Peer Reviewed

1

Document Type

Article

Publication Date

1-5-2013

Keywords

Adult, Aged, Aged, 80 and over, Animals, Antidiarrheals, Bile Acids and Salts, Colon, Epithelial Cells, Humans, Male, Mice, Mice, Inbred C57BL, Middle Aged, Potassium Channel Blockers, Sodium-Potassium-Exchanging ATPase, Ursodeoxycholic Acid

Funder/Sponsor

Science Foundation Ireland & NBIP Ireland

Comments

This is the peer reviewed version of the following article:Kelly OB, Mroz MS, Ward JB, Colliva C, Scharl M, Pellicciari R, Gilmer JF, Fallon PG, Hofmann AF, Roda A, Murray FE, Keely SJ. Ursodeoxycholic acid attenuates colonic epithelial secretory function. The Journal of Physiology. 2013; ;591(9):2307-18 which has been published in final form at 10.1113/jphysiol.2013.252544 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

Abstract

Dihydroxy bile acids, such as chenodeoxycholic acid (CDCA), are well known to promote colonic fluid and electrolyte secretion, thereby causing diarrhoea associated with bile acid malabsorption. However, CDCA is rapidly metabolised by colonic bacteria to ursodeoxycholic acid (UDCA), the effects of which on epithelial transport are poorly characterised. Here, we investigated the role of UDCA in the regulation of colonic epithelial secretion. Cl(-) secretion was measured across voltage-clamped monolayers of T84 cells and muscle-stripped sections of mouse or human colon. Cell surface biotinylation was used to assess abundance/surface expression of transport proteins. Acute (15 min) treatment of T84 cells with bilateral UDCA attenuated Cl(-) secretory responses to the Ca(2+) and cAMP-dependent secretagogues carbachol (CCh) and forskolin (FSK) to 14.0 ± 3.8 and 40.2 ± 7.4% of controls, respectively (n = 18, P < 0.001). Investigation of the molecular targets involved revealed that UDCA acts by inhibiting Na(+)/K(+)-ATPase activity and basolateral K(+) channel currents, without altering their cell surface expression. In contrast, intraperitoneal administration of UDCA (25 mg kg(-1)) to mice enhanced agonist-induced colonic secretory responses, an effect we hypothesised to be due to bacterial metabolism of UDCA to lithocholic acid (LCA). Accordingly, LCA (50-200 μm) enhanced agonist-induced secretory responses in vitro and a metabolically stable UDCA analogue, 6α-methyl-UDCA, exerted anti-secretory actions in vitro and in vivo. In conclusion, UDCA exerts direct anti-secretory actions on colonic epithelial cells and metabolically stable derivatives of the bile acid may offer a new approach for treating intestinal diseases associated with diarrhoea.

Disciplines

Medical Molecular Biology | Medical Sciences

Citation

Kelly OB, Mroz MS, Ward JB, Colliva C, Scharl M, Pellicciari R, Gilmer JF, Fallon PG, Hofmann AF, Roda A, Murray FE, Keely SJ. Ursodeoxycholic acid attenuates colonic epithelial secretory function. The Journal of Physiology. 2013; ;591(9):2307-18

PubMed ID

23507881

DOI Link

10.1113/jphysiol.2013.252544

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

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