{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:08:21Z","timestamp":1790467701486,"version":"4.1.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T00:00:00Z","timestamp":1721952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81800470 82370554 82070544"],"award-info":[{"award-number":["81800470 82370554 82070544"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Vitamin D\/Vitamin D receptor (VD\/VDR) signaling and the Notch pathway are involved in intestinal barrier restoration in colitis; however, their relationship and underlying mechanism are largely unknown. Therefore, this study aimed to investigate the role and mechanism of VD\/VDR and the Notch pathways in intestinal barrier protection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Genetic <jats:italic>Vdr<\/jats:italic> knockout (VDR KO) and VD deficient (VDd) mice were established, and colitis was induced by feeding 2.5% dextran sodium sulfate (DSS) water. Mechanistic studies, including real-time PCR, immunofluorescence, Western blotting and dual-luciferase reporter assays, were performed on cultured Caco-2 cells and intestinal organoids.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>VD deficiency and VDR genetical KO increased the severity of DSS-induced colitis in mice, which presented a higher disease activity index score, increased intestinal permeability, and more severe intestinal histological damage than controls, accompanied by decreased and disrupted claudin-1 and claudin-3. Moreover, inhibition of Notch pathway by LY411,575 aggravated the severity of DSS-induced colitis and intestinal injury. In Caco-2 cells and intestinal organoids, the expression of Notch-1, N1ICD and Hes1 decreased upon downregulation or KO of VDR but increased upon paricalcitol (PAR, a VDR agonist) treatment. Meanwhile, PAR rescued claudin-1 and claudin-3 impairments that resulted from TNF-\u03b1 exposure but failed to restore claudin-3 upon Notch inhibition. The dual-luciferase reporter assay further suggested that VD\/VDR positively regulated the Notch signaling pathway by modulating Notch-1 transcription.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>VD\/VDR positively modulates Notch activation by promoting Notch-1 transcription to maintain intestinal tight junction integrity and barrier function. This highlights the VD\/VDR-Notch pathway as a potential new therapeutic target for protecting the intestinal barrier against ulcerative colitis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1421577","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T04:35:01Z","timestamp":1721968501000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Vitamin D\/vitamin D receptor protects intestinal barrier against colitis by positively regulating Notch pathway"],"prefix":"10.3389","volume":"15","author":[{"given":"Yanni","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoyu","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Geng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuailing","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1002\/ueg2.12317","article-title":"Implications of the changing epidemiology of inflammatory bowel disease in a changing world","volume":"10","author":"Agrawal","year":"2022","journal-title":"United Eur. 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