Inhibition of CFTR-mediated intestinal chloride secretion as potential therapy for bile acid diarrhea

Tianying Duan, Onur Cil, C. Ming Tse, Rafiquel Sarker, Ruxian Lin, Mark Donowitz, Alan S. Verkman

Research output: Contribution to journalArticlepeer-review

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. FASEB J. 33, 10924–10934 (2019). www.fasebj.org.

Original languageEnglish (US)
Pages (from-to)10924-10934
Number of pages11
JournalFASEB Journal
Volume33
Issue number10
DOIs
StatePublished - Oct 1 2019

Keywords

  • BAD
  • CFTR inhibitor
  • chloride channel
  • cystic fibrosis
  • intestinal fluid secretion

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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