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

Supervisors: Andreas KolbDr Gordon McDougallKaren ScottClaus-Dieter Mayer

Project Description:

Background
Bile acid metabolism is a critical component of the digestion process. Bile acids emulsify dietary lipids for enzymatic digestion into glycerol and fatty acids, and 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 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, 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 significantly modulate the composition of the bile acid pool, e.g. through bile acid hydrolase which removes the amino acid moiety, altering the biological 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. Other groups have shown similar anti-obesogenic effects of other natural or pharmaceutical compounds which are also associated with a shift in bile acid composition. At present we do not know whether the pharmacological effects on microbiome and bile acid pool composition are dependent on each other, and if so which one of the changes is causal. We have also shown a change 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.

Proposed project
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, caecal and faecal samples from rodent and human experiments. Microbiome composition will be tested using qPCR and next generation sequencing. Plant metabolites will be derived from our stock of plant extracts and from natural product libraries to which we have access. [2] The effect of different microbiomes on the modification of bile acids will be studied in vitro and in vivo using the same model systems. Bile acid composition will be measured using mass spectrometry, HPLC and microbiological assays. The dataset will enable a predictive modelling of bile acid metabolism in response to specific microbiome compositions. This will aid the rational design of probiotics with defined effects on bile acid signalling.

[3] Expression of genes encoding enzymes involved in bile acid synthesis and modification will be analysed in liver and gut cell lines. In addition, tissue samples collected from a rodent experiment. These data will assess the consequences of bile acid composition on signalling pathways relevant to metabolic health.

The project will provide the student with interdisciplinary training in the areas of microbiology (provided in the lab of Dr Karen Scott), natural product chemistry (Dr Gordon McDougall), bioinformatics/statistics (Dr Claus Mayer) and molecular cell biology (Dr Andreas Kolb).

References:

1.     Li, T., Chiang, J.Y.L., 2015. Bile acids as metabolic regulators. Curr. Opin. Gastroenterol. 31, 159–65. doi:10.1097/MOG.0000000000000156.
2.     McDougall, G.J., Allwood, J.W., Pereira-Caro, G., Brown, E.M., Ternan, N., Verrall, S., Stewart, D., Lawther, R., O’Connor, G., Rowland, I., Crozier, A., Gill, C.I.R., 2016. Nontargeted LC-MS n Profiling of Compounds in Ileal Fluids That Decrease after Raspberry Intake Identifies Consistent Alterations in Bile Acid Composition. J. Nat. Prod. 79, 2606–2615. doi:10.1021/acs.jnatprod.6b00532.
3.     Wahlström, A., Sayin, S.I., Marschall, H.-U., Bäckhed, F., 2016. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab. 24, 41–50. doi:10.1016/J.CMET.2016.05.005.

To apply for this project, please go to this link.

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