Introduction: Bile acids, classically known for their roles in dietary fat absorption are now recognised as hormones critical to regulating intestinal and metabolic function, 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 intestinal epithelium occurs in inflammatory bowel disease, colorectal cancer, obesity and diabetes, whereas FXR activation prevents disease progression in pre-clinical models. Thus, strategies to upregulate epithelial FXR expression have been proposed to treat such conditions. Previous studies suggest that a particular class of plant-derived phytochemicals, denoted KFS1, modulates FXR activity. Plant sources have been reported to contain these phytochemicals, such as KFS1, which are proposed to have FXR modulatory activity. Aim: The aim of the current study was to investigate the potential for developing plant extracts, rich in phytochemicals, such as KFS1, as a new novel nutraceutical-based approach to treat and prevent intestinal and metabolic diseases. Methods: T84 colonic epithelial cells and primary cultures of murine epithelial colonic enteroids were employed to examine the effects of a common-dietary phytochemcial, KFS1, and a KFS1-rich plant extract on FXR expression and FXR signaling in vitro. Ex vivo studies were carried out on human colonic tissue obtained during endoscopy with ethical approval from Beaumont Hospital. In vivo studies in C57BL/6 mice were carried out and proximal colonic tissue were examined with ethical approval from the HPRA. Expression of FXR and FGF19/15, an established marker of FXR activation, was assessed by qRT-PCR, ELISA and immunoblotting. Data are expressed as mean ± SEM for a series of n experiments. Results: KFS1 treatment (5 µM; 24hrs) increased FXR mRNA and protein expression in T84 cells by 4.2 ± 0.4 (p<0.05; n = 4) and 1.7 ± 0.1 fold (p<0.05; n = 7), respectively. KFS1 also enhanced FGF-19 protein expression, an established marker of FXR activity, in response to the FXR agonist, GW4064 (5 µM), by 4.1 ± 0.5 fold (p<0.001; n = 7). Similarly, KFS1 significantly upregulated FXR expression by 2.1 ± 0.4 fold in human biopsies (p<0.05; n = 6). Oral KFS1 administration to mice had a tendency to upregulate colonic epithelial FXR signalling in vivo and increased FXR expression and GW4064-induced FGF15 mRNA by 2.3 ± 0.2 (p<0.01; n = 4) and 2.2 ± 0.1 fold (p<0.01; n = 4) in murine epithelial colonic enteroids. Finally, a methanolic KFS1-rich plant extract, denoted QE1, verified by LC/MS to contain KFS1, increased FXR protein expression in T84 cells by 1.8 ± 0.2 fold (p<0.05; n = 5) and enhanced GW4064-induced FGF19 protein release by 1.9 ± 0.1 fold (p<0.01; n = 9). Conclusion: In conclusion, our data demonstrate that KFS1-containing plant extracts modulate expression and activity of the nuclear bile acid receptor, FXR, in the intestinal epithelium. Given the critical role of FXR in maintenance of gut health and metabolic function, 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 and metabolic disorders.