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 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 language | English |
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Pages (from-to) | 808-817 |
Number of pages | 10 |
Journal | Gut |
Volume | 63 |
Issue number | 5 |
Early online date | 7 Apr 2014 |
DOIs | |
Publication status | Published - May 2014 |
Keywords
- 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