Molecular pathways: pathogenesis and clinical implications of microbiome alteration in esophagitis and Barrett esophagus

Abstract

Esophageal adenocarcinoma is preceded by the development of reflux-related intestinal metaplasia or Barrett esophagus, which is a response to inflammation of the esophageal squamous mucosa, reflux esophagitis. Gastroesophageal reflux impairs the mucosal barrier in the distal esophagus, allowing chronic exposure of the squamous epithelium to the diverse microbial ecosystem or microbiome and inducing chronic inflammation. The esophageal microbiome is altered in both esophagitis and Barrett esophagus, characterized by a significant decrease in gram-positive bacteria and an increase in gram-negative bacteria in esophagitis and Barrett esophagus. Lipopolysaccharides (LPS), a major structure of the outer membrane in gram-negative bacteria, can upregulate gene expression of proinflammatory cytokines via activation of the Toll-like receptor 4 and NF-κB pathway. The potential impact of LPS on reflux esophagitis may be through relaxation of the lower esophageal sphincter via inducible nitric oxide synthase and by delaying gastric emptying via cyclooxygenase-2. Chronic inflammation may play a critical role in the progression from benign to malignant esophageal disease. Therefore, analysis of the pathways leading to chronic inflammation in the esophagus may help to identify biomarkers in patients with Barrett esophagus for neoplastic progression and provide insight into molecular events suitable for therapeutic intervention in prevention of esophageal adenocarcinoma development in patients with reflux esophagitis and Barrett esophagus.

©2012 AACR.

Figures

Figure 1

Hypothetical activation of NF-kB pathway by type II microbiome in the esophagus. The type I microbiome, more closely associated with normal esophagus, is dominated by Gram-positive bacteria, while the type II microbiome, mainly associated with abnormal esophagus, including reflux esophagitis and Barrett's esophagus, contains a larger proportion of Gram-negative bacteria. The increased Gram-negative bacterial components, such as LPS might thus directly stimulate TLRs (mainly TLR4) leading to activation of the classical NF-kB pathway (p50/RELA; middle); LPS might also stimulate inflammatory cells, like macrophages, to release cytokines that bind to cytokine receptors on esophageal epithelial cells to trigger the alternative NF-B pathway (p52/RelB; left). Moreover, Peptidoglycan from Gram-negative bacteria might act on NOD-like receptors to activate the NF-kB pathway (right). NF-kB activation up-regulates the expression of its downstream genes encoding a variety of cytokines, inducible enzymes, and proteins that provoke inflammation, relaxes smooth muscles, and regulate cell proliferation and apoptosis. Known NF-kB regulated enzymes include iNOS that relaxes the lower esophageal sphincter and COX2 that delays gastric emptying. The end effects could be the induction of gastroesophageal reflux, metaplasia, and/or neoplasia. The effect could be prevented by reversion of the type II to type I microbiome using antibiotics or probiotics, NF-kB inhibitors, or selective inhibitors to iNOS or COX2 (Aspirin).