title: Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon.
abstract: Ward JB, Lajczak NK, Kelly OB, O'Dwyer AM, Giddam AK, Ní Gabhann J, Franco P, Tambuwala MM, Jefferies CA, Keely S, Roda A, Keely SJ.Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon.Am J Physiol Gastrointest Liver Physiol312: G550-G558, 2017. First published March 30, 2017; doi:10.1152/ajpgi.00256.2016.-Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1β, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions.NEW & NOTEWORTHYOn the basis of its cytoprotective and anti-inflammatory actions, the secondary bile acid ursodeoxycholic acid (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic acid, as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metabolism of UDCA is necessary for the full expression of its protective effects against colonic inflammation.
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: Joseph B J
authors.initials: JBJ
authors.lastname: Ward
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: Natalia K
authors.identifier: http://orcid.org/0000-0002-1277-0761
authors.initials: NK
authors.lastname: Lajczak
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: Orlaith B
authors.initials: OB
authors.lastname: Kelly
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: Aoife M
authors.initials: AM
authors.lastname: O'Dwyer
authors.affiliation: School of Biomedical Science and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Ashwini K
authors.initials: AK
authors.lastname: Giddam
authors.affiliation: Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Joan
authors.initials: J
authors.lastname: Ní Gabhann
authors.affiliation: Department. of Chemistry, University of Bologna, Bologna, Italy.
authors.forename: Placido
authors.initials: P
authors.lastname: Franco
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland; and.
authors.forename: Murtaza M
authors.initials: MM
authors.lastname: Tambuwala
authors.affiliation: Division of Rheumatology, Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, California.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Jefferies
authors.affiliation: School of Biomedical Science and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Keely
authors.affiliation: Department. of Chemistry, University of Bologna, Bologna, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Roda
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland; skeely@rcsi.ie.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Keely
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001419:Bacteria / Q000378:metabolism; D001711:Biotransformation; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000069196:Gastrointestinal Microbiome; D019073:HT29 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008095:Lithocholic Acid / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D013997:Time Factors; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C092692:6-methylursodeoxycholic acid; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D008095:Lithocholic Acid; D014580:Ursodeoxycholic Acid; D016264:Dextran Sulfate
keywords: barrier function; bile acid; cytokine; epithelium; inflammatory bowel disease