Gastroesophageal reflux disease – functional dyspepsia overlap: From pathophysiological mechanisms to therapeutic strategy

Abstract

The article addresses an urgent challenge of gastroesophageal reflux disease functional dyspepsia overlap. Studies reported a high prevalence rate of this phenomenon (up to 41% of patients with gastroesophageal reflux disease), which is associated with decreased quality of life and refractoriness against conventional therapy. The pathophysiological mechanisms underlying this overlap involve the unified continuum that includes delayed gastric emptying, impaired fundic accommodation, increased epithelial permeability of the esophageal and duodenal mucosa, visceral hypersensitivity, and duodenal dysbiosis. The overlap should be diagnosed by using an integrative approach that would combine the Lyon Consensus 2.0 (2023) for objectification of reflux and the revised Rome V criteria (2026) for functional dyspepsia. Proton pump inhibitors remain the mainstay of the therapeutic strategy; however, the efficacy of monotherapy is often suboptimal in overlapping disease state. Adding prokinetic agents is a justified treatment for the predominating postprandial distress syndrome, as well as rifaximin for the verified bacterial overgrowth syndrome. Rebamipide (Rebagit) plays a special role in the treatment. Its cytoprotective effect specifically targets a key pathogenetic link of the overlap (increased epithelial permeability), resulting in simultaneous treatment of both the esophageal and gastroduodenal components of symptoms. Rebamipide restores mucosal barrier integrity by increasing the expression of tight junction proteins. It also stimulates the synthesis of mucins and endogenous prostaglandins, and exhibits anti-inflammatory activity, reducing neutrophil migration and inhibiting production of reactive oxygen species. These properties are crucial both for the esophagus, where the impact of refluxate on nerve endings is reduced due to restoration of intercellular contacts, and for the duodenum, where rebamipide reduces barrier dysfunction underlying duodenal hypersensitivity.