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

64 Citations (Scopus)


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 Ca(2+) 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 Ca(2+) 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
Pages (from-to)808-817
Number of pages10
Issue number5
Early online date7 Apr 2014
Publication statusPublished - May 2014


  • Animals
  • Antidiarrheals
  • Blotting, Western
  • Caco-2 Cells
  • Cells, Cultured
  • Colon
  • Diarrhea
  • Electrodiagnosis
  • Humans
  • Intestinal Mucosa
  • Ion Transport
  • Isoxazoles
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Cytoplasmic and Nuclear
  • Sodium-Hydrogen Antiporter
  • Evaluation Studies
  • Journal Article
  • Research Support, Non-U.S. Gov't


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