Premium
Bacterial metabolism of Ursodeoxycholic Acid is necessary for its protective actions in a mouse model of intestinal inflammation
Author(s) -
Lajczak Natalia Katarzyna,
Ward Joseph B,
Goggins Bridie J,
Keely Simon,
Keely Stephen J
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1049.2
Subject(s) - ursodeoxycholic acid , proinflammatory cytokine , medicine , bile acid , cytokine , pharmacology , inflammation , lithocholic acid , pathogenesis , deoxycholic acid , inflammatory bowel disease , chemistry , disease
Background Although inflammatory bowel disease (IBD) represents a significant health and economic burden, current therapies are often ineffective. Altered intestinal epithelial barrier function has been well‐documented to contribute to IBD pathogenesis, with dysregulation of cytokine and antimicrobial protein (AMP) production, along with disrupted mucosal restitution being apparent. Although, the secondary bile acid, ursodeoxycholic acid (UDCA), has been well‐documented to have cytoprotective and anti‐inflammatory actions, its potential for treating IBD has not been well‐investigated. Methods C57BL/6 mice were given dextran sodium sulphate (DSS, 2.5%) in drinking water for 5 days to induce intestinal inflammation, with severity being recorded as disease activity index (DAI). Mice received Na + ‐UDCA, a non‐metabolisable analogue of UDCA, 6‐methyl‐UDCA (6‐MUDCA), or lithocholic acid (LCA) via IP injection each day. Cytokine and HβD release from cultured colonic epithelial cells was analysed by Meso Scale Discovery Assay or ELISA. Wound healing was assessed by scratch assay with wound closure being measured after 48 hrs. Results In DSS‐treated mice, UDCA (30 mg/kg) significantly reduced DAI from 10.0 ± 0.3 in mice treated with DSS alone to 7.2 ± 0.7 in those co‐treated with UDCA (n = 6 – 12, p < 0.001). In cultured monolayers of T 84 colonic epithelial cells, UDCA (50 – 150 μM) attenuated epithelial secretion of the proinflammatory AMP, HβD‐2, (n = 3, p < 0.001), while levels of TNF‐α, IL‐8 and Il‐1β were also significantly reduced (n = 4, p < 0.05). In wound healing studies in vitro, UDCA enhanced colonic epithelial migration and restitution, findings which were mirrored in an in vivo model of colonic mucosal healing in endoscopically wounded mice. Finally, further in vivo studies revealed that the metabolically stable UDCA analogue, 6‐MUDCA, was ineffective in preventing inflammation in the DSS model, while LCA (30 mg/kg), the primary bacterial metabolite of UDCA, was protective, reducing DAI to 5.2 ± 0.6 (n=5, p ≤ 0.001). Discussion/Conclusion Together, our data demonstrate anti‐inflammatory and pro‐healing properties of UDCA in the colon, suggesting a potential role for the bile acid in treatment of IBD. However, in vivo , microbial metabolism to LCA appears to be important for the therapeutic actions of UDCA to be observed.