Esophageal mucosal sensory nerves and potential mechanoreceptors in patients with ineffective esophageal motility

Abstract

Background: Ineffective esophageal motility (IEM) is the most common motility disorder. However, little is known about its pathophysiology. Vagal afferent nerves convey esophageal intraluminal bolus information to solitary nucleus, which is likely to be involved with esophageal primary and secondary peristalsis (SP). We hypothesized that altered mucosal sensory afferents underlie the pathogenesis of IEM. Methods:We prospectively collected esophageal biopsies from 38 patients with proton pump inhibitor-refractory reflux symptoms from January to December 2019.All patients underwent high-resolution manometry for the evaluation of primary and secondary peristalsis, and off-PPI 24-h impedance-pH studies. Biopsies were analyzed using immunohistochemistry for identification of calcitonin gene-related peptide-immunoreactive (CGRP-IR) nerves and qPCR for mRNA expression of potential mechanoreceptors. Key Results: Overall 32 patients were finally analyzed which consisted of 11 patients with normal motility and 21 patients with IEM. The position of mucosal CGRP-IR nerves from the esophageal lumen did not differ between the two groups (the proximal esophagus (p = 0.52), the mid-esophagus (p = 0.92), the distal esophagus (p = 0.29)) with the similar reflux profile. No difference was seen in the position of CGRP-IR nerves between patients with successful triggering of SP and those unable to trigger SP. There was also no difference in mRNA expression of each potential mechanoreceptors (TRPA1, TRPV1, TRPV4, ASIC1, ASIC3) between the two groups. Conclusions and Inferences:Our study showed that mucosal sensory afferents nerve position and mRNA expression of potential mechanoreceptors did not correlate to weak esophageal contraction.

Superficial oesophageal mucosal innervation may contribute to severity of symptoms in oesophageal motility disorders

“…CGRP‐immunoreactive nerves were identified and captured using All‐in‐One Fluorescence Microscope BZ‐X800 (Keyence) under the 488‐nm excitation setting. The location of CGRP‐immunoreactive nerves was measured by an investigator (AS) blinded to clinical data, as the number of cell layers from the oesophageal lumen to an identified nerve, as previously described 19,24,25 . The rationale for this method of the distance from nerve to the stimulus is directly relevant to the threshold for evoking action potentials 26 .…”

“…The location of CGRP-immunoreactive nerves was measured by an investigator (AS) blinded to clinical data, as the number of cell layers from the oesophageal lumen to an identified nerve, as previously described. 19,24,25 The rationale for this method of the distance from nerve to the stimulus is directly relevant to the threshold for evoking action potentials. 26 All nerve fibres identified in each section were recorded, and the median number of cell layers both in the proximal and distal oesophagus were calculated for each patient.…”

“…moderate, severe or disabling) [7 cell layers (4-9)] compared to those with weak chest pain (i.e. mild)[10 cell layers (8-13), p = 0.040] despite similar BEDQ score[16 (9-24) for weak chest pain versus 25(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) for strong chest pain, p = 0.275]…”