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Title: The role of bile acids and farnesoid X receptor in ileal Crohn's disease
Author: Speight, Richard Alexander
ISNI:       0000 0004 5991 0383
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2015
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The aetiopathogenesis of Crohn’s disease (CD) is characterised by epithelial barrier dysfunction and immune dysregulation in a genetically susceptible host. Exposure to a western diet, a dysbiosis and bile acid (BA) dysmetabolism have also been implicated. The BA receptor, farnesoid-x receptor (FXR), is central to the crosstalk between the host and its microbiota. FXR acts to maintain the epithelial barrier and has an immuno-modulatory function although the mechanism is not fully understood. The first aim of this study was to investigate the effect of FXR agonism using invitro models of cytokine-induced epithelial barrier dysfunction. Functional and morphological studies of Caco-2 cell monolayers demonstrated that FXR acts to maintain epithelial cell morphology, probably via a mechanism involving the regulation of myosin light chain kinase expression. FXR agonism was also able to abolish the IL-8 response of HT29 cells to stimulation with TNFα. The second aim of this study was to investigate the link between a westernlifestyle diet, impaired BA signalling and ileal inflammation in a mouse model of obesity. Animals fed a western-lifestyle diet expressed more ileal inflammatory cytokine. There was a trend to suggest that supplementation with an FXR agonist reduced inflammatory cytokine expression. Finally, this study aimed to both measure FXR activity in patients with ileal CD, but also to optimise an ex-vivo tissue culture model to assay the effect of FXR agonism on ileal mucosal cytokine production. FXR activity was significantly reduced in patients with ileal CD as compared with controls. An ex-vivo tissue culture model was optimised, but there was no evidence that FXR agonism could attenuate the response of primary tissue to stimulation with inflammatory cytokine. xiv In summary, the data presented support the hypothesis that disrupted bile acid signalling, via FXR, may predispose to the development of ileal CD by impairing gut epithelial immune homeostasis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available