Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo

Magdalena S. Mroz, Niamh Keating, Joseph B. Ward, Rafiquel Sarker, Silvie Amu, Gabriella Aviello, Mark Donowitz, Padraic G. Fallon, Stephen J. Keely

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Bile acids are important regulators of intestinal physiology, and the nuclear bile acid receptor, farnesoid X receptor (FXR), is emerging as a promising therapeutic target for several intestinal disorders. Here, we investigated a role for FXR in regulating intestinal fluid and electrolyte transport and the potential for FXR agonists in treating diarrhoeal diseases. Design: Electrogenic ion transport was measured as changes in short-circuit current across voltage-clamped T84 cell monolayers or mouse tissues in Ussing chambers. NHE3 activity was measured as BCECF fluorescence in Caco-2 cells. Protein expression was measured by immunoblotting and cell surface biotinylation. Antidiarrhoeal efficacy of GW4064 was assessed using two in vivo mouse models: the ovalbumin-induced diarrhoea model and cholera toxin (CTX)-induced intestinal fluid accumulation. Results: GW4064 (5 μmol/L; 24 h), a specific FXR agonist, induced nuclear translocation of the receptor in T84 cells and attenuated Cl- secretory responses to both Ca2+ and cAMP-dependent agonists. GW4064 also prevented agonist-induced inhibition of NHE3 in Caco-2 cells. In mice, intraperitoneal administration of GW4064 (50 mg/mL) also inhibited Ca2+ and cAMP-dependent secretory responses across ex vivo colonic tissues and prevented ovalbumin-induced diarrhoea and CTX-induced intestinal fluid accumulation in vivo. At the molecular level, FXR activation attenuated apical Cl- currents by inhibiting expression of cystic fibrosis transmembrane conductance regulator channels and inhibited basolateral Na+/K+-ATPase activity without altering expression of the protein. Conclusions: These data reveal a novel antisecretory role for the FXR in colonic epithelial cells and suggest that FXR agonists have excellent potential for development as a new class of antidiarrheal drugs.

Original languageEnglish (US)
Pages (from-to)808-817
Number of pages10
JournalGut
Volume63
Issue number5
DOIs
StatePublished - May 1 2014

ASJC Scopus subject areas

  • Gastroenterology

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