Article Text
Abstract
Background & aims Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation, resulting from dysregulation of the mucosal immune system and compromised intestinal epithelial barrier function. The bile salt, nuclear farnesoid X receptor (FXR), was recently implicated in intestinal antibacterial defence and barrier function. The aim of this study was to investigate the therapeutic potential of FXR agonists in the treatment of intestinal inflammation in complementary in vivo and in vitro models.
Methods Colitis was induced in wild-type (WT) and Fxr-null mice using dextran sodium sulfate, and in WT mice using trinitrobenzenesulfonic acid. Mice were treated with vehicle or the FXR agonist INT-747, and colitis symptoms were assessed daily. Epithelial permeability assays and cytokine expression analysis were conducted in mouse colon and enterocyte-like cells (Caco-2/HT29) treated with medium or INT-747. Inflammatory cytokine secretion was determined by ELISA in various human immune cell types.
Results INT-747-treated WT mice are protected from DSS- and TNBS-induced colitis, as shown by significant reduction of body weight loss, epithelial permeability, rectal bleeding, colonic shortening, ulceration, inflammatory cell infiltration and goblet cell loss. Furthermore, Fxr activation in intestines of WT mice and differentiated enterocyte-like cells downregulates expression of key proinflammatory cytokines and preserves epithelial barrier function. INT-747 significantly decreases tumour necrosis factor α secretion in activated human peripheral blood mononuclear cells, purified CD14 monocytes and dendritic cells, as well as in lamina propria mononuclear cells from patients with IBD.
Conclusions FXR activation prevents chemically induced intestinal inflammation, with improvement of colitis symptoms, inhibition of epithelial permeability, and reduced goblet cell loss. Furthermore, FXR activation inhibits proinflammatory cytokine production in vivo in the mouse colonic mucosa, and ex vivo in different immune cell populations. The findings provide a rationale to explore FXR agonists as a novel therapeutic strategy for IBD.
- FXR
- DSS-induced IBD
- TNBS-induced IBD
- intestinal permeability
- immune modulation
- epithelial permeability
- gut inflammation
- IBD models
- intestinal barrier function
- mucosal barrier
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Footnotes
See Commentary, p 432
Linked articles 233304.
Funding LWJK is funded by the University Utrecht High Potentials program, and AM by the Italian Association for Cancer Research (AIRC, Milan, Italy), European Research Council Starting Independent Grant Ideas, Italian Ministry of Health and Education (FIRB- IDEAS 2008 RBID08C9N7), European Community's Seventh Framework Programme FP7/2007– 2013 under Grant Agreement No 202272 (LipidomicNet), Cariplo Fundation Milan, Telethon Fundation (GGP08259), University of Bari. SM is a fellow of CariSPAQ (L'Aquila, Italy). SWCVM is funded by the Netherlands Organisation for Scientific Research (NWO).
Competing interests GP, GL and LA are with Intercept Pharmaceuticals. The other authors declare no competing interests.
Ethics approval This study was conducted with the approval of the Istituto Clinico Humanitas, Milan, Italy.
Provenance and peer review Not commissioned; externally peer reviewed.