{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T11:03:23Z","timestamp":1784027003271,"version":"3.55.0"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T00:00:00Z","timestamp":1740355200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB 1449 - 431232613"],"award-info":[{"award-number":["SFB 1449 - 431232613"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["82DZL009C1 01GL2401A"],"award-info":[{"award-number":["82DZL009C1 01GL2401A"]}],"id":[{"id":"10.13039\/501100002347","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>Intestinal current measurement (ICM) provides a sensitive bioassay for assessment of cystic fibrosis transmembrane conductance regulator (CFTR) function in rectal biopsies <jats:italic>ex vivo<\/jats:italic> and is used as a diagnostic tool for cystic fibrosis (CF). Furthermore, ICM was shown to be sensitive to detect pharmacological rescue of CFTR function by CFTR modulators in people with CF carrying responsive <jats:italic>CFTR<\/jats:italic> mutations. Results from clinical trials of CFTR modulators across age groups indicate that CFTR function in the sweat duct may be age-dependent with children reaching higher levels than adults. However, little is known about age dependency of CFTR function in the intestinal epithelium.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated CFTR-mediated chloride secretion in rectal biopsies from 258 people without CF and 72 people with pancreatic-insufficient CF from 1 month to 68\u00a0years of age. Change in transepithelial short-circuit current in response to cyclic adenosine monophosphate (cAMP)-mediated (100\u00a0\u03bcM IBMX, 1\u00a0\u00b5M forskolin, basolateral) and cholinergic (100\u00a0\u03bcM carbachol, basolateral) stimulation was assessed as a readout for CFTR function using perfused micro-Ussing chambers. Furthermore, quantitative real-time PCR of <jats:italic>CFTR<\/jats:italic> and morphometric analysis of epithelial cells lining the crypts and surface of the rectal mucosa were performed to assess regulation at the levels of gene expression and epithelial cell densities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that CFTR-mediated chloride secretion across rectal tissues, as determined from cAMP-mediated as well as cholinergic chloride-secretory responses was highest during infancy and early childhood and declined with age in people without CF (both P &amp;lt; 0.001). Although, there was no difference in cAMP-mediated currents in people with CF, potassium-secretory responses induced by cholinergic stimulation were also reduced with increasing age. Transcript analyses showed that <jats:italic>CFTR<\/jats:italic> mRNA expression was slightly increased with increasing age in people without CF (P &amp;lt; 0.05). Morphometric analyses demonstrated that CFTR expressing colonocytes at the crypt base were decreased with age (P &amp;lt; 0.05). A secondary analysis of the ICM data of our previous studies on the effects of lumacaftor\/ivacaftor on CFTR function in <jats:italic>F508del<\/jats:italic> -homozygous people with CF aged 12\u00a0years and older and 2\u201311\u00a0year old children showed correlations of the change in cAMP-mediated and cholinergic chloride secretory response with the age of people with CF (P &amp;lt; 0.01 and P &amp;lt; 0.05, respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results demonstrate that CFTR function in the rectal epithelium is reduced with increasing age and indicate that this change is likely due to a decline in the number of secretory colonocytes at the crypt base. These findings suggest that differences in CFTR expressing cells may explain increased functional responses to CFTR modulator therapies in children compared to adult people with CF.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1537095","type":"journal-article","created":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T06:39:14Z","timestamp":1740379154000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Intestinal current measurement detects age-dependent differences in CFTR function in rectal epithelium"],"prefix":"10.3389","volume":"16","author":[{"given":"Simon Y.","family":"Graeber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Sommerburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Berges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Hirtz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Scheuermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Duerr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus A.","family":"Mall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S40","DOI":"10.1016\/j.jcf.2017.06.013","article-title":"Cystic Fibrosis and disorders of the large intestine: DIOS, constipation, and colorectal cancer","volume":"16","author":"Abraham","year":"2017","journal-title":"J. Cyst. Fibros."