Lucas Wauters1, Matthias Ceulemans2, Dennis Frings2, Maarten Lambaerts2, Alison Accarie2, Joran Toth2, Raf Mols3, Patrick Augustijns3, Gert De Hertogh4, Lukas Van Oudenhove2, Jan Tack1, Tim Vanuytsel5. 1. Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium; Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium. 2. Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium. 3. Drug Delivery and Disposition, Katholieke Universiteit Leuven, Leuven, Belgium. 4. Department of Pathology, University Hospitals Leuven, Leuven, Belgium. 5. Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium; Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium. Electronic address: tim.vanuytsel@uzleuven.be.
Abstract
BACKGROUND & AIMS: Despite the growing recognition of duodenal alterations in the pathophysiology of functional dyspepsia (FD), the effect and mechanism of proton pump inhibitors (PPIs) or first-line therapy remain unclear. We studied duodenal and systemic alterations in relation to PPI therapy in patients with FD and healthy volunteers (HVs). METHODS: We performed a prospective interventional study assessing symptoms (Patient Assessment of Gastrointestinal Symptom Severity Index), duodenal alterations, and systemic factors in patients with FD ("FD-starters") and HVs before and after PPI therapy (pantoprazole 40 mg once daily for 4 weeks). Duodenal mucosal eosinophils, mast cells and permeability were quantified. Luminal pH and bile salts were determined in duodenal aspirates. Procedures were also performed in PPI-refractory patients with FD ("FD-stoppers") before and 8 weeks after PPI withdrawal. Between- and within-group changes from baseline and associations with duodenal or systemic factors were analyzed using linear mixed models. RESULTS: The study was completed by 30 HV, 27 FD-starters, and 18 FD-stoppers. Symptoms and duodenal eosinophils, mast cells (all, P < .0001), and paracellular passage (P = .02) were significantly higher in FD-starters vs HVs and reduced with PPI therapy. Symptoms and duodenal immune cells also decreased in FD-stoppers off PPIs. In contrast, immune cells and permeability increased in HVs on PPIs. Dyspeptic symptoms correlated with eosinophils before and during PPI therapy, and increased eosinophils and permeability in HVs on PPIs were associated with changes in bile salts. CONCLUSIONS: We provide the first prospective evidence for eosinophil-reducing effects as a therapeutic mechanism of PPIs in FD, with differential effects in HVs pointing to a role of luminal changes. ClinicalTrials.gov, Number: NCT03545243.
BACKGROUND & AIMS: Despite the growing recognition of duodenal alterations in the pathophysiology of functional dyspepsia (FD), the effect and mechanism of proton pump inhibitors (PPIs) or first-line therapy remain unclear. We studied duodenal and systemic alterations in relation to PPI therapy in patients with FD and healthy volunteers (HVs). METHODS: We performed a prospective interventional study assessing symptoms (Patient Assessment of Gastrointestinal Symptom Severity Index), duodenal alterations, and systemic factors in patients with FD ("FD-starters") and HVs before and after PPI therapy (pantoprazole 40 mg once daily for 4 weeks). Duodenal mucosal eosinophils, mast cells and permeability were quantified. Luminal pH and bile salts were determined in duodenal aspirates. Procedures were also performed in PPI-refractory patients with FD ("FD-stoppers") before and 8 weeks after PPI withdrawal. Between- and within-group changes from baseline and associations with duodenal or systemic factors were analyzed using linear mixed models. RESULTS: The study was completed by 30 HV, 27 FD-starters, and 18 FD-stoppers. Symptoms and duodenal eosinophils, mast cells (all, P < .0001), and paracellular passage (P = .02) were significantly higher in FD-starters vs HVs and reduced with PPI therapy. Symptoms and duodenal immune cells also decreased in FD-stoppers off PPIs. In contrast, immune cells and permeability increased in HVs on PPIs. Dyspeptic symptoms correlated with eosinophils before and during PPI therapy, and increased eosinophils and permeability in HVs on PPIs were associated with changes in bile salts. CONCLUSIONS: We provide the first prospective evidence for eosinophil-reducing effects as a therapeutic mechanism of PPIs in FD, with differential effects in HVs pointing to a role of luminal changes. ClinicalTrials.gov, Number: NCT03545243.
Authors: Christopher J Black; Peter A Paine; Anurag Agrawal; Imran Aziz; Maria P Eugenicos; Lesley A Houghton; Pali Hungin; Ross Overshott; Dipesh H Vasant; Sheryl Rudd; Richard C Winning; Maura Corsetti; Alexander C Ford Journal: Gut Date: 2022-07-07 Impact factor: 31.793
Authors: Marc E Rothenberg; Shawna K B Hottinger; Nirmala Gonsalves; Glenn T Furuta; Margaret H Collins; Nicholas J Talley; Kathryn Peterson; Calies Menard-Katcher; Macie Smith; Ikuo Hirano; Robert M Genta; Mirna Chehade; Sandeep K Gupta; Jonathan M Spergel; Seema S Aceves; Evan S Dellon Journal: J Allergy Clin Immunol Date: 2021-12-22 Impact factor: 10.793
Authors: Susrutha Puthanmadhom Narayanan; Daniel R O'Brien; Mayank Sharma; Thomas C Smyrk; Rondell P Graham; Madhusudan Grover; Adil E Bharucha Journal: Clin Gastroenterol Hepatol Date: 2021-10-02 Impact factor: 13.576