Chronopharmacology of Proton Pump Inhibitors in Irregular Meal Timing:Emerging Implications of Breakfast Skipping in Gastroesophageal RefluxDisease (GERD)

Abstract

Gastroesophageal reflux disease (GERD) is a highly prevalent gastrointestinal disorder associated with substantial impairment in
quality of life and increasing healthcare burden worldwide. Proton pump inhibitors (PPIs) remain the cornerstone of GERD
pharmacotherapy; howev er, a considerable proportion of patients continue to experience persistent reflux symptoms despite standard treatment. Emerging evidence suggests that irregular meal timing, particularly breakfast skipping, may contribute to both GER D pathogenesis and sub optimal therapeutic response to PPIs. This review examines the chronopharmacological relationship between proton pump inhibitor efficacy, circadian regulation of gastric acid secretion, and disrupted meal timing patterns. Circadian rhythms regulate multipl e gastrointestinal functions, including gastric acid secretion, lower esophageal sphincter tone, gastric motility, and mucosal defense mechanisms, all of which influence reflux pathophysiology. PPIs exhibit meal dependent pharmacodynamics, requiring admini stration prior to food induced proton pump activation for optimal acid suppression. Breakfast omission disrupts this synchronization, potentially impairing proton pump inhibition, reducing intragastric pH control, and increasing the risk of n octurnal acid breakthrough and refractory GERD symptoms. Additionally, prolonged fasting and circadian misalignment may exacerbate reflux through mechanisms involving transient lower esophageal sphincter relaxations, delayed gastric emptying, autonomic dysregulation, neuroimmune signaling, and gut brain axis dysfunction. This review further discusses chronotherapeutic strategies, including individualized PPI dosing schedules, split dose therapy, chrono nutrition approaches, and the emerging role of potassium competitive acid blockers in patients with irregular meal timing. Despite growing epidemiological and mechanistic evidence, significant research gaps remain regarding the direct impact of breakfast skipping on PPI pharmacodynamics and GERD outcomes. Future chronopharm acological and precision medicine based investigations may facilitate more individualized and effective GERD management strategies.