• Ahsen Ustaoglu, Akinari Sawada, Chung Lee, Wei-Yi Lei, Chien-Lin Chen, Richard Hackett, Daniel Sifrim, Madusha Peiris, and Philip Woodland.
• Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
• Am. J. Physiol. Gastrointest. Liver Physiol. 2021 May 1; 320 (5): G804-G815.

AbstractThe underlying causes of heartburn, characteristic symptom of gastroesophageal 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 characterized TRPV1, TRPM8, and ASIC3 expression in esophageal mucosa of patients with GERD. We studied 10 patients with NERD, 10 with erosive reflux disease (ERD), 7 with functional heartburn (FH), and 8 with Barrett's esophagus (BE). Biopsies obtained from the distal esophageal mucosa were costained with TRPV1, TRPM8, or ASIC3, and CGRP, CD45, or E-cadherin. RNA expression of TRPV1, TRPM8, and ASIC3 was assessed using qPCR. Patients with NERD had significantly increased expression of TRPV1 on superficial sensory nerves compared with 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 patients with NERD and ERD (P ≤0.0001). TRPM8 was expressed on submucosal CD45+ leukocytes. Superficial localization of TRPV1-immunoreactive nerves in NERD, and increased ASIC3 coexpression 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 patients with NERD, raising the enticing possibility of topical antagonists for these ion channels as a therapeutic option.NEW & NOTEWORTHY We demonstrate for the first time that increased pain perception in patients with nonerosive reflux disease likely results from expression of acid-sensitive channels on superficial mucosal afferents and esophageal epithelial cells, raising the potential for topical therapy.

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