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Development of “FXR-targeted” Nutraceuticals for Treatment of Intestinal Diseases

RCSI StAR International PhD Programme Research Projects

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Prof S Keely , Dr S Das Applications accepted all year round Competition Funded PhD Project (Students Worldwide)

About the Project

The incidence of intestinal diseases, such as colorectal cancer (CRC) and inflammatory bowel disease (IBD), is significantly higher in Western societies than elsewhere in the world. Research suggests that the development of such diseases involves many inter-related factors, one of the most important of which is our diet. Indeed, diets high in fat and but low fibre are now strongly linked to the development of both intestinal inflammation and cancer. Also emerging as a critical determinant of disease development is the microbiome. This is the vast community of trillions of bacteria that live in our gut and which is now known to play crucial roles in regulating many aspects of our physiology, including metabolism, immunity, and inflammation. The microbiome communicates with us through producing chemical messengers that interact with receptors expressed on the epithelial cells lining the intestinal wall. Important among these messengers are various nutrients from our diet and bile acids which are produced in the liver.

When they enter the colon from the small intestine, the microbiome metabolises nutrients and bile acids, thereby altering their ability to activate specific receptors present on the epithelium. One of these receptors, farnesoid X receptor (FXR), has been shown in preclinical studies to prevent the development of colon cancer and inflammation. With this in mind, FXR has become a hot target for pharmaceutical development.

However, development of synthetic FXR modulating drugs is expensive and risky and there are still no FXRtargeted drugs in clinical trials for the treatment of intestinal disease. Nutraceuticals, or functional foods, provide an alternative approach to treat intestinal disorders. Previous studies in our lab have found that certain chemicals found in common dietary plants (i.e., phytochemicals) can increase levels of FXR expression in intestinal epithelial cells. Given the capacity of FXR to suppress cancer cell growth and dampen inflammation, these findings have important physiological and pathophysiological implications. Thus, diets deficient in FXR-acting phytochemicals could predispose individuals to the development of colon cancer and IBD, while on the other hand, their supplementation to the diet could provide an effective means to treat, or even prevent, the occurrence of these diseases. With this in mind, our laboratory primarily focusses on developing our understanding of how dietary components, the microbiome, and bile acids interact to regulate intestinal physiology and pathophysiology, with a view to exploiting these interactions for disease treatment

This PhD project is based on the hypothesis that, by virtue of their ability to enhance FXR expression in the gut, dietary plant-derived phytochemicals have the capacity to be developed as a new class of “FXRtargeted” nutraceutical. The project consists of three Specific Aims: i) To investigate at the molecular pathways by which certain phytochemicals regulate FXR expression in intestinal epithelial cells, ii) to investigate the effects of FXR-targeted phytochemicals on cell growth, death, and inflammation in the gut, and iii) to test plant extracts rich in FXR-targeted phytochemicals in a preclinical model of intestinal disease.

Overall, we expect this project to further develop FXR-targeted nutraceuticals for the prevention and treatment of intestinal disease.

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