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3133","DOI":"10.3390\/ijms21093133","article-title":"What role does CFTR play in development, differentiation, regeneration and cancer?","volume":"21","author":"Amaral","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1188051","DOI":"10.3389\/fphar.2023.1188051","article-title":"Effects of lumacaftor-ivacaftor therapy on cystic fibrosis transmembrane conductance regulator function in F508del homozygous patients with cystic fibrosis aged 2-11 years","volume":"14","author":"Berges","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.jcf.2022.10.001","article-title":"The risk of colorectal cancer in individuals with mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene: an English population-based study","volume":"22","author":"Birch","year":"2023","journal-title":"J. Cyst. Fibros."},{"key":"B5","doi-asserted-by":"publisher","first-page":"86","DOI":"10.5694\/mja18.00241","article-title":"Chronic idiopathic constipation in adults: epidemiology, pathophysiology, diagnosis and clinical management","volume":"209","author":"Black","year":"2018","journal-title":"Med. J. Aust."},{"key":"B6","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1146\/annurev.med.58.071905.105316","article-title":"Airway surface dehydration in cystic fibrosis: pathogenesis and therapy","volume":"58","author":"Boucher","year":"2007","journal-title":"Annu. Rev. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1941","DOI":"10.1056\/NEJMra1813799","article-title":"Muco-obstructive lung diseases","volume":"380","author":"Boucher","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/S2213-2600(14)70132-8","article-title":"A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial","volume":"2","author":"Boyle","year":"2014","journal-title":"Lancet Respir. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1554","DOI":"10.1016\/j.jcmgh.2022.02.007","article-title":"A proximal-to-distal survey of healthy adult human small intestine and colon epithelium by single-cell transcriptomics","volume":"13","author":"Burclaff","year":"2022","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1016\/S2213-2600(24)00208-X","article-title":"The expanded French compassionate programme for elexacaftor-tezacaftor-ivacaftor use in people with cystic fibrosis without a F508del CFTR variant: a real-world study","volume":"12","author":"Burgel","year":"2024","journal-title":"Lancet Respir. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"108819","DOI":"10.1016\/j.celrep.2021.108819","article-title":"Human gastrointestinal epithelia of the esophagus, stomach, and duodenum resolved at single-cell resolution","volume":"34","author":"Busslinger","year":"2021","journal-title":"Cell Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1053\/j.gastro.2023.03.214","article-title":"American gastroenterological association-American college of gastroenterology clinical practice guideline: pharmacological management of chronic idiopathic constipation","volume":"164","author":"Chang","year":"2023","journal-title":"Gastroenterology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1111\/j.1365-2036.2007.03540.x","article-title":"Cumulative incidence of chronic constipation: a population-based study 1988-2003","volume":"26","author":"Choung","year":"2007","journal-title":"Aliment. Pharmacol. Ther."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e73905","DOI":"10.1371\/journal.pone.0073905","article-title":"Multicenter intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function","volume":"8","author":"Clancy","year":"2013","journal-title":"PLoS One"},{"key":"B16","doi-asserted-by":"publisher","first-page":"28832","DOI":"10.1038\/s41598-024-80108-8","article-title":"CFTR expression decreases with age in several airway cell types","volume":"14","author":"Corcoran","year":"2024","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.jcf.2004.05.034","article-title":"Ex vivo CF diagnosis by intestinal current measurements (ICM) in small aperture, circulating Ussing chambers","volume":"3","author":"De Jonge","year":"2004","journal-title":"J. Cyst. Fibros."},{"key":"B18","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1007\/BF02207282","article-title":"Crypt base cells show forskolin-induced Cl-secretion but no cation inward conductance","volume":"431","author":"Ecke","year":"1996","journal-title":"Pflugers Arch."},{"key":"B19","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1038\/s41586-021-03852-1","article-title":"Cells of the human intestinal tract mapped across space and time","volume":"597","author":"Elmentaite","year":"2021","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1146\/annurev.physiol.67.031103.153530","article-title":"Secretion and absorption by colonic crypts","volume":"67","author":"Geibel","year":"2005","journal-title":"Annu. Rev. Physiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1164\/rccm.202301-0084OC","article-title":"Phase 3 Open-Label Clinical Trial of Elexacaftor\/Tezacaftor\/Ivacaftor in Children Aged 2-5 Years with Cystic Fibrosis and at Least One F508del Allele","volume":"208","author":"Goralski","year":"2023","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1164\/rccm.201710-1983OC","article-title":"Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis","volume":"197","author":"Graeber","year":"2018","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1164\/rccm.201507-1271LE","article-title":"Intestinal current measurements detect activation of