ReferenceID 340
Inhibition of CFTR-mediated intestinal chloride secretion as potential therapy for bile acid diarrhea
FASEB J
Bile acid diarrhea (BAD) is common with ileal resection, Crohn's disease, and diarrhea-predominant irritable bowel syndrome. Here, we demonstrate the efficacy of cystic fibrosis transmembrane conductance regulator (CFTR
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Record Fields
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- Reference Id
- 340
- Evidence Id
- 16930
- Core Evidence Id
- 16930
- Source Reference Id
- 648
- Herb2 Reference Id
- HBREF001088
- Subject Paper Key
- HBIN020281_31268738
- Pubmed Id
- 31268738
- Doi
- 10.1096/fj.201901166R
- Paper Title
- Inhibition of CFTR-mediated intestinal chloride secretion as potential therapy for bile acid diarrhea
- Paper Abstract
- Bile acid diarrhea (BAD) is common with ileal resection, Crohn's disease, and diarrhea-predominant irritable bowel syndrome. Here, we demonstrate the efficacy of cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor (R)-benzopyrimido-pyrrolo-oxazine-dione-27 (BPO-27) in reducing bile acid-induced fluid and electrolyte secretion in colon. Short-circuit current measurements in human T84 colonic epithelial cells and planar colonic enteroid cultures showed a robust secretory response following mucosal but not serosal addition of chenodeoxycholic acid (CDCA) or its taurine conjugate, which was fully blocked by CFTR inhibitors, including (R)-BPO-27. (R)-BPO-27 also fully blocked CDCA-induced secretory current in murine colon. CFTR activation by CDCA primarily involved Ca2+ signaling. In closed colonic loops in vivo, luminal CDCA produced a robust secretory response, which was reduced by 70% by (R)-BPO-27 or in CFTR-deficient mice. In a rat model of BAD produced by intracolonic infusion of CDCA, (R)-BPO-27 reduced the elevation in stool water content by >55%. These results implicate CFTR activation in the colon as a major prosecretory mechanism of CDCA, a bile acid implicated in BAD, and support the potential therapeutic efficacy of CFTR inhibition in bile acid-associated diarrheas.-Duan, T., Cil, O., Tse, C. M., Sarker, R., Lin, R., Donowitz, M., Verkman, A. S. Inhibition of CFTR-mediated intestinal chloride secretion as potential therapy for bile acid diarrhea.
- Journal
- FASEB J
- Publish Year
- 2019
- Experiment Subject
- mouse; cells
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Paper Title Cn
- Paper Title En
- Inhibition of CFTR-mediated intestinal chloride secretion as potential therapy for bile acid diarrhea
- Bilingual Status
- semi_complete