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Nutraceutical Targeting of the Bile Acid Receptor, Farnesoid X Receptor, for Intestinal Disease.

thesis
posted on 18.10.2021, 09:38 authored by Ciara FallonCiara Fallon

Bile acids, classically known for their roles in dietary fat absorption, are now recognised as hormones critical to regulating many aspects of intestinal physiology, including mucosal immune responses, epithelial proliferation/apoptosis, and transepithelial transport and barrier function. Downregulation of the nuclear bile acid receptor, farnesoid X receptor (FXR), in the intestinal epithelium has been shown to be associated with inflammatory bowel disease and colorectal cancer, whereas FXR activation prevents disease progression in preclinical models. Furthermore, treatment with FXR agonists improves symptoms of diarrhoeal disease, both in preclinical models and in patients with bile acid diarrhoea. Thus, strategies to upregulate epithelial FXR expression and activate FXR signalling have been proposed to treat such intestinal disorders. The “xxxx”, xxxx, contains pentacyclic triterpenes (PCTs), a particular class of plant-derived phytochemicals, that have been previously proposed to modulate FXR activity. The primary goal of this thesis was to investigate the potential for developing extracts of xxxx as a novel nutraceutical-based approach to treat/prevent intestinal diseases. These studies show that PCTs and xxxx extracts, confirmed to contain PCTs, upregulate colonic epithelial FXR expression and activity in a range of human and murine in vitro, ex vivo and in vivo models. Furthermore, we report novel anti-secretory effects of PCTs and PCT-rich xxxx extracts via FXR-induced downregulation of colonic epithelial cystic fibrosis transmembrane conductance regulator (CFTR) expression. In summary, this thesis demonstrates that PCTs and PCT-containing xxxx extracts modulate expression and activity of the nuclear bile acid receptor, FXR, in colonic epithelial cells. Given the critical roles of FXR in maintenance of gut health, such extracts have significant therapeutic and commercial potential to be developed as a novel first-in-class “FXR-targeted nutraceutical” for treatment and prevention of common intestinal disorders.

Funding

RCSI StAR PhD Programme

Dr Ciaran Barry Scholarship

Science Foundation Ireland (SFI)

History

First Supervisor

Dr Stephen J Keely

Second Supervisor

Prof. Helen Sheridan

Comments

Submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2021

Published Citation

Fallon, C.M., Nutraceutical Targeting of the Bile Acid Receptor, Farnesoid X Receptor, for Intestinal Disease. [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2021

Degree Name

Doctor of Philosophy (PhD)

Date of award

30/11/2021

Programme

  • Doctor of Philosophy (PhD)