- Title
- The bile acids, deoxycholic acid and ursodeoxycholic acid, regulate colonic epithelial wound healing
- Creator
- Mroz, Magdalena S.; Lajczak, Natalia K.; Goggins, Bridie J.; Keely, Simon; Keely, Stephen J.
- Relation
- NHMRC.1021582 http://purl.org/au-research/grants/nhmrc/1021582
- Relation
- American Journal of Physiology: Gastrointestinal and Liver Physiology Vol. 314, Issue 3, p. G378-G387
- Publisher Link
- http://dx.doi.org/10.1152/ajpgi.00435.2016
- Publisher
- American Physiological Society
- Resource Type
- journal article
- Date
- 2018
- Description
- 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.
- Subject
- epithelium; farnesoid X receptor; migration; ursodeoxycholic acid; wound healing
- Identifier
- http://hdl.handle.net/1959.13/1406731
- Identifier
- uon:35651
- Identifier
- ISSN:0193-1857
- Language
- eng
- Full Text
- Reviewed
- Hits: 3030
- Visitors: 3397
- Downloads: 225
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT02 | Author final version | 955 KB | Adobe Acrobat PDF | View Details Download |