mutant CFTR in patients with cystic fibrosis with the G551D mutation treated with ivacaftor","volume":"192","author":"Graeber","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1016\/S0140-6736(23)01608-2","article-title":"The future of cystic fibrosis treatment: from disease mechanisms to novel therapeutic approaches","volume":"402","author":"Graeber","year":"2023","journal-title":"Lancet"},{"key":"B25","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1164\/rccm.202201-0219OC","article-title":"Effects of Elexacaftor\/Tezacaftor\/Ivacaftor Therapy on Lung Clearance Index and Magnetic Resonance Imaging in Patients with Cystic Fibrosis and One or Two F508del Alleles","volume":"206","author":"Graeber","year":"","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1164\/rccm.202110-2249OC","article-title":"Effects of Elexacaftor\/Tezacaftor\/Ivacaftor Therapy on CFTR Function in Patients with Cystic Fibrosis and One or Two F508del Alleles","volume":"205","author":"Graeber","year":"","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1693","DOI":"10.1056\/NEJMra2216474","article-title":"Cystic fibrosis","volume":"389","author":"Grasemann","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1146\/annurev.physiol.62.1.467","article-title":"Role of CFTR in the colon","volume":"62","author":"Greger","year":"2000","journal-title":"Annu. Rev. Physiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1152\/physiologyonline.1997.12.2.62","article-title":"Regulation of ion transport in colonic crypts","volume":"12","author":"Greger","year":"1997","journal-title":"Physiology"},{"key":"B30","article-title":"Bright futures: guidelines for health supervision of infants","volume-title":"Children, and adolescents: pocket guide","author":"Hagan","year":"2017"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e1047","DOI":"10.1093\/cid\/ciac561","article-title":"Risk factors for mortality among children younger than age 5 Years with severe diarrhea in low- and middle-income countries: findings from the world health organization-coordinated global rotavirus and pediatric diarrhea surveillance networks","volume":"76","author":"Hartman","year":"2023","journal-title":"Clin. Infect. Dis."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1940","DOI":"10.1016\/S0140-6736(19)32597-8","article-title":"Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial","volume":"394","author":"Heijerman","year":"2019","journal-title":"Lancet"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1053\/j.gastro.2004.07.006","article-title":"CFTR Cl-channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis","volume":"127","author":"Hirtz","year":"2004","journal-title":"Gastroenterology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.1111\/j.1476-5381.1995.tb16645.x","article-title":"Characterization of muscarinic receptors mediating contractions of circular and longitudinal muscle of human isolated colon","volume":"115","author":"Kerr","year":"1995","journal-title":"Br. J. Pharmacol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1152\/physrev.00026.2001","article-title":"Electrolyte transport in the mammalian colon: mechanisms and implications for disease","volume":"82","author":"Kunzelmann","year":"2002","journal-title":"Physiol. Rev."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e2451022","DOI":"10.1002\/eji.202451022","article-title":"Gut bacteria, host immunity, and colorectal cancer: from pathogenesis to therapy","volume":"54","author":"Li","year":"2024","journal-title":"Eur. J. Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1136\/gutjnl-2013-304695","article-title":"Evidence that two distinct crypt cell types secrete chloride and potassium in human colon","volume":"63","author":"Linley","year":"2014","journal-title":"Gut"},{"key":"B38","doi-asserted-by":"publisher","first-page":"4261","DOI":"10.2147\/CMAR.S248539","article-title":"CFTR functions as a tumor suppressor and is regulated by DNA methylation in colorectal cancer","volume":"12","author":"Liu","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.1164\/rccm.202310-1836OC","article-title":"Pharmacological improvement of cystic fibrosis transmembrane conductance regulator function rescues airway epithelial homeostasis and host defense in children with cystic fibrosis","volume":"209","author":"Loske","year":"2024","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1172\/JCI2729","article-title":"The amiloride-inhibitable Na+ conductance is reduced by the cystic fibrosis transmembrane conductance regulator in normal but not in cystic fibrosis airways","volume":"102","author":"Mall","year":"","journal-title":"J. Clin. Invest."