Mucosal neuroimmune mechanisms in gastro-oesophageal reflux disease (GORD) pathogenesis

Abstract

Gastro-oesophageal reflux disease (GORD) is a chronic condition characterised by visceral pain in the distal oesophagus. The current first-line treatment for GORD is proton pump inhibitors (PPIs), however, PPIs are ineffective in a large cohort of patients and long-term use may have adverse effects. Emerging evidence suggests that nerve fibre number and location are likely to play interrelated roles in nociception in the oesophagus of GORD patients. Simultaneously, alterations in cells of the oesophageal mucosa, namely epithelial cells, mast cells, dendritic cells, and T lymphocytes, have been a focus of GORD research for several years. The oesophagus of GORD patients exhibits both macro- and micro-inflammation as a response to chronic acidic reflux at the epithelium. In other conditions of the GI tract, such as IBS and IBD, well-characterised bidirectional processes between immune cells and mucosal nerve fibres contribute to pathogenesis and symptom generation. Sensory alterations in these conditions such as nerve fibre outgrowth and hypersensitivity can be driven by inflammatory processes, which promote visceral pain signalling. This review will examine what is currently known of the molecular pathways linking inflammation and sensory perception leading to the development of GORD symptoms and explore potentially relevant mechanisms in other GI regions which may indicate new areas in GORD research.

Keywords: Gastro-oesophageal reflux disease; Mucosal immunity; Neuroimmune.

Fig. 1

Potential neuro-immune interactions in the oesophagus of GORD patients, resulting in pain and inflammation. a In the healthy oesophagus, microbial products, epithelial cells, and mucosal immune cells may act symbiotically to promote mucosal tolerance and barrier function. b In GORD oesophagus, bacterial dysbiosis may lead to immune cell activation and direct activation of sensory afferent fibres. High levels of reflux as well as increased epithelial permeability allow exposure of superficial sensory nerves, immune cells, and epithelial cells to acid and bile salts, resulting in the production of inflammatory mediators, as well as TRPV1 activation of CGRP + sensory nerves. Degranulating mast cells release histamine and prostaglandins, including prostaglandin D2 (PGD2) which may activate H1 receptor and Prostaglandin D2 receptor 1 (DP1) on sensory afferent nerve fibres, respectively. Substance P released from afferent fibres in response to neuronal activation may bind NK1R on mast cells, T lymphocytes, and epithelial cells to promote the expression of inflammatory genes. Created with BioRender.com

Fig. 2

CGRP + Substance P + nerve fibres in a papilla of a non-erosive reflux disease (NERD) patient. The basal layer of the epithelium is indicated with a ‘B’. The papilla is marked with an arrowhead. Scale bar = 20 µm

Fig. 3

NK1R + T lymphocytes in the oesophageal epithelium of two non-erosive reflux disease (NERD) patients. A Interepithelial T lymphocytes positive for the substance P receptor, NK1R. B A T lymphocyte in an oesophageal papilla expressing NK1R. NK1R + T lymphocytes are marked with an arrowhead. Scale bar = 20 µm