Heartburn sensation in nonerosive reflux disease: pattern of superficial sensory nerves expressing TRPV1 and epithelial cells expressing ASIC3 receptors

Abstract

The underlying causes of heartburn, characteristic symptom of gastro-esophageal reflux disease(GERD), remain incompletely understood. Superficial afferent innervation of the esophageal mucosa in nonerosive reflux disease(NERD) may drive nociceptive reflux perception, but its acid-sensing role has not yet been established. Transient receptor potential vanilloid subfamily member-1(TRPV1), transient receptor potential Melastatin 8(TRPM8), and acid sensing ion channel 3(ASIC3) are regulators of sensory nerve activity and could be important reflux-sensing receptors within the esophageal mucosa. We characterised TRPV1, TRPM8, and ASIC3 expression in esophageal mucosa of GERD patients. We studied 10 NERD, 10 erosive reflux disease(ERD), 7 functional heartburn(FH), and 8 Barrett's esophagus(BE) patients. Biopsies obtained from the distal esophageal mucosa were co-stained with TRPV1, TRPM8, or ASIC3, and CGRP, CD45, or E-cadherin. RNA expression of TRPV1, TRPM8, and ASIC3 was assessed using qPCR. NERD patients had significantly increased expression of TRPV1 on superficial sensory nerves compared to ERD (p=0.028) or BE (p=0.017). Deep intrapapillary nerve endings did not express TRPV1 in all phenotypes studied. ASIC3 was exclusively expressed on epithelial cells most significantly in NERD and ERD patients (p=<0.0001). TRPM8 was expressed on submucosal CD45+ leukocytes. Superficial localisation of TRPV1-immunoreactive nerves in NERD, and increased ASIC3 co-expression on epithelial cells in NERD and ERD suggests a mechanism for heartburn sensation. Esophageal epithelial cells may play a sensory role in acid reflux perception and act interdependently with TRPV1-expressing mucosal nerves to augment hypersensitivity in NERD patients, raising the enticing possibility of topical antagonists for these ion channels as a therapeutic option.

Peripheral and central employment of acid-sensing ion channels during early bilaterian evolution

“…In mammals, chemosensors such as ASIC and transient receptor potential channels (e.g. TRPV1) are expressed in sensory neurons innervating the gastrointestinal tract [17], but oesophageal, intestinal, and lung epithelial cells also express ASICs, potentially contributing to acid-induced secretions, transport, and inflammation [68–70]. The gastrointestinal expression of ASICs may reflect a chemosensory role, like that mediated by ASICs in neurons innervating the lungs and skin of mammals [71, 72].…”

Esophageal Reflux Hypersensitivity: A Comprehensive Review

“…Besides, our recent study showed that TRPV1 is frequently expressed on superficial afferent nerves in the esophageal epithelium whereas occasional expression was seen on deep nerves around basal layer. 62 On the other hand, a randomized controlled study by Krarup et al 63 showed no inhibitory effect of TRPV1 antagonist on chest pain induced by heat, distension or electronic current in the esophagus. With regard to other TRPs receptors, transient receptor potential melastatin 8 (TRPM8) might be involved in esophageal hypersensitivity as menthol (i.e., TRPM8 agonists) infusion into the esophagus triggers different sensation in healthy subjects (cold sensation) and GERD patients (heartburn).…”

Progress on the Mechanism of Visceral Hypersensitivity in Nonerosive Reflux Disease

“…When esophageal sensory nerve endings are stimulated by chemical, mechanical, temperature, or pressure changes, the expression of these acid-sensitive receptors also changes accordingly and further affects the release of neurotransmitters or changes in the electrophysiology of the esophageal mucosa. This results in potential inflammation, immunity, hyperalgesia, and NERD VH (Table 1) [13,[16][17][18][19][20][21].…”