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

摘要: Background and AimsA leaky gut barrier has been implicated in the initiation progression of a multitude diseases, e.g., inflammatory bowel disease, irritable syndrome, celiac colorectal cancers. Here we asked how Chromogranin A (CgA), major hormone produced by enteroendocrine cells, Catestatin (CST), most abundant CgA-derived proteolytic peptide, affect barrier. Methods ResultsUltrastructural studies on colons from (CST: hCgA352-372) knockout (CST-KO) mice revealed (i) altered morphology tight (TJ) adherens (AJ) junctions desmosomes, indicative junctional stress (ii) an increased infiltration immune cells compared to controls. Flow cytometry confirmed these be macrophages CD4+ T cells. Gene expression that multiple TJ-markers were reduced, with concomitant compensatory elevation AJ desmosome markers. Consistently, levels plasma FITC-dextran elevated CST-KO mice, confirming leakiness gut. Leaky correlated inflammation higher ratio Firmicutes Bacteroidetes, dysbiotic pattern commonly encountered diseases. Supplementation recombinant CST reversed this key phenotypes. CgA-KO either alone, or pro-inflammatory CgA fragment pancreastatin (PST: CgA250-301) showed permeability is regulated antagonistic roles two peptide hormones: reduces PST increases leakiness. ConclusionWe conclude cell-derived hormone, regulates permeability. both necessary sufficient reduce acts primarily via antagonizing effects PST. What you need knowO_ST_ABSBackground ContextC_ST_ABSThe intestinal disrupted many diseases such as Crohns disease. (CgA) proteolytically cleaved into bioactive peptides including catestatin (CST) (PST). The role unknown. New findingsCgA efficiently processed processing might decreased during active promotes epithelial function counteracting LimitationsThe complete mechanism regulation likely involves complex interplay between system, metabolism, epithelium, system microbiota. ImpactOur findings indicate modulator functions correlates disease severity could target for therapeutic interventions