{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:57:16Z","timestamp":1785430636913,"version":"3.56.0"},"reference-count":78,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dongguk University College of Medicine Research Fund","award":["K-2026-G0002-00007"],"award-info":[{"award-number":["K-2026-G0002-00007"]}]},{"award":["K-2026-G0002-00007"],"award-info":[{"award-number":["K-2026-G0002-00007"]}],"id":[{"id":"https:\/\/ror.org\/057q6n778","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Current inflammatory bowel disease (IBD) therapies suppress immune pathways, yet epithelial recovery can remain incomplete. This review evaluates whether intestinal chloride and bicarbonate transport can support a distinct, adjunctive pharmacological strategy. Rather than cataloguing transport proteins, we compare the cystic fibrosis transmembrane conductance regulator (CFTR), SLC26A3\/down-regulated in adenoma (DRA), and TMEM16A\/ANO1 against an evidence hierarchy of human disease relevance, causal epithelial biology, pharmacological tractability, target engagement, functional rescue, and developability. CFTR and DRA form the most coherent module linking bicarbonate availability to mucin expansion, epithelial surface pH, fluid balance, and barrier organization, but their liabilities differ. CFTR is structurally and clinically druggable, yet its modulators are genotype-directed, and broad activation may worsen diarrhea. DRA has stronger evidence for a colonic barrier role and emerging support from human organoids, but no validated activator or stabilizer. TMEM16A has abundant chemical tools, yet uncertain selectivity, wide extra-epithelial expression, and no established disease-modifying role in IBD. No intervention has achieved mucosal healing through anion-transport rescue in IBD. We therefore define the decisive experiments required before translation: confirmation of persistent functional defects in human tissue, selective exposure-linked rescue in patient-derived epithelium, direct target engagement, and protection against hypersecretion or electrolyte imbalance. The evidence supports focused, mechanism-based evaluation of the CFTR-DRA axis rather than empirical repurposing.<\/jats:p>","DOI":"10.3390\/ijms27146356","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T07:54:13Z","timestamp":1784534053000},"page":"6356","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epithelial Chloride and Bicarbonate Transport in Intestinal Barrier Failure: A Molecular Target-Validation Assessment of CFTR and SLC26A3\/DRA in Inflammatory Bowel Disease"],"prefix":"10.3390","volume":"27","author":[{"given":"Yohan","family":"Seo","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine, Dongguk University, Gyeongju 38066, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1053\/j.gastro.2020.12.031","article-title":"STRIDE-II: An update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD: Determining therapeutic goals for treat-to-target strategies in IBD","volume":"160","author":"Turner","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1136\/gutjnl-2023-329964","article-title":"Different levels of healing in inflammatory bowel diseases: Mucosal, histological, transmural, barrier and complete healing","volume":"72","author":"Neurath","year":"2023","journal-title":"Gut"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1053\/j.gastro.2024.10.001","article-title":"AGA living clinical practice guideline on pharmacological management of moderate-to-severe ulcerative colitis","volume":"167","author":"Singh","year":"2024","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1056\/NEJMra2002697","article-title":"Pathophysiology of inflammatory bowel diseases","volume":"383","author":"Chang","year":"2020","journal-title":"N. 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