1. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease
- Author
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Giuseppe Penna, Raffaella Maria Gadaleta, Bas Oldenburg, Marguerite E.I. Schipper, Saskia W.C. van Mil, Stefania Murzilli, Gilles Laverny, Antonio Moschetta, Luciano Adorini, Silvio Danese, Peter D. Siersema, Leo W. J. Klomp, Karel J. van Erpecum, Willem Renooij, Ellen C.L. Willemsen, Gadaleta, Rm, van Erpecum, Kj, Oldenburg, B, Willemsen, Ecl, Renooij, W, Murzilli, S, Klomp, Lwj, Siersema, Pd, Schipper, Mei, Danese, S, Penna, G, Laverny, G, Adorini, L, Moschetta, A, and van Mil, Swc
- Subjects
medicine.medical_specialty ,Colon ,Drug Evaluation, Preclinical ,Receptors, Cytoplasmic and Nuclear ,Inflammation ,Bile acid ,Biology ,Chenodeoxycholic Acid ,Inflammatory bowel disease ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Ileum ,Internal medicine ,medicine ,Animals ,Humans ,Colitis ,030304 developmental biology ,0303 health sciences ,Goblet cell ,Reverse Transcriptase Polymerase Chain Reaction ,Tumor Necrosis Factor-alpha ,Dextran Sulfate ,Gastroenterology ,PostScript ,Inflammatory Bowel Diseases ,medicine.disease ,inflammatory bowel disorders ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,Intestinal Absorption ,Trinitrobenzenesulfonic Acid ,Cancer research ,Cytokines ,030211 gastroenterology & hepatology ,Farnesoid X receptor ,Cytokine secretion ,Caco-2 Cells ,Inflammation Mediators ,medicine.symptom - 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 a 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. RI van Mil, Saskia/C-3751-2009
- Published
- 2011