Esophageal Mucosal Mast Cell Density and Degranulation are Increased in Gastro-Esophageal Reflux Disease 2026 Madusha Peiris et al

[Andy]

Abstract​

Introduction: Gastro-esophageal reflux disease (GERD) is a chronic condition encompassing visceral pain - experienced as heartburn and, in some cases, inflammation of the esophageal mucosa. Although mast cell dysregulation has been described in disorders of gut-brain interaction, it has been understudied in GERD. We aimed to characterize mast cell localization and degranulation in GERD esophageal mucosa.

Methods: Distal esophageal biopsies were collected from healthy control (HC; N=10), functional heartburn (FH; N=9), non-erosive reflux disease (NERD; N=13), and erosive reflux disease (ERD; N=12) subjects. Immunohistochemistry was used to visualize tryptase expression in the esophageal mucosa. The localization of tryptase+ mast cells were identified as intraepithelial or papillary, and the degranulation state of individual mast cells was determined based on tryptase staining pattern.

Results: There was an increased density of mast cells in the esophageal papillae and epithelium of ERD patients compared to HCs. The density of degranulated intraepithelial mast cells was significantly higher in FH and ERD subjects compared to HCs, with a trend towards increase in NERD. In NERD and ERD, the density of degranulated mast cells in papillae was significantly higher than HCs. In FH, density of intraepithelial mast cells positively correlated with RDQ score.

Conclusions: Mast cells are more numerous in the esophageal mucosa of ERD subjects, and activity is increased in FH, NERD, and ERD subjects. This could contribute to mucosal inflammation, barrier dysfunction, and visceral hypersensitivity in GERD patients. Future studies should investigate the role of mucosal mast cells in GERD, representing a possible future treatment target.

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[SNT Gatchaman]

In DGBIs, including irritable bowel syndrome (IBS) and functional dyspepsia (FD), mast cell infiltration into the intestinal mucosa has been thoroughly demonstrated [15-18]. […] In both IBS and FD, the extent of mast cell infiltration has also been correlated with markers of intestinal permeability [16, 18].

[15] Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome (2004, Gastroenterology)

[16] Mucosal Mast Cell Count Is Associated With Intestinal Permeability in Patients With Diarrhea Predominant Irritable Bowel Syndrome (2013, Journal of Neurogastroenterology and Motility)

[17] Activation of Eosinophils and Mast Cells in Functional Dyspepsia: an Ultrastructural Evaluation (2018, Nature Scientific Reports)

[18] Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia (2014, Gut)

Only in FH [Functional Heartburn] subjects, the density of intraepithelial mast cells correlated with RDQ score. These findings suggest a potential role of mucosal mast cells in GERD pathophysiology, particularly in FH, which may represent a treatment target in a subset of patients.

Surprisingly, a significantly greater density of degranulated intraepithelial mast cells was detected in FH subjects compared to healthy controls, although this was variable, with 5/9 samples above the range observed in healthy controls in this study.. As FH patients experience physiological levels of reflux, their symptom onset is not correlated to acid exposure, and they are more likely to experience psychological comorbidities such as depressive and anxiety disorders, this condition is often thought, like many DGBIs, to be caused primarily by central sensitization and symptom hypervigilance above any peripheral mucosal mechanism [35, 36].

our finding of higher mast cell degranulation may illustrate a role of these cells in promoting low-grade inflammation and visceral hypersensitivity in a subset of FH patients, and mirrors findings in other DGBIs such as functional dyspepsia [17]. It is possible that psychological stress, which is particularly prevalent in FH patients [35, 36], contributes to the mast cell degranulation which was observed in the esophageal mucosa, since stress stimuli induce peripheral mast cell degranulation in rats and humans [40-44]. The statistically significant positive correlation between reflux symptom score (RDQ) and intraepithelial mast cell density observed, exclusively, in FH patients may indicate a role of mast cells in the pathophysiology, specifically, of FH.

As the first investigation into mast cell localization and degranulation in healthy controls and well-phenotyped GERD patients, this study indicates a role of mast cells in GERD pathogenesis, including FH. Due to the multifunctional nature of mast cells, their increased activity could lead to visceral hypersensitivity, mucosal inflammation, and loss of barrier integrity. This is of particular importance in GERD patients without mucosal inflammation, for which mucosal mechanisms of symptom generation are poorly understood.