DIETARY FIBRES REGULATE BILE ACID METABOLISM INDEPENDENT OF THE MICROBIOTA BY SUPPRESSING THE PRODUCTION OF SIGNALLING MOLECULE FGF15 IN THE ILEUM

Abstract

Dietary fibres alter the microbiota and are linked to lower cholesterol levels. In the liver, bile acids are produced from cholesterol and excreted into the duodenum, where they enable lipid digestion. After reaching the ileum most bile acids are re-absorbed, and induce the expression of signalling molecule FGF19 (Fgf15 in mice). FGF15/19 travels to the liver where it inhibits CYP7A1, the rate-limiting enzyme in de novo bile acid synthesis. Here we investigated the effects of dietary fibres on bile acid metabolism in the small intestine and liver. Mice were fed a chow or a fibre-free diet (FFD) for up to 6 months. Some mice were treated with broad-spectrum antibiotics and a subset of mice on the FFD were supplemented with fructooligosaccharides (FOS) with or without antibiotics. Bile acids were measured using HPLC, gene expression was measured using Q-PCR and the microbiota was analysed using 16S sequencing.The expression of Fgf15 was increased on the FFD at all time points (3 days to 6 months), while the absorbance of bile acids, as measured by gene expression and bile acid secretion, was not changed during the early (up to 2 weeks) timepoints. Although we observed large differences in small intestinal microbiota between the diets, this did not cause the change in Fgf15 expression. Depleting the microbiota with antibiotics did not change the effect of the FFD on Fgf15. Supplementing mice on the FFD with FOS in their drinking water led to a decrease in Fgf15 expression, in both conventional and antibiotic treated mice. Cyp7a1 was consequently induced by the fibre-rich diets (chow and added FOS in drinking water).In conclusion, dietary fibres modulate the expression of Fgf15 independent of the microbiota and via this mechanism play an important role in bile acid and cholesterol homeostasis