Duodenal Mucosal Barrier in Functional Dyspepsia

Susrutha Puthanmadhom Narayanan, Daniel R. O'Brien, Mayank Sharma, Thomas Christopher Smyrk, Rondell Graham, Madhusudan Grover, Adil E. Bharucha

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims: In addition to gastric sensorimotor dysfunctions, functional dyspepsia (FD) is also variably associated with duodenal micro-inflammation and epithelial barrier dysfunction, the pathogenesis and clinical significance of which are unknown. Our hypothesis was that miRNAs and/or inflammation degrade epithelial barrier proteins, resulting in increased duodenal mucosal permeability in FD. Methods: We compared the duodenal mucosal gene expression and miRNAs, in vivo permeability (lactulose-mannitol excretion between 0 and 60 and 60 and 120 minutes after saccharide ingestion), ex vivo assessments (transmucosal resistance, fluorescein isothiocyanate [FITC]-dextran flux, and basal ion transport), and duodenal histology (light and electron microscopy) in 40 patients with FD and 24 controls. Results: Compared with controls, the mRNA expression of several barrier proteins (zonula occludens-1, occludin, claudin-12, and E-cadherin) was modestly reduced (ie, a fold change of 0.8–0.85) in FD with increased expression of several miRNAs (eg, miR-142-3p and miR-144-3-p), which suppress these genes. The urinary lactulose excretion and the lactulose:mannitol ratio between 60 and 120 minutes were greater in FD than in controls (P <.05). The FITC-dextran flux, which reflects paracellular permeability, was inversely correlated (r = –0.32, P =.03) with transmucosal resistance and directly correlated (r = 0.4, P =.02) with lactulose:mannitol ratio. Other parameters (mucosal eosinophils, intraepithelial lymphocytes, and mast cells, transmucosal resistance, FITC-dextran flux, average intercellular distance, and proportion of dilated junctions) were not significantly different between groups. Conclusions: In FD, there is a modest reduction in the expression of several duodenal epithelial barrier proteins, which may be secondary to up-regulation of regulatory miRNAs, and increased small intestinal permeability measured in vivo.

Original languageEnglish (US)
JournalClinical Gastroenterology and Hepatology
DOIs
StateAccepted/In press - 2021

Keywords

  • Duodenal Epithelial Permeability
  • Inflammation
  • Intestinal Barrier
  • Tight Junction Gene Expression

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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