RT Journal Article SR Electronic T1 Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.09.19.304303 DO 10.1101/2020.09.19.304303 A1 Elke M. Muntjewerff A1 Kechun Tang A1 Lisanne Lutter A1 Gustaf Christoffersson A1 Mara J.T. Nicolasen A1 Hong Gao A1 Gajanan D. Katkar A1 Soumita Das A1 Martin ter Beest A1 Wei Ying A1 Pradipta Ghosh A1 Sahar El Aidy A1 Bas Oldenburg A1 Geert van den Bogaart A1 Sushil K. Mahata YR 2021 UL http://biorxiv.org/content/early/2021/03/09/2020.09.19.304303.abstract AB Aim A ‘leaky’ gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancers. 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, 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 CST-KO mice displayed (i) elongated tight, adherens junctions and desmosomes similar to IBD patients, and (ii) gut inflammation. Consistently, 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 via antagonizing the effects of PST.Competing Interest StatementThe authors have declared no competing interest.