Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB097

Poster Communications

Neutraceutical targeting of the bile acid receptor, farnesoid X receptor, for intestinal disease.

C. M. Fallon1, J. Smyth1, N. K. Lajczak-McGinley1, H. Sheridan2, S. J. Keely1

1. Department of Molecular Medicine, The Royal College of Surgeons in Ireland, Dublin 9, Ireland. 2. School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland.

Introduction: Dysregulated bile acid metabolism has been linked to the pathogenesis of intestinal disorders, including inflammatory bowel disease (IBD) and cancer. The nuclear bile acid receptor, farnesoid X receptor (FXR), represents a promising target for treatment of these diseases. Previous studies suggest that a class of plant-derived phytochemicals are modulators of FXR activity. The aim of this study was to investigate the effects of a lead natural compound, denoted KFS1, on FXR activation in colonic epithelial cells. Methods: Polarised monolayers of T84 colonic epithelial cells were treated bilaterally with the FXR agonist, GW4064 (5μM) and KFS1 (1-100μM) for 24 hr. Expression of FXR and FGF-19 were measured by RT-qPCR. Transepithelial electrical resistance (TEER) was measured using the EVOM2 Voltohmmeter. Results: GW4064 (5µM) induced an 1100±457 fold increase in FGF-19 mRNA expression in T84 cells (n=22,p<0.05). At 50µM and 100µM, KFS1 increased levels of FGF-19 expression by 218.28±196.81 and 93.66±75.16 fold, respectively (n=3). KFS1 also reduced TEER by 60.24%±5.02% and 64.35%±6.18%, respectively (n=7), suggesting it exerts toxic actions at these concentrations. Interestingly, at lower concentrations that did not alter TEER, KFS1, but not GW4064, increased FXR mRNA expression. KFS1 (5µM and 10µM) increased FXR expression by 4.16±0.37 fold and 3.28 ±0.35 fold, respectively (p<0.05;n=4). Moreover, treatment with KFS1 (1, 5, or 10µM) for 1hr prior to treatment with GW4064 potentiated GW4064-induced FGF-19 expression by 2.5±0.76 fold; 2.86±0.21 fold; p<0.01, and 4.64±0.5 fold; p<0.01, respectively (n=6) Conclusion: Our data suggest that KFS1 modulates FXR signalling in colonic epithelial cells. At high concentrations, KFS1 may act as an FXR agonist, which appears to induce cellular toxicity. At lower concentrations, KFS1 increases FXR expression, which may prime cells for agonist-induced FXR activation. These findings suggest that foods, or food supplements, rich in these plant-derived phytochemicals have potential for development as FXR-targeted neutraceuticals.

Where applicable, experiments conform with Society ethical requirements