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Dysfunction of either causes luminal acidosis, altered mucus properties, and inflammation. While physical and functional interactions have been demonstrated in heterologous systems, their relationship in native epithelium is not fully established. We investigated the distinct roles of SLC26A3 and CFTR using human intestinal organoids with inducible SLC26A3 overexpression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human colonic and rectal organoids from healthy controls and cystic fibrosis patients with F508del mutations were studied in the proliferative state with high endogenous CFTR expression and inducible SLC26A3 overexpression. Real\u2010time surface pH measurements, electrophysiological analysis, forskolin\u2010induced swelling assays, and confocal microscopy were employed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Steady\u2010state surface pH was lower in CF versus healthy organoids (7.23\u2009\u00b1\u20090.03 vs. 7.34\u2009\u00b1\u20090.03). SLC26A3 overexpression normalized surface pH in CF organoids and CFTR\u2010inhibited organoids, equalizing responses between genotypes. SLC26A3 overexpression corrected abnormal morphology and significantly improved intracellular MUC2 distribution in CF organoids. However, SLC26A3 did not restore fluid secretion in CF organoids or enhance CFTR\u2010mediated electrogenic anion secretion in Ussing chambers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>SLC26A3 and CFTR perform distinct yet complementary functions. SLC26A3 dominates surface pH regulation and maintains bicarbonate efflux independently of CFTR, while CFTR drives agonist\u2010stimulated fluid secretion. SLC26A3's ability to restore pH homeostasis and normalize mucin intracellular distribution in CF organoids demonstrates its critical importance for maintaining colonic mucosal health.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70157","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T13:02:18Z","timestamp":1767790938000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Distinct Roles of\n                    <scp>SLC26A3<\/scp>\n                    and\n                    <scp>CFTR<\/scp>\n                    in Surface\n                    <scp>pH<\/scp>\n                    Regulation and Bicarbonate Secretion in Human Intestinal Epithelium"],"prefix":"10.1111","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4775-9535","authenticated-orcid":false,"given":"Mahdi","family":"Amiri","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4366-8436","authenticated-orcid":false,"given":"Azam","family":"Salari","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9600-2769","authenticated-orcid":false,"given":"Ursula","family":"Seidler","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-024-02914-3"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.mcg.0000155521.81382.3a"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.34.794"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/ibd\/izaa256"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2022.12.017"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-022-07812-1"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2022.12.011"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.13498"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-014-1595-y"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI73193"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(12)60283-2"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.12220"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15323"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-012-2209-1"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-437X(00)00088-5"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.9.4166"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.mpg.0000214161.37574.9a"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21498"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2008.10.004"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.04.004"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00151.2010"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00590.2023"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1115"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00493.2004"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2019.01.002"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.892112"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00454.2009"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdf580"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.039818"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00582138"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-004-1342-x"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(20)31364-0"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.172364"},{"issue":"6","key":"e_1_2_11_35_1","first-page":"422","article-title":"Mechanisms of Sodium, Potassium and Chloride Transport by the Renal Distal Tubule","volume":"13","author":"Ellison D. 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