Ursodeoxycholic acid attenuates colonic epithelial secretory function

Abstract

Key points• Although diarrhoeal diseases represent a significant health and economic burden to society, therapeutic options remain limited.• While several bile acids are known to stimulate epithelial Cl − 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.• We report that in contrast to other bile acids, UDCA exerts anti-secretory actions on colonic epithelial cells in vitro.• In contrast, in vivo 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, in vivo administration of a metabolically stable analogue of UDCA, 6α-methyl-UDCA, was anti-secretory.• 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.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 T 84 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 84 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 ( 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.

Lithocholic acid attenuates cAMP-dependent Cl− secretion in human colonic epithelial T84 cells

“…As shown in Fig. 3D, and in contrast to the findings of Kelly et al (42), LCA did not change CCH-stimulated I sc in our T84 preparations. Therefore, for the remainder of the study, we probed the nature of the inhibition of cAMP-stimulated I sc by LCA, using FSK as the cAMP-dependent secretagogue.…”

“…Thus, they reported that LCA inhibits both basal-and carbachol (CCH)-stimulated I sc in rat distal colonic mucosa, stripped of underlying muscle within 10 min of addition (77). In contrast, in both stripped human colonic preparations and in T84 cells (42), they found that pretreatment with LCA (50 -250 M) for 15 min potentiates the action of CCH.…”

Helminths and intestinal barrier function

“…This process must disrupt the epithelial barrier but neither the mechanism of the transepithelial passage nor any physiologic/pathophysiological consequences of this are well understood. S. mansoni, and other flukes (e.g., Clonorchis sinensis (human), Fasciola hepatica (cattle)), infect or affect the liver with implications for bile flow and bile salt formation: 47 bile acids can directly affect epithelial permeability and electolyte transport, 48,49 but we are unaware of data in support of the possibility that infection with these flatworms affect epithelial permeability indirectly via bile salts.…”

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

“…A third area not discussed is the role of bile acids in colonic secretion ( 447,448 ) and absorption ( 449 ), as well as recent work suggesting that bile acid activation of TGR5 is essential for normal defecation, at least in the mouse ( 70 ). Details of the biochemical mechanism(s) for bile acid-induced intestinal secretion are being elucidated by several laboratories, among these being that of Stephen Keely in Dublin ( 448 ), and that of Mrinalini Rao in Chicago ( 450 ).…”