title: Bile acids but not acidic acids induce Barrett's esophagus.
abstract: Barrett's esophagus (BE) is associated with the development of esophageal adenocarcinoma (EAC). Bile acids (BAs) refluxing into the esophagus contribute to esophageal injury, which results in BE and subsequent EAC. We developed two animal models to test the role of BAs in the pathogenesis of BE. We surgically generated BA reflux, with or without gastric acid, in rats. In a second experiment, we fed animals separately with BAs and gastric acid. Pathologic changes were examined and the expression of Muc2 and Cdx2 in BE tissue was tested by immunostaining. Inflammatory factors in the plasma, as well as differentiation genes in BE were examined through highly sensitive ELISA and semi-quantitative RT-PCR techniques. We found that BAs are sufficient for the induction of esophagitis and Barrett's-like metaplasia in the esophagus. Overexpression of inflammatory cells, IL-6, and TNF-α was observed both in animals fed with BAs and surgically generated BA reflux. Furthermore, elevated levels of Cdx2, Muc2, Bmp4, Kit19, and Tff2 (differentiation genes in BE) were found in BA-treated rats. In conclusion, BAs, but not gastric acid, are a major causative factor for BE. We confirmed that BAs contribute to the development of BE by inducing the inflammatory response in the esophagus. Inhibiting BAs may be a promising therapy for BE.
authors.affiliation: Department of Thoracic Surgery, Qianfoshan Hospital, Shandong University Jinan, Peoples R China.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Pathology, Qi Lu Hospital, Shandong University Jinan, Peoples R China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich Switzerland.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Gai
authors.affiliation: Department of Thoracic Surgery, Qianfoshan Hospital, Shandong University Jinan, Peoples R China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Endoscopy, Qianfoshan Hospital, Shandong University Jinan, Peoples R China.
authors.forename: Xinyong
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department of Thoracic Surgery, Qi Lu Hospital, Shandong University Jinan, Peoples R China.
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001471:Barrett Esophagus / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D001647:Bile Acids and Salts; D000071616:CDX2 Transcription Factor; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology; D004947:Esophagus / Q000378:metabolism / Q000473:pathology*; D005744:Gastric Acid; D005764:Gastroesophageal Reflux / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D008297:Male; D055262:Mucin-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D000071616:CDX2 Transcription Factor; C541055:Cdx2 protein, rat; D018398:Homeodomain Proteins; C524628:Muc2 protein, rat; D055262:Mucin-2; D014157:Transcription Factors
keywords: Barrett’s esophagus; bile acids; esophageal adenocarcinoma; esophageal reflux