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In the intestine, CF manifests as obstructive syndromes, dysbiosis, inflammation, and an increased risk for gastrointestinal cancer. Cftr knockout (KO) mice recapitulate CF intestinal disease, including intestinal hyperproliferation. Previous studies using Cftr KO intestinal organoids (enteroids) indicate that crypt epithelium maintains an alkaline intracellular pH (pH<jats:sub>i<\/jats:sub>). We hypothesized that Cftr has a cell-autonomous role in downregulating pH<jats:sub>i<\/jats:sub>that is incompletely compensated by acid-base regulation in its absence. Here, 2\u2032,7\u2032-bis(2-carboxyethyl)-5(6)-carboxyfluorescein microfluorimetry of enteroids showed that Cftr KO crypt epithelium sustains an alkaline pH<jats:sub>i<\/jats:sub>and resistance to cell acidification relative to wild-type. Quantitative real-time PCR revealed that Cftr KO enteroids exhibit downregulated transcription of base (HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>)-loading proteins and upregulation of the basolateral membrane HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>-unloader anion exchanger 2 (Ae2). Although Cftr KO crypt epithelium had increased Ae2 expression and Ae2-mediated Cl<jats:sup>\u2212<\/jats:sup>\/HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>exchange with maximized gradients, it also had increased intracellular Cl<jats:sup>\u2212<\/jats:sup>concentration relative to wild-type. Pharmacological reduction of intracellular Cl<jats:sup>\u2212<\/jats:sup>concentration in Cftr KO crypt epithelium normalized pH<jats:sub>i<\/jats:sub>, which was largely Ae2-dependent. We conclude that Cftr KO crypt epithelium maintains an alkaline pH<jats:sub>i<\/jats:sub>as a consequence of losing both Cl<jats:sup>\u2212<\/jats:sup>and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>efflux, which impairs pH<jats:sub>i<\/jats:sub>regulation by Ae2. Retention of Cl<jats:sup>\u2212<\/jats:sup>and an alkaline pH<jats:sub>i<\/jats:sub>in crypt epithelium may alter several cellular processes in the proliferative compartment of Cftr KO intestine.<\/jats:p>","DOI":"10.1152\/ajpgi.00236.2015","type":"journal-article","created":{"date-parts":[[2015,11,6]],"date-time":"2015-11-06T04:09:09Z","timestamp":1446782949000},"page":"G70-G80","source":"Crossref","is-referenced-by-count":28,"title":["Cellular chloride and bicarbonate retention alters intracellular pH regulation in Cftr KO crypt epithelium"],"prefix":"10.1152","volume":"310","author":[{"given":"Nancy M.","family":"Walker","sequence":"first","affiliation":[{"name":"Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinghua","family":"Liu","sequence":"additional","affiliation":[{"name":"Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri; 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