Role of microbial dysbiosis in the pathogenesis of esophageal mucosal disease: A paradigm shift from acid to bacteria?

Abstract

Genomic sequencing, bioinformatics, and initial speciation (e.g., relative abundance) of the commensal microbiome have revolutionized the way we think about the "human" body in health and disease. The interactions between the gut bacteria and the immune system of the host play a key role in the pathogenesis of gastrointestinal diseases, including those impacting the esophagus. Although relatively stable, there are a number of factors that may disrupt the delicate balance between the luminal esophageal microbiome (EM) and the host. These changes are thought to be a product of age, diet, antibiotic and other medication use, oral hygiene, smoking, and/or expression of antibiotic products (bacteriocins) by other flora. These effects may lead to persistent dysbiosis which in turn increases the risk of local inflammation, systemic inflammation, and ultimately disease progression. Research has suggested that the etiology of gastroesophageal reflux disease-related esophagitis includes a cytokine-mediated inflammatory component and is, therefore, not merely the result of esophageal mucosal exposure to corrosives (i.e., acid). Emerging evidence also suggests that the EM plays a major role in the pathogenesis of disease by inciting an immunogenic response which ultimately propagates the inflammatory cascade. Here, we discuss the potential role for manipulating the EM as a therapeutic option for treating the root cause of various esophageal disease rather than just providing symptomatic relief (i.e., acid suppression).

Keywords: Bacteriocins; Barrett’s esophagus; Dysbiosis; Eosinophilic esophagitis; Esophageal cancer; Esophagitis; Gastroesophageal reflux disease; Microbiome; Prebiotics; Probiotics.

Figure 1

Environmental factors alter the local esophageal microbiome, which normally has a gram-positive to gram-negative gradient, towards increased proportion of gram-negatives. Activation of Toll-like-receptor-4 by gram-negative lipopolysaccharide leads towards an inflammatory cascade that results in lymphocyte infiltration. In addition, gastric acid activates transient receptor potential cation channel subfamily V member 1 on local nerve fibers and results in calcitonin gene-related peptide and substance P expression, which contributes to the local inflammatory response as well as pain. LPS: Lipopolysaccharide; TLR: Toll-like-receptor; NF-κB: nuclear factor-kappa beta; IFN: Interferon; ROS: Reactive oxygen species; TRPV1: Transient receptor potential cation channel subfamily V member 1; CGRP: Calcitonin gene-related peptide.