Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides
Muntjewerff, Elke M; Tang, Kechun; Lutter, Lisanne; Christoffersson, Gustaf; Nicolasen, Mara J T; Gao, Hong; Katkar, Gajanan D; Das, Soumita; Ter Beest, Martin; Ying, Wei; Ghosh, Pradipta; Aidy, Sahar El; Oldenburg, Bas; van den Bogaart, Geert; Mahata, Sushil K
(2021) Acta physiologica (Oxford, England), volume 232, issue 2
(Article)
Abstract
AIM: A "leaky" gut barrier has been implicated in the initiation and progression of a multitude of diseases, for example, 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: hCgA 352-372 ), the
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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 analysed 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: CgA 250-301 ). 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 (a) elongated tight, adherens junctions and desmosomes similar to IBD patients, (b) elevated expression of Claudin 2, and (c) gut inflammation. Plasma FITC-dextran measurements showed increased intestinal paracellular permeability in the CST-KO mice. This correlated with a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in various diseases. Supplementation of CST-KO mice with recombinant CST restored paracellular permeability and reversed inflammation, whereas CgA-KO 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.
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Keywords: Catestatin, chromogranin A, enteroendocrine cells, epithelial tight junctions, gut barrier, inflammatory bowel disease, Physiology, Journal Article
ISSN: 1748-1716
Publisher: Wiley
Note: Funding Information: The authors thank Zbigniew Mikulski (La Jolla Institute for Immunology, CA, USA) and Kiek Verrijp (Radboud University Medical Center, Netherland) for technical support with the histology and immunohistochemistry. This work was supported by grants from the Veterans Affairs (I01 BX003934 to SKM), the Human Frontier Science Program (HFSP; RGY0080/2018 to G.v.d.B), the Netherlands Organization for Scientific Research (NWO‐ALWVIDI864.14.001 to G.v.d.B), and European Research Council (grant agreement No. 862137 to G.v.d.B). GC is supported by grants from the Swedish Research Council and the Swedish Society for Medical Research. SEA is funded by is supported by a Rosalind Franklin Fellowship, co‐funded by the European Union and University of Groningen, The Netherlands. EMM is supported by a Short‐Term EMBO Fellowship (EMBO7887). Funding Information: The authors thank Zbigniew Mikulski (La Jolla Institute for Immunology, CA, USA) and Kiek Verrijp (Radboud University Medical Center, Netherland) for technical support with the histology and immunohistochemistry. This work was supported by grants from the Veterans Affairs (I01 BX003934 to SKM), the Human Frontier Science Program (HFSP; RGY0080/2018 to G.v.d.B), the Netherlands Organization for Scientific Research (NWO-ALWVIDI864.14.001 to G.v.d.B), and European Research Council (grant agreement No. 862137 to G.v.d.B). GC is supported by grants from the Swedish Research Council and the Swedish Society for Medical Research. SEA is funded by is supported by a Rosalind Franklin Fellowship, co-funded by the European Union and University of Groningen, The Netherlands. EMM is supported by a Short-Term EMBO Fellowship (EMBO7887). Publisher Copyright: © 2021 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd
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