Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides

Elke M Muntjewerff, Kechun Tang, Lisanne Lutter, Gustaf Christoffersson, Mara J T Nicolasen, Hong Gao, Gajanan D Katkar, Soumita Das, Martin Ter Beest, Wei Ying, Pradipta Ghosh, Sahar El Aidy, Bas Oldenburg, Geert van den Bogaart*, Sushil K Mahata*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

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Samenvatting

AIM: A 'leaky' gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease (IBD), irritable bowel syndrome, and celiac disease. Here we show how pro-hormone Chromogranin A (CgA), produced by the enteroendocrine cells, and Catestatin (CST: hCgA352-372 ), the most abundant CgA-derived proteolytic peptide, affect the gut barrier.

METHODS: Colon tissues from region-specific CST-knockout (CST-KO) mice, CgA-knockout (CgA-KO) and WT mice were analyzed by immunohistochemistry, Western blot, ultrastructural and flowcytometry studies. FITC-dextran assays were used to measure intestinal barrier function. Mice were supplemented with CST or CgA fragment pancreastatin (PST: CgA250-301 ). The microbial composition of cecum was determined. CgA and CST levels were measured in blood of IBD patients.

RESULTS: Plasma levels of CST were elevated in IBD patients. CST-KO mice displayed (i) elongated tight, adherens junctions and desmosomes similar to IBD patients, (ii) elevated expression of Claudin 2, and (iii) gut inflammation. Plasma FITC-dextran measurements showed increased intestinal paracellular permeability in the CST-knockout mice. This correlated with a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in various diseases. Supplementation of CST-knockout mice with recombinant CST restored paracellular permeability and reversed inflammation, whereas CgA-knockout mice supplementation with CST and/or PST in CgA-KO mice showed that intestinal paracellular permeability is regulated by the antagonistic roles of these two peptides: CST reduces and PST increases permeability.

CONCLUSION: The pro-hormone CgA regulates the intestinal paracellular permeability. CST is both necessary and sufficient to reduce permeability and primarily acts by antagonizing PST.

Originele taal-2English
Artikelnummere13655
TijdschriftActa physiologica
Volume232
Nummer van het tijdschrift2
Vroegere onlinedatum30-mrt-2021
DOI's
StatusPublished - jun-2021

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