Pyeongwi‐San, a Traditional Digestant, Mitigates Proton Pump Inhibitor‐Induced Dyspepsia Through Gut Microbial and Cholinergic Mechanisms in Mice
Jing‐Hua Wang, Song‐Yi Han, Kyung Jae Lee, Mi Young Lim, Hojun KimABSTRACT
Background
Long‐term use of proton pump inhibitors (PPIs) is frequently associated with gastrointestinal (GI) side effects, including dyspepsia, mediated through alterations in gastric pH, impaired GI motility, and gut microbiota dysbiosis. Traditional East Asian herbal formulas—Pyeongwi‐san (PS), Yijung‐tang (YT), and Shihosogan‐tang (ST)—have long been employed clinically for GI disorders; however, their comparative efficacy and mechanistic profiles in PPI‐induced GI dysfunction remain undefined.
Purpose
This study aimed to compare the therapeutic efficacy and underlying mechanisms of PS, YT, and ST in a murine model of PPI‐induced GI dysfunction, with particular focus on motility, mucosal integrity, gut microbiota modulation, and relevant biomarker responses.
Methods
Male C57BL/6 mice received oral esomeprazole (160 mg/kg/day) for 4 weeks to induce dyspeptic symptoms. Concurrently, animals were administered PS, YT, or ST (1 g/kg/day), or mosapride (3 mg/kg/day) as a positive control. Outcome measures included gastric acid secretion, intragastric pH, GI motility (gastric emptying and intestinal transit), mucosal histopathology, serum and intestinal hormone levels (secretin, acetylcholine), fecal short‐chain fatty acid (butyrate) concentrations, gut microbiota composition (diversity indices and taxonomic profiling), mucosal barrier gene expression (MUC2, ZO‐1, Occludin), proinflammatory cytokines (IL‐1β, TNF‐α), and H + /K + ‐ATPase protein expression.
Results
Esomeprazole reliably suppressed gastric acid secretion, elevated intragastric pH, impaired GI motility, induced mucosal injury, and caused gut microbiota dysbiosis. Among the three herbal formulas tested, PS showed significant improvements across a broader range of measured endpoints relative to the PPI group. PS significantly improved gastric emptying and intestinal transit times ( p < 0.05 vs. PPI group), whereas mosapride improved gastric emptying but showed no significant effect on intestinal transit. It further elevated serum secretin, intestinal acetylcholine, and fecal butyrate levels ( p < 0.05 vs. PPI group); restored gut microbiota alpha‐diversity; and upregulated mucosal barrier genes. PS also suppressed proinflammatory cytokine expression and modulated H + /K + ‐ATPase protein expression, indicative of integrated gastroprotective and prokinetic mechanisms. YT and ST also showed significant effects on selected endpoints.
Conclusion
PS most effectively attenuated PPI‐induced GI dysfunction through a multi‐target mechanism encompassing prokinetic activity, gut microbiota restoration, mucosal barrier reinforcement, and immunomodulatory regulation of key hormones and cytokines. These findings position PS as a promising botanical candidate for the management of PPI‐related dyspepsia, warranting further investigation in controlled clinical trials.