},{"key":"B41","doi-asserted-by":"publisher","first-page":"G709","DOI":"10.1152\/ajpgi.1999.277.3.G709","article-title":"CFTR-mediated inhibition of epithelial Na+ conductance in human colon is defective in cystic fibrosis","volume":"277","author":"Mall","year":"1999","journal-title":"Am. J. Physiology-Gastrointestinal Liver Physiology"},{"key":"B42","doi-asserted-by":"publisher","first-page":"G1274","DOI":"10.1152\/ajpgi.1998.275.6.G1274","article-title":"Cholinergic ion secretion in human colon requires coactivation by cAMP","volume":"275","author":"Mall","year":"","journal-title":"Am. J. Physiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"G200","DOI":"10.1152\/ajpgi.00137.2001","article-title":"Activation of ion secretion via proteinase-activated receptor-2 in human colon","volume":"282","author":"Mall","year":"2002","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.jcf.2004.05.035","article-title":"Assessment of CFTR function in rectal biopsies for the diagnosis of cystic fibrosis","volume":"3","author":"Mall","year":"","journal-title":"J. Cyst. Fibros."},{"key":"B45","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1053\/j.gastro.2003.10.049","article-title":"The DeltaF508 mutation results in loss of CFTR function and mature protein in native human colon","volume":"126","author":"Mall","year":"","journal-title":"Gastroenterology"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.1038\/sj.bjp.0703520","article-title":"Effect of genistein on native epithelial tissue from normal individuals and CF patients and on ion channels expressed in Xenopus oocytes","volume":"130","author":"Mall","year":"","journal-title":"Br. J. Pharmacol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"G617","DOI":"10.1152\/ajpgi.2000.278.4.G617","article-title":"Defective cholinergic Cl(-) secretion and detection of K(+) secretion in rectal biopsies from cystic fibrosis patients","volume":"278","author":"Mall","year":"","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1164\/rccm.202202-0392OC","article-title":"Efficacy and Safety of Elexacaftor\/Tezacaftor\/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study","volume":"206","author":"Mall","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/s41572-024-00538-6","article-title":"Cystic fibrosis","volume":"10","author":"Mall","year":"2024","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B50","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1164\/rccm.200708-1233OC","article-title":"Development of chronic bronchitis and emphysema in beta-epithelial Na+ channel-overexpressing mice","volume":"177","author":"Mall","year":"2008","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B51","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1111\/j.1469-7793.1999.0251o.x","article-title":"Basolateral K+ channel involvement in forskolin-activated chloride secretion in human colon","volume":"519","author":"McNamara","year":"1999","journal-title":"J. Physiol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/S2213-2600(18)30460-0","article-title":"Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study","volume":"7","author":"McNamara","year":"2019","journal-title":"Lancet Respir. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1056\/NEJMoa1908639","article-title":"Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele","volume":"381","author":"Middleton","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.1370","article-title":"Cancer and inflammation","volume":"9","author":"Munn","year":"2017","journal-title":"Wiley Interdiscip. Rev. Syst. Biol. Med."},{"key":"B55","doi-asserted-by":"publisher","first-page":"e167957","DOI":"10.1172\/JCI167957","article-title":"Pharmacologic improvement of CFTR function rapidly decreases sputum pathogen density, but lung infections generally persist","volume":"133","author":"Nichols","year":"2023","journal-title":"J. Clin. Invest"},{"key":"B56","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1164\/rccm.202108-1986OC","article-title":"Clinical effectiveness of elexacaftor\/tezacaftor\/ivacaftor in people with cystic fibrosis: a clinical trial","volume":"205","author":"Nichols","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B57","doi-asserted-by":"publisher","first-page":"S44","DOI":"10.1002\/ppul.27013","article-title":"Pancreas and pancreatitis: exocrine pancreatic insufficiency","volume":"59","author":"Ramsey","year":"2024","journal-title":"Pediatr. Pulmonol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"e24445","DOI":"10.1371\/journal.pone.0024445","article-title":"The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients","volume":"6","author":"Roth","year":"2011","journal-title":"PLoS One"},{"key":"B59","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/s00018-016-2391-y","article-title":"Role of CFTR in epithelial physiology","volume":"74","author":"Saint-Criq","year":"2017","journal-title":"Cell Mol. Life Sci."},{"key":"B60","doi-asserted-by":"publisher","first-page":"2202153","DOI":"10.1183\/13993003.02153-2022","article-title":"Longitudinal effects of elexacaftor\/tezacaftor\/ivacaftor on sputum viscoelastic properties, airway infection and inflammation in patients with cystic fibrosis","volume":"62","author":"Schaupp","year":"2023","journal-title":"Eur. Respir. J."},{"key":"B61","doi-asserted-by":"publisher","first-page":"989","DOI":"10.3390\/cancers15030989","article-title":"Lower expression of CFTR is associated with higher mortality in a meta-analysis of individuals with colorectal cancer","volume":"15","author":"Scott","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B62","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1002\/ijc.33431","article-title":"Cystic fibrosis F508del carriers and cancer risk: Results from the UK Biobank","volume":"148","author":"Shi","year":"2021","journal-title":"Int. J. Cancer"},{"key":"B63","doi-asserted-by":"publisher","first-page":"233","DOI":"10.3322\/caac.21772","article-title":"Colorectal cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"B64","doi-asserted-by":"publisher","first-page":"e47708","DOI":"10.1371\/journal.pone.0047708","article-title":"Measurements of CFTR-mediated Cl-secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis","volume":"7","author":"Sousa","year":"2012","journal-title":"PLoS One"},{"key":"B65","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1016\/j.trecan.2024.07.006","article-title":"CFTR and colorectal cancer susceptibility: an urgent need for further studies","volume":"10","author":"Spelier","year":"2024","journal-title":"Trends Cancer"},{"key":"B66","doi-asserted-by":"publisher","first-page":"2400004","DOI":"10.1183\/13993003.00004-2024","article-title":"Impact of elexacaftor\/tezacaftor\/ivacaftor therapy on lung clearance index and magnetic resonance imaging in children with cystic fibrosis and one or two F508del alleles","volume":"64","author":"Stahl","year":"","journal-title":"Eur. Respir. J."},{"key":"B67","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1513\/AnnalsATS.202208-684OC","article-title":"Effects of lumacaftor\/ivacaftor on cystic fibrosis disease progression in children 2 through 5 Years of age homozygous for F508del-CFTR: a phase 2 placebo-controlled clinical trial","volume":"20","author":"Stahl","year":"2023","journal-title":"Ann. Am. Thorac. Soc."},{"key":"B68","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.1513\/AnnalsATS.202402-201OC","article-title":"Long-term impact of lumacaftor\/ivacaftor treatment on cystic fibrosis disease progression in children 2-5 Years of age homozygous for F508del-CFTR: a phase 2, open-label clinical trial","volume":"21","author":"Stahl","year":"","journal-title":"Ann. Am. Thorac. Soc."},{"key":"B69","doi-asserted-by":"publisher","first-page":"2387","DOI":"10.1074\/jbc.270.5.2387","article-title":"The A2b adenosine receptor mediates cAMP responses to adenosine receptor agonists in human intestinal epithelia","volume":"270","author":"Strohmeier","year":"1995","journal-title":"J. Biol. Chem."},{"key":"B70","doi-asserted-by":"publisher","first-page":"3504","DOI":"10.1038\/onc.2017.3","article-title":"CFTR is a tumor suppressor gene in murine and human intestinal cancer","volume":"36","author":"Than","year":"2017","journal-title":"Oncogene"},{"key":"B71","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1038\/nrgastro.2015.111","article-title":"Secretory diarrhoea: mechanisms and emerging therapies","volume":"12","author":"Thiagarajah","year":"2015","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1093\/gerona\/glt106","article-title":"Age-associated remodeling of the intestinal epithelial barrier","volume":"68","author":"Tran","year":"2013","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"B73","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1172\/JCI116993","article-title":"Determinants of mild clinical symptoms in cystic fibrosis patients. Residual chloride secretion measured in rectal biopsies in relation to the genotype","volume":"93","author":"Veeze","year":"1994","journal-title":"J. Clin. Invest"},{"key":"B74","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/0016-5085(91)90017-f","article-title":"Ion transport abnormalities in rectal suction biopsies from children with cystic fibrosis","volume":"101","author":"Veeze","year":"1991","journal-title":"Gastroenterology"},{"key":"B75","unstructured":"Diarrhoeal disease\n          \n          \n          2024"},{"key":"B76","doi-asserted-by":"publisher","first-page":"a009746","DOI":"10.1101\/cshperspect.a009746","article-title":"The cystic fibrosis of exocrine pancreas","volume":"3","author":"Wilschanski","year":"2013","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B77","doi-asserted-by":"publisher","first-page":"1522","DOI":"10.1164\/rccm.202102-0509OC","article-title":"A Phase 3 Open-Label Study of Elexacaftor\/Tezacaftor\/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele","volume":"203","author":"Zemanick","year":"2021","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B78","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1164\/rccm.200803-442OC","article-title":"Preventive but not late amiloride therapy reduces morbidity and mortality of lung disease in betaENaC-overexpressing mice","volume":"178","author":"Zhou","year":"2008","journal-title":"Am. J. Respir. Crit. Care Med."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1537095\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T06:39:21Z","timestamp":1740379161000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1537095\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,24]]},"references-count":78,"alternative-id":["10.3389\/fphar.2025.1537095"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1537095","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,24]]},"article-number":"1537095"}}