The impact of soft-fruit phytochemicals on the gut microbiome and bile acid metabolism

Bile acid metabolism is a critical component of the digestion process. Bile acids emulsify dietary lipids to prepare them for enzymatic digestion into glycerol and fatty acids and subsequent absorption into the gut epithelium. Intestinal bile acid concentrations are under a feedback loop control of the enterohepatic cycle. This is possible because bile acids also act as signalling molecules throughout the gut. An increase in bile acids, and hence bile acid signalling, leads to an increase in FGF15/19 expression and secretion, which in turn reduces expression of the key bile acid synthesis gene Cyp7A1.
Disturbance of bile acid synthesis by either overexpressing or inactivating the key enzyme Cyp7A1 in transgenic animals dramatically reduces nutrient uptake and generates resistance to obesity but has significant side-effects. However smaller modulations of bile acid activity can have beneficial effects on metabolic health. Bile acids are synthesized in the liver, stored in the gallbladder and released in response to food intake. As part of the synthesis process bile acids are conjugated to amino acids to increase their solubility. Microbial enzymes modulate the composition of the bile acid pool, e.g. through bile salt hydrolase which removes the amino acid moiety, altering the biological signalling effects of bile acids.
We have recently shown that blueberry extracts have a strong anti-obesogenic effect in mice. This is associated with a dramatic shift in both, intestinal bile acid and microbiome composition. At present we do not know whether the two effects are dependent on each other, and if so which one of the changes is causal. We have also shown changes in bile acid composition in response to soft-fruit supplementation in human intervention trials suggesting that the health benefits seen in rodents can be translated into the human situation.

The proposed project seeks to assess the interaction of soft fruit phytochemicals with the gut microbiota and bile acid metabolism using a combination of experiments in animal model systems, in vitro models of microbial digestion, and human intervention trials.
[1] We will test the effects of plant secondary metabolites on the composition and relevant enzymatic activities of human and rodent microbiomes. This will be done using in vitro experiments using anaerobic microbiological fermentors and, in vivo, using ileal, and faecal samples from rodent and human experiments. Microbiome composition will be tested using next generation sequencing. [2] The effect of different microbiomes on bile acid composition will be studied in vitro and in rodent model systems. Bile acid composition will be measured using mass spectrometry, HPLC and microbiological assays. [3] Expression of genes responsive to bile acid signalling will be analysed in liver, gut and adipose cell lines (and cell-based assay systems based on them) and rodent tissue samples. These data will assess the consequences of bile acid composition on signalling pathways relevant to metabolic health.