Epithelial acid imbalance in patients with eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease of the esophagus that is triggered by specific foods and, if left untreated, can result in considerable morbidity.¹ Although the clinical significance of this condition is widely acknowledged, the cellular and molecular mechanisms that underlie its pathophysiology are an active area of research. The sine qua non of EoE is the presence of eosinophilic inflammation in the esophagus. However, there are other key histopathologic features of EoE that can provide important insights into the mechanisms of this disease.¹

One key histologic feature of the esophagus of a patient with EoE beyond eosinophil infiltrates is the development of dilated intercellular spaces (DISs) between epithelial cells.² Development of DISs in patients with EoE has been an area of recent investigational focus because it can contribute to increased mucosal permeability³ and therefore food allergen exposure. However, DISs are not only present in EoE but also characteristic of the esophageal inflammation observed with gastroesophageal reflux disease (GERD). In the case of GERD, DISs are thought to result from exposure of the epithelium to gastric acid, whereas EoE-associated DISs are ultimately refractory to gastric acid suppression alone and require allergen removal or topical corticosteroid therapy to resolve.² Thus EoE and GERD share a nonspecific feature of esophageal inflammation that has historically been associated with acid-mediated damage and can impair mucosal integrity.

In this issue of the Journal, Zeng et al⁴ provide important insights into the etiology of EoE-associated DISs. The authors found altered expression of gene networks associated with regulation of intracellular pH and acid-protective mechanisms in esophageal biopsy specimens of pediatric patients with EoE. The gene encoding sodium-hydrogen exchanger member 3 (NHE3), an epithelial sodium-proton exchanger that is expressed in the apical membrane of epithelial cells, was particularly upregulated in the epithelia of patients with EoE and correlated with disease activity in esophageal biopsy specimens. The authors went on to show that IL-13 upregulates NHE3 expression in a signal transducer and activator of transcription 6–dependent manner and that the resulting acidification of the intercellular space contributes to epithelial DISs.

Given these new observations, it is intriguing to speculate as to whether NHE3 upregulation in the context of EoE is pathologic or compensatory. In other disease settings, sodium-hydrogen exchangers (NHEs) seem to play a primarily protective role. For example, these channels are downregulated in experimental models and patients with colitis and infectious diarrhea and promote the maintenance of normal commensal microbiota under physiologic settings.⁵ In addition, much of what we know of NHE function in the context of disease comes from studies of NHE1 in cancer cells. In this setting NHE1 helps drive a pathologic reversal of the cellular membrane hydrogen ion gradient, resulting in an acidic extracellular pH and alkaline intracellular pH. This “proton reversal” alters the thermodynamic balance and molecular energetics of the cell away from oxidative phosphorylation and towards aerobic glycolysis (a change known as the Warburg effect). This shift in metabolism allows the cell to quickly meet high energy demands, such as those required for proliferation.⁶

Although the proton reversal observed in patients with cancer is clearly pathologic, a similar phenomenon in the setting of EoE could well be adaptive. The resulting shift to glycolytic metabolism can promote protective cell proliferation in response to exposure of the esophageal mucosa to a noxious stimulus. Indeed, NHE expression is increased in the esophagi of patients with GERD,⁷ where they are thought to contribute to the epithelial proliferation that precedes development of Barrett esophagus. EoE is also associated with a proliferative basal zone hyperplasia,² which might be supported by glycolytic cellular metabolism.

Finally, it is interesting to place this work in context with a subset of patients with EoE who initially or partially respond to proton pump inhibitor (PPI) therapy alone, so-termed PPI-responsive EoE (PPI-REE).⁸ Researchers have hypothesized that PPI-REE is the result of subclinical GERD exacerbating an antigen-mediated esophageal eosinophilia or some non-acid-related benefit of PPIs, such as immune modulation. However, it is also possible that PPIs are acting to influence acid balance in the epithelium. In addition to their well-known role in inhibiting gastric acid secretion, PPIs also inhibit the nongastric H⁺-K⁺-ATPase (ATP12A) and V-type H⁺-ATPases, both of which are expressed in epithelial cells and cause intracellular alkalization in response to type 2 cytokines (Fig 1).⁹ Furthermore, V-type H⁺-ATPases are voltage coupled to secondary Na⁺-dependent transporters, providing a potential electrochemical link between these channels and NHEs.⁵ If this mechanism is in play, the initial or partial response to PPI therapy observed in patients with PPI-REE might be a result of direct inhibition of epithelial proton extrusion, with any primary failure or subsequent relapse of PPI therapy in patients with EoE resulting from IL-13–mediated or compensatory upregulation of NHE3.^1,10

FIG 1.

Major proton extrusion channels of the esophageal epithelium. H+-K+-ATPases (K+ ATPase), V-type H+-ATPases (V-ATPase), and NHEs are expressed in the esophageal epithelium under various settings. PPIs directly inhibit K+-ATPase and V-ATPase function, whereas cariporide and S3226 inhibit NHEs. V-ATPases are voltage coupled to NHEs.

In sum, the work by Zeng et al⁴ is important because it highlights that previously unappreciated cellular acid regulatory pathways are highly active in esophageal epithelial cells of patients with EoE. This fundamental observation not only answers a long-standing question in the field regarding the mechanistic origins of DISs but also provides new avenues for investigations aimed at understanding the role of epithelial acid balance in EoE pathogenesis.