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 Physiol 312: 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 & NOTEWORTHY On 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.