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Here, we investigated the role of MCs in dextran sulfate sodium (DSS)\u2010induced colitis using a Kit\u2010independent MC\u2010deficient model (Cpa3\u2010Cre; Mcl1\n                    <jats:sup>fl\/fl<\/jats:sup>\n                    ), in which selective deletion of the anti\u2010apoptotic gene\n                    <jats:italic>Mcl1<\/jats:italic>\n                    ablates MCs. Despite efficient and tissue\u2010wide MC depletion, MC\u2010deficient mice exhibited macroscopic and histological disease severity comparable to control mice. However, MC deficiency significantly altered epithelial and immune responses during acute intestinal injury. Specifically, MC\u2010deficient mice displayed increased colonic MUC2 expression, together with decreased tight\u2010junction integrity. The impaired epithelial barrier was associated with increased bacterial infiltration and selective accumulation of myeloid cells, including neutrophils, dendritic cells, and macrophages, alongside increased TNF\u2010\u03b1 and reduced VEGF levels. Systemically, in DSS\u2010treated mice, MC deficiency was associated with splenomegaly and increased splenic neutrophils and dendritic cells. Importantly, adoptive transfer of bone marrow\u2010derived MCs restored the epithelial barrier\u2010associated features and reduced neutrophil accumulation. Collectively, these findings identify MCs as key regulators of epithelial\u2013myeloid crosstalk contributing to the maintenance of barrier integrity and limiting excessive myeloid accumulation and bacterial exposure rather than acting as primary drivers of tissue injury.\n                  <\/jats:p>","DOI":"10.1002\/eji.70292","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T11:05:01Z","timestamp":1791457501000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mast Cells Regulate Epithelial Barrier Integrity and Myeloid Immune Responses in Experimental Colitis"],"prefix":"10.1002","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4961-5130","authenticated-orcid":false,"given":"Alessia","family":"Carnevale","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia\u2010Fondazione Cenci Bolognetti 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