title: Ursodeoxycholic acid attenuates colonic epithelial secretory function.
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.
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Orlaith B
authors.initials: OB
authors.lastname: Kelly
authors.forename: Magdalena S
authors.initials: MS
authors.lastname: Mroz
authors.forename: Joseph B J
authors.initials: JB
authors.lastname: Ward
authors.forename: Carolina
authors.initials: C
authors.lastname: Colliva
authors.forename: Michael
authors.initials: M
authors.lastname: Scharl
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
authors.forename: Padraic G
authors.initials: PG
authors.lastname: Fallon
authors.forename: Alan F
authors.initials: AF
authors.lastname: Hofmann
authors.forename: Aldo
authors.initials: A
authors.lastname: Roda
authors.forename: Frank E
authors.initials: FE
authors.lastname: Murray
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Keely
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism; D003106:Colon / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D026902:Potassium Channel Blockers / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D000930:Antidiarrheals; D001647:Bile Acids and Salts; D026902:Potassium Channel Blockers; D014580:Ursodeoxycholic Acid; D000254:Sodium-Potassium-Exchanging ATPase