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Mining and Modelling the Human Gut Microbiome to Elucidate its Metabolic Potential

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  • Full or part time
    Dr S Duncan
    Dr P Louis
    Dr Grietje Holtrop
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

Supervisors: Dr Sylvia Duncan, Dr Petra Louis and Dr Grietje Holtrop (Rowett Institute of Nutrition & Health)

The human large intestine harbours a dense population of bacteria many of which have important roles for the both gut and general health. The human gut microbiota largely live on dietary non-digestible carbohydrates and peptides, which are mainly fermented to primary metabolites such as short-chain fatty acids (SCFAs; acetate, propionate and butyrate) and gases (Flint et al, 2015; Louis & Flint, 2017). The main SCFAs are taken up by the gut mucosa and have important impacts on host physiology, as regulators of gene expression and as signalling molecules. Propionate contributes to gluconeogenesis in the liver and has been linked to satiety and reduction of cholesterol. Butyrate is used preferentially as an energy source for the colonocytes and protects against colorectal cancer.

Other bacterial fermentation products such as lactate can be produced by many different gut bacteria, including bifidobacteria, however lactate does not usually accumulate to high levels in healthy individuals. In certain disease states, in particular in severe Inflammatory Bowel Disease (IBD), however, lactate has been found to accumulate, while SCFA levels are reduced (Vernia et al, 1988). This goes hand in hand with changes in microbiota composition away from the profiles usually seen in healthy individuals. It is therefore important to understand the processes in the microbiota underlying the shift towards lactate production, in order to develop novel prevention and treatment strategies for IBD. Certain