Ursodeoxycholic acid attenuates colonic epithelial secretory function. (10th April 2013)

• Record Type: Journal Article
• Authors: Kelly, Orlaith B.; Mroz, Magdalena S.; Ward, Joseph B. J.; Colliva, Carolina; Scharl, Michael; Pellicciari, Roberto; Gilmer, John F.; Fallon, Padraic G.; Hofmann, Alan F.; Roda, Aldo; Murray, Frank E.; Keely, Stephen J.
• Is Part Of: Journal of physiology. Volume 591:Number 9(2013:May)
• Page Start: 2307
• Page End: 2318
• Publication Date: 2013-04-10
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2013.252544
• Languages: English
• ISSNs: 0022-3751

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Key points</title> <p> <list id="l1" list-type="simple"> <list-item> <label> </label> <p>Although diarrhoeal diseases represent a significant health and economic burden to society, therapeutic options remain limited.</p> </list-item> <list-item> <label> </label> <p>While several bile acids are known to stimulate epithelial Cl<sup>−</sup> secretion, the major driving force for fluid secretion in the intestine, the effects of ursodeoxycholic acid (UDCA) on epithelial transport function are not well described.</p> </list-item> <list-item> <label> </label> <p>We report that in contrast to other bile acids, UDCA exerts anti‐secretory actions on colonic epithelial cells <italic>in vitro</italic>.</p> </list-item> <list-item> <label> </label> <p>In contrast, <italic>in vivo</italic> administration of UDCA enhances epithelial secretory function, an affect we ascribe to being due to its bacterial metabolism to lithocholic acid. In keeping with this hypothesis, <italic>in vivo</italic> administration of a metabolically stable analogue of UDCA, 6α‐methyl‐UDCA, was anti‐secretory.</p> </list-item> <list-item> <label> </label> <p>Our findings reveal novel anti‐secretory actions of UDCA and suggest that metabolically stable analogues of bile acid may be useful for development as a new class of anti‐diarrhoeal drug.</p> </list-item> </list> </p> <p> <bold>Abstract </bold> 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<sup>−</sup> secretion was measured across voltage‐clamped monolayers of T<sub>84</sub> 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 T<sub>84</sub> cells with bilateral UDCA attenuated Cl<sup>−</sup> secretory responses to the Ca<sup>2+</sup> and cAMP‐dependent secretagogues carbachol (CCh) and forskolin (FSK) to 14.0 ± 3.8 and 40.2 ± 7.4% of controls, respectively (<italic>n</italic>= 18, <italic>P</italic> < 0.001). Investigation of the molecular targets involved revealed that UDCA acts by inhibiting Na<sup>+</sup>/K<sup>+</sup>‐ATPase activity and basolateral K<sup>+</sup> channel currents, without altering their cell surface expression. In contrast, intraperitoneal administration of UDCA (25 mg kg<sup>−1</sup>) 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 μ<sc>m</sc>) enhanced agonist‐induced secretory responses <italic>in vitro</italic> and a metabolically stable UDCA analogue, 6α‐methyl‐UDCA, exerted anti‐secretory actions <italic>in vitro</italic> and <italic>in vivo</italic>. 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.</p> </abstract>