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- W2118910939 abstract "<h3>Objective</h3> 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. <h3>Design</h3> Electrogenic ion transport was measured as changes in short-circuit current across voltage-clamped T<sub>84</sub> 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. <h3>Results</h3> GW4064 (5 μmol/L; 24 h), a specific FXR agonist, induced nuclear translocation of the receptor in T<sub>84</sub> cells and attenuated Cl<sup>−</sup> secretory responses to both Ca<sup>2+</sup> 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<sup>2+</sup> 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<sup>−</sup> currents by inhibiting expression of cystic fibrosis transmembrane conductance regulator channels and inhibited basolateral Na<sup>+</sup>/K<sup>+</sup>-ATPase activity without altering expression of the protein. <h3>Conclusions</h3> 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." @default.
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- W2118910939 date "2013-08-05" @default.
- W2118910939 modified "2023-10-10" @default.
- W2118910939 title "Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo" @default.
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- W2118910939 doi "https://doi.org/10.1136/gutjnl-2013-305088" @default.
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