Dietary regulation of the signalling molecule FGF15 in the ileum and its effect on the gut-liver axis

The intestinal hormone Fibroblast Growth Factor 19 (FGF19, rodent homologue FGF15) has recently been linked to both positive and negative health outcomes. The expression of FGF15/19 is regulated by the bile acid-sensing transcription factor farnesoid X receptor in the ileum. After its production, this enterokine travels to the liver where it blocks de novo bile acid production via CYP7A1. Circulating FGF15/19 levels are known to rise postprandially which can influence both blood cholesterol and glucose levels. However, the influence of dietary patterns on the regulation of FGF15/19 expression is largely unknown. \n \nIn this thesis, dietary regulation of FGF15 is explored in rodent studies. Mice fed a high starch (HS) diet showed increased expression of FGF15 compared to mice fed a chow control diet. The importance of starch digestion was confirmed by acarbose treatment, which inhibited both starch digestion and FGF15 expression. Further, increased glucose in the ileum was shown to induce the expression of FGF15. Importantly, this regulation was found to be independent of the microbiota. In addition, in mice fed HS diets supplemented with soluble fibres, FGF15 expression was suppressed. This latter effect may also contribute to the known cholesterol-lowering effects of soluble fibres. \n \nWhile the HS diet induced the expression of FGF15, this work highlights the long-term negative health effects of such a diet, showing dysregulation of the gut-liver axis in our mouse model that eventually led to increases in cell proliferation, and, in some mice, the development of hepatic carcinoma. Reducing HS diets in a caloric restriction(definition) (CR) model counteracted these negative health effects and in the long term downregulated the expression of FGF15. Decreased FGF15 expression correlated with a reduction in ileal bile acids in the CR model. \n \nIn conclusion, we showed that increased luminal glucose reaching the ileum, consumption of soluble fibre, and long-term CR influenced the expression of the important gut-hormone FGF15. This influence on its regulation may influence gut-liver health with a profound impact on systemic bile acids and cholesterol levels.