The bile acids, deoxycholic acid and ursodeoxycholic acid, regulate colonic epithelial wound healing.
The intestinal epithelium constitutes an innate barrier which, upon injury, undergoes self-repair processes known as restitution. Although bile acids are known as important regulators of epithelial function in health and disease, their effects on wound healing processes are not yet clear. Here we set out to investigate the effects of the colonic bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on epithelial restitution. Wound healing in T84 cell monolayers grown on transparent, permeable supports was assessed over 48 h with or without bile acids. Cell migration was measured in Boyden chambers. mRNA and protein expression were measured by RT-PCR and Western blotting. DCA (50-150 µM) significantly inhibited wound closure in cultured epithelial monolayers and attenuated cell migration in Boyden chamber assays. DCA also induced nuclear accumulation of the farnesoid X receptor (FXR), whereas an FXR agonist, GW4064 (10 µM), inhibited wound closure. Both DCA and GW4064 attenuated the expression of CFTR Cl- channels, whereas inhibition of CFTR activity with either CFTR-inh-172 (10 µM) or GlyH-101 (25 µM) also prevented wound healing. Promoter/reporter assays revealed that FXR-induced downregulation of CFTR is mediated at the transcriptional level. In contrast, UDCA (50-150 µM) enhanced wound healing in vitro and prevented the effects of DCA. Finally, DCA inhibited and UDCA promoted mucosal healing in an in vivo mouse model. In conclusion, these studies suggest bile acids are important regulators of epithelial wound healing and are therefore good targets for development of new drugs to modulate intestinal barrier function in disease treatment. NEW & NOTEWORTHY The secondary bile acid, deoxycholic acid, inhibits colonic epithelial wound healing, an effect which appears to be mediated by activation of the nuclear bile acid receptor, FXR, with subsequent downregulation of CFTR expression and activity. In contrast, ursodeoxycholic acid promotes wound healing, suggesting it may provide an alternative approach to prevent the losses of barrier function that are associated with mucosal inflammation in IBD patients.
['Mroz|Magdalena S|MS|', 'Lajczak|Natalia K|NK|0000-0002-1277-0761', 'Goggins|Bridie J|BJ|', 'Keely|Simon|S|', 'Keely|Stephen J|SJ|']
D000818:Animals D002465:Cell Movement D049109:Cell Proliferation D003106:Colon D019005:Cystic Fibrosis Transmembrane Conductance Regulator D003840:Deoxycholic Acid D005260:Female D057809:HEK293 Cells D006801:Humans D007413:Intestinal Mucosa D008810:Mice, Inbred C57BL D011401:Promoter Regions, Genetic D018160:Receptors, Cytoplasmic and Nuclear D047488:Retinoid X Receptors D015398:Signal Transduction D014158:Transcription, Genetic D014580:Ursodeoxycholic Acid D014945:Wound Healing
ursodeoxycholic acid wound healing epithelium migration farnesoid X receptor