1. Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease.
- Author
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Nijmeijer, Rian M, Gadaleta, Raffaella M, van Mil, Saskia WC, van Bodegraven, Adriaan A, Crusius, J Bart A, Dijkstra, Gerard, Hommes, Daan W, de Jong, Dirk J, Stokkers, Pieter CF, Verspaget, Hein W, Weersma, Rinse K, van der Woude, C Janneke, Stapelbroek, Janneke M, Schipper, Marguerite EI, Wijmenga, Cisca, van Erpecum, Karel J, Oldenburg, Bas, and Dutch Initiative on Crohn, Colitis (ICC)
- Subjects
Dutch Initiative on Crohn ,Colitis ,Colon ,Ileum ,Humans ,Colitis ,Ulcerative ,Inflammatory Bowel Diseases ,Receptors ,Cytoplasmic and Nuclear ,RNA ,Messenger ,Case-Control Studies ,Gene Expression ,Polymorphism ,Single Nucleotide ,Female ,Male ,Genetic Variation ,General Science & Technology - Abstract
BackgroundWe previously showed that activation of the bile salt nuclear receptor Farnesoid X Receptor (FXR) protects against intestinal inflammation in mice. Reciprocally, these inflammatory mediators may decrease FXR activation. We investigated whether FXR activation is repressed in the ileum and colon of inflammatory bowel disease (IBD) patients in remission. Additionally, we evaluated whether genetic variation in FXR is associated with IBD.MethodsmRNA expression of FXR and FXR target gene SHP was determined in ileal and colonic biopsies of patients with Crohn's colitis (n = 15) and ulcerative colitis (UC; n = 12), all in clinical remission, and healthy controls (n = 17). Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 Crohn's disease (CD) and 1193 UC) and in 853 healthy controls.ResultsmRNA expression of SHP in the ileum is reduced in patients with Crohn's colitis but not in patients with UC compared to controls. mRNA expression of villus marker Villin was correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients. None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD.ConclusionsFXR activation in the ileum is decreased in patients with Crohn's colitis. This may be secondary to altered enterohepatic circulation of bile salts or transrepression by inflammatory signals but does not seem to be caused by the studied SNPs in FXR. Increasing FXR activity by synthetic FXR agonists may have benefit in CD patients.
- Published
- 2011