Volume 153, Issue 5, Pages 1230-1239 (November 2017) Superficial Esophageal Mucosal Afferent Nerves May Contribute to Reflux Hypersensitivity in Nonerosive Reflux Disease  Philip Woodland, Joanne Li Shen Ooi, Federica Grassi, Kornilia Nikaki, Chung Lee, James A. Evans, Nikolaos Koukias, Christos Triantos, Stuart A. McDonald, Madusha Peiris, Rubina Aktar, L. Ashley Blackshaw, Daniel Sifrim  Gastroenterology  Volume 153, Issue 5, Pages 1230-1239 (November 2017) DOI: 10.1053/j.gastro.2017.07.017 Copyright © 2017 AGA Institute Terms and Conditions

Figure 1 Data points are median value per patient. In HV (left panel) the mucosal sensory innervation is deeper in the distal esophagus than in the proximal esophagus (P = .0078). This is in contrast to the distribution seen in NERD (right panel), where the nerve afferents are equidistant from the lumen in the proximal and distal esophagus (P = .233). Gastroenterology 2017 153, 1230-1239DOI: (10.1053/j.gastro.2017.07.017) Copyright © 2017 AGA Institute Terms and Conditions

Figure 2 Relative distributions of distal esophageal nerves in HV, NERD, ERD, and BE. Each data point is median nerve location per patient. The nerves are significantly more superficial in the NERD group (P < .001 compared with HV, ERD, and BE), whereas the distributions are of a similar depth in HV, ERD, and BE (P = NS between HV, ERD, and BE). Gastroenterology 2017 153, 1230-1239DOI: (10.1053/j.gastro.2017.07.017) Copyright © 2017 AGA Institute Terms and Conditions

Figure 3 CGRP (green) and PGP (purple) co-localizing nerve fibers within the esophageal mucosal epithelium. The top panels demonstrate a superficial fiber in a patient with NERD. The lower panels demonstrate a deep fiber typical of BE, ERD, or HV. Gastroenterology 2017 153, 1230-1239DOI: (10.1053/j.gastro.2017.07.017) Copyright © 2017 AGA Institute Terms and Conditions

Figure 4 In NERD, the higher the distal esophageal acid exposure time on reflux testing the deeper the nerve afferents were found to be within the esophageal mucosa. Each data point is median nerve location for 1 patient (P = .0462, r = 0.5607). Gastroenterology 2017 153, 1230-1239DOI: (10.1053/j.gastro.2017.07.017) Copyright © 2017 AGA Institute Terms and Conditions

Figure 5 A full-thickness section demonstrating the relative location of a superficial nerve fiber (CRGP, in green). In our study, nerve fibers in NERD were located superficially, ie, close to the esophageal lumen, and far above the basal epithelial region involved in DIS that is implicated as the point of entry of acid and bile in NERD. Gastroenterology 2017 153, 1230-1239DOI: (10.1053/j.gastro.2017.07.017) Copyright © 2017 AGA Institute Terms and Conditions