gene expression.	2 years
Correlation between Enterobacteriaceae (from 16S) and NOTCH3 expression in BE tissue.	The within-individual correlation will be calculated.	2 years

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Cancer Institute (NCI); Weill Medical College of Cornell University
• Investigators: Principal Investigator: Julian Abrams, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2021
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: August 30, 2022
• First Submitted That Met QC Criteria: August 30, 2022
• First Posted (Actual): September 1, 2022

Study Record Updates

• Last Update Posted (Actual): August 30, 2023
• Last Update Submitted That Met QC Criteria: August 29, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Microbiome; Saliva
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Precancerous Conditions; Adenocarcinoma; Esophageal Neoplasms; Barrett Esophagus
• Other Study ID Numbers: AAAT2456; R01CA255298 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No