Shifts in Serum Bile Acid Profiles Associated with Barrett’s Esophagus and Stages of Progression to Esophageal Adenocarcinoma

Abstract

Introduction: Reflux bile acids are thought to promote EAC, but the role of systemic bile acids is unknown. This study aimed to assess associations between systemic bile acids and stages of Barrett’s esophagus (BE) progression. Methods: Subjects with and without BE were enrolled in this multi-center cross-sectional study. Targeted serum bile acid profiling was performed, and a subset of subjects completed a validated food frequency questionnaire. RNA sequencing was performed on BE or gastric cardia tissue to assess bile acid associations with gene expression. Results: 141 subjects were enrolled with serum bile acids profiled (49 non-BE; 92 BE: 44 no dysplasia, 25 indefinite/low grade dysplasia, 23 high grade dysplasia/EAC). Lower Healthy Eating Index score, older age, higher body mass index, and no proton pump inhibitor use were associated with increased levels of multiple bile acids. Global bile acid pools were distinct between non-BE and stages of BE neoplasia (p=0.004). Increasing cholic acid was associated with high grade dysplasia/EAC compared to non-BE, even after adjusting for EAC risk factors (aOR 2.03, 95% CI 1.11-3.71) as was the combination of unconjugated primary bile acids (aOR 1.81, 95% CI 1.04-3.13). High cholic acid levels were associated with tissue gene expression changes including increased DNA replication and reduced lymphocyte differentiation genes. Discussion: Alterations in serum bile acids are independently associated with advanced neoplasia in BE and may contribute to neoplastic progression. Future studies should explore associated gut microbiome changes, pro-neoplastic effects of bile acids, and whether these bile acids, particularly cholic acid, represent potential biomarkers or viable therapeutic targets for advanced neoplasia in BE.