The Actions of Ursodeoxycholic Acid and its derivatives on Colonic Epithelial Transport and Barrier Function

Background: Intestinal disorders, including infectious diseases (ID), inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), are common in the European population and on a global scale and are typically associated with inflammation and/or dysregulated intestinal fluid movement, leading to the clinical endpoint of diarrhoea. Although the health and economic burden of diarrhoeal disease is tremendous, there is still a lack of safe and effective drugs for their treatment. Insults to the intestinal epithelium are critical in the pathogenesis of many of the above-mentioned intestinal disorders as these cells govern the transport and barrier functions of the intestine and also participate in initiation of inflammatory responses. As such, these cells represent excellent targets for the development of new drugs to treat intestinal diseases. Ursodeoxycholic acid (UDCA), the therapeutic component of bear bile, used in traditional Chinese medicine, also has a large evidence base and is commonly used in conventional medical practice to treat cholestatic disorders and hepatic inflammation. Other bile acids (BAs) are also known to exert regulatory effects on colonic epithelial transport, cell growth and immunity. Little however is known, to date, about the effects of UDCA and its metabolites on colonic epithelial transport function and immunity. Methods: T84 cells, a colonic epithelial cell line used as a reductionist model of chloride (Cl-) secretion, were cultured until they reached confluency and a trans-epithelial resistance of >1000 ohms.cm-2 was achieved. These polarised monolayers of T84 cells, resected colonic mucosa from C57 black mice, Sprague-Dawley rats and surgically resected sections or endoscopic biopsy specimens of human colon were mounted in Ussing chambers and changes in short circuit (Isc) measured. This technique is reflective of changes in Cl- secretion. Confocal imaging was used to visualise localisation of transport proteins. Western blotting and surface biotinylation were used to determine protein expression and abundance. Intracellular calcium (Ca2+) was measured using Fura/ 2AM fluorescence and MetaFluor imaging. ELISA measurements were used to assess cytokine levels. Results: The acute effects of UDCA on Cl- secretion in colonic epithelial cell model, in treated mice and on ex vivo rat and human colonic tissues were examined. 18 UDCA, unlike other dihydroxy BAs, did not alter basal Cl- secretion in the T84 colonic epithelial cell line. UDCA in fact exerted potent inhibitory actions in T84 cell monolayers, significantly attenuating responses to both Ca2+ and cyclic-AMP (cAMP) -dependent secretory agonists (Carbachol (CCh) and Forskolin (FSK) respectively, p Conclusion: UDCA has predominantly anti-secretory and anti-inflammatory effects in the colonic epithelium. Through direct delivery, modification of its structure or targeting of the molecular targets identified in these studies, these beneficial effects could be utilised to treat inflammatory and secretory colonic diseases.