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Title: Investigating Fibroblast Growth Factor 19 expression in primary and secondary bile acid diarrhoea
Author: Nolan, Jonathan David
ISNI:       0000 0004 5989 7916
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Introduction: Bile acid diarrhoea (BAD) results from excess bile acids (BA) in the colon. Most BAs are reabsorbed at the terminal ileum. Increased colonic BA occur secondary to ileal disease or resection (common in Crohn's disease [CD]) leading to BA malabsorption and secondary BAD (SBAD). Primary BAD (PBAD) occurs in the absence of overt ileal disease or malabsorption. The peptide FGF19 is produced from enterocytes in response to BA absorption and is a negative regulator of BA synthesis. Defects in FGF19 production may underlie the excess faecal BA loss observed in PBAD. Aim: This thesis reports studies testing the following hypotheses: (1) Ileal FGF19 expression is altered in both CD and PBAD; (2) Serum FGF19 is a diagnostic marker of BAD in CD; (3) Stimulating FGF19 with a BA analogue in patients with SBAD will have beneficial symptomatic effects. Methods: Groups of patients underwent fasting blood sampling or ileal biopsies during colonoscopy. Serum FGF19 was measured and biopsies were studied for expression of FGF19 transcripts and other genes before and after incubation with BA. RNA extraction, cDNA synthesis and RT-PCR were used for relative quantification of gene expression. A genotype study on a candidate SNP in the DIET1 gene was performed on a cohort of PBAD patients. Results: Serum FGF19 levels were lower in CD patients with ileal resection, or diarrhoea or active disease. FGF19 transcripts were strongly induced by BAs in ileal explants but were lower in CD compared to controls. Baseline and BA-stimulated ileal FGF19 expression were related to measures of faecal BA loss. The DIET1 variant was associated with FGF19 levels. An open-label, pilot trial of the BA analogue, Obeticholic acid (OCA), in patients with SBAD produced variable changes in FGF19 levels and symptomatic improvement. Conclusion: This work increases awareness of FGF19 and dysregulated BA homeostasis in the pathophysiology of certain chronic diarrhoeal diseases. FGF19 holds promise in guiding therapy for BAD.
Supervisor: Walters, Julian ; Thursz, Mark Sponsor: Bardhan Research and Education Trust ; Broad Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral