The Role of Leaky Gut in Functional Dyspepsia

Lucas Wauters, Matthias Ceulemans, Jolien Schol, Ricard Farré, Jan Tack, Tim Vanuytsel, Lucas Wauters, Matthias Ceulemans, Jolien Schol, Ricard Farré, Jan Tack, Tim Vanuytsel

Abstract

Patients with functional dyspepsia (FD) complain of epigastric symptoms with no identifiable cause. Increased intestinal permeability has been described in these patients, especially in the proximal small bowel or duodenum, and was associated with mucosal immune activation and symptoms. In this review, we discuss duodenal barrier function, including techniques currently applied in FD research. We summarize the available data on duodenal permeability in FD and factors associated to increased permeability, including mucosal eosinophils, mast cells, luminal and systemic factors. While the increased influx of antigens into the duodenal mucosa could result in local immune activation, clinical evidence for a causal role of permeability is lacking in the absence of specific barrier-protective treatments. As both existing and novel treatments, including proton pump inhibitors (PPI) and pre- or probiotics may impact duodenal barrier function, it is important to recognize and study these alterations to improve the knowledge and management of FD.

Keywords: duodenum; functional dyspepsia; gut-brain-axis; immunology; permeability.

Conflict of interest statement

LW reports financial support for research from Danone and MyHealth; has served on the advisory board of Naturex; has served on the Speaker bureau for Dr. Falk Pharma, Takeda and MyHealth. TV reports financial support for research from Danone, MyHealth, Takeda and VectivBio; has served on the Speaker bureau for Abbott, Dr. Falk Pharma, Fresenius Kabi, Menarini, Remedus, Takeda, Truvion, and VectivBio; reports consultancy fees from Baxter, Dr. Falk Pharma, Takeda, VectivBio, and Zealand Pharma. JT has given Scientific advice to Adare, AlfaWassermann, Arena, Bayer, Christian Hansen, Clasado, Danone, Devintec, Falk, FitForMe, Grünenthal, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Neurogastrx, Neutec, Novartis, Nutricia, Reckitt Benckiser, Ricordati, Shionogi, Takeda, Truvion, Tsumura, Zealand, and Zeria pharmaceuticals, has received research support from Biohit, Shire, Sofar, and Takeda, and has served on the Speaker bureau for Abbott, Allergan, AstraZeneca, FitForMe, Janssen, Kyowa Kirin, Mayoly, Menarini, Mylan, Novartis, Schwabe Parmaceuticals, Takeda, Wellspect, and Zeria. All the fundings reported were outside of this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Wauters, Ceulemans, Schol, Farré, Tack and Vanuytsel.

Figures

FIGURE 1
FIGURE 1
Luminal and cellular elements of the duodenal barrier. (A) The intestinal lumen is separated from the epithelium by a mucus layer formed by mucin glycoproteins, mainly MUC2 from goblet cells, in which bacterial residence is limited by the secretion of antimicrobial peptides (from Paneth or epithelial cells) and sIgA (from plasma cells). (B) Tight junctions, adherens junctions and desmosomes are important cell-to-cell adhesion proteins that regulate the epithelial barrier function, and initiate and stabilize enterocyte adhesion in the gut. AMP, antimicrobial peptides; MUC2, Mucin 2; sIgA, secretory immunoglobulin A; ZO, zonula occludens. This figure was created with elements from Smartservier.
FIGURE 2
FIGURE 2
Functional assessment of permeability (ex vivo). (A) Experimental set-up of Ussing chambers. (B) Equivalent electrical circuit model with the transcellular (Rtrans or sum of apical (Rapi) and basolateral (Rbas) resistances) and the paracellular (Rpara) resistances in a simple epithelium (TEER is the sum of all individual resistances). Fd4, fluorescein isothiocyanate-labeled 4 kDa dextran; TEER, transepithelial electrical resistance.
FIGURE 3
FIGURE 3
Duodenal permeability in functional dyspepsia. Increased permeability is observed in functional dyspepsia using in vivo and ex vivo techniques and associated with a dysregulation of cell-to-cell adhesion proteins, of which the main findings are summarized. CLDN, claudin; CLE, confocal laser endomicroscopy; Fd4, fluorescein isothiocyanate-labeled 4 kDa dextran; IHC, immunohistochemistry; OCLN, occludin; TEER, transepithelial electrical resistance; TEM, transmission electron microscopy; ZO, zonula-occludens.

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Source: PubMed

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