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Proton Pump Inhibitors Reduce Duodenal Eosinophilia, Mast Cells, and Permeability in Patients With Functional Dyspepsia

  • Lucas Wauters
    Affiliations
    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
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  • Matthias Ceulemans
    Affiliations
    Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium
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  • Dennis Frings
    Affiliations
    Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium
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  • Maarten Lambaerts
    Affiliations
    Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium
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  • Alison Accarie
    Affiliations
    Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium
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  • Joran Toth
    Affiliations
    Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium
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  • Raf Mols
    Affiliations
    Drug Delivery and Disposition, Katholieke Universiteit Leuven, Leuven, Belgium
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  • Patrick Augustijns
    Affiliations
    Drug Delivery and Disposition, Katholieke Universiteit Leuven, Leuven, Belgium
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  • Gert De Hertogh
    Affiliations
    Department of Pathology, University Hospitals Leuven, Leuven, Belgium
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  • Lukas Van Oudenhove
    Affiliations
    Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium
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  • Jan Tack
    Affiliations
    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
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  • Tim Vanuytsel
    Correspondence
    Correspondence Address correspondence to: Tim Vanuytsel, MD, PhD, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.
    Affiliations
    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
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Published:December 17, 2020DOI:https://doi.org/10.1053/j.gastro.2020.12.016

      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.

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      EPS (epigastric pain syndrome), FD4 (fluorescein isothiocyanate-labelled 4kDa dextran), FD (functional dyspepsia), GI (gastrointestinal), HV (healthy volunteer), PDS (postprandial distress syndrome), PPI (proton pump inhibitor), PSS (Perceived Stress Scale)
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