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

Applications are invited for this self-funded 36 Month project within the Rowett Institute at the University of Aberdeen.

Background:

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.

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 have collected 16S sequencing data of the gut microbiome in a mouse model system. The data derived from this study will be analysed using suitable bioinformatic tools. The dataset will be compared with other available datasets from mouse and human studies.
2. We will directly test the effects of plant secondary metabolites on the composition and relevant enzymatic activities of synthetic microbiomes relevant to the human gut in anaerobic microbiological fermentors.
3. The effect of different microbes and microbiomes on bile acid composition will be studied using mass spectrometry, HPLC and cell-based assays.
4. Expression of genes responsive to signalling by different bile acids will be analysed in liver and gut cell lines, and rodent tissue samples. 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 (Dr Karen Scott), bioinformatics (Dr Claus Mayer), natural product chemistry, and molecular cell biology (Dr Andreas Kolb).

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

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Applicants to this project should hold a minimum of a 2:1 UK Honours degree (or international equivalent) in a relevant subject.

We encourage applications from all backgrounds and communities, and are committed to having a diverse, inclusive team.

Informal enquiries are encouraged, please contact Dr Andreas Kolb (a.kolb@abdn.ac.uk) for further information.

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APPLICATION PROCEDURE:

Please note: This is a self-funded opportunity.

• Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php
• You should apply for Medical Sciences (PhD) to ensure your application is passed to the correct team.
• Please clearly note the name of the supervisor and the project title on the application form. If this is not included, your application may not be considered for the project.
• Candidates should have (or expect to achieve) a minimum of a 2:1 UK Honours degree (or international equivalent) at undergraduate level.
• Your application must include: a personal statement, an up-to-date copy of your academic CV, and clear copies of your educational certificates and transcripts.
• If you are still undertaking your undergraduate degree, it is helpful to the selection panel if you could provide documentation showing your grades to date (this can be a screenshot from an online portal).
• Please note: Project supervisors will not respond to requests for funding assistance.
• If you require any additional assistance in submitting your application or have any queries about the application process, please don't hesitate to contact us at pgrs-admissions@abdn.ac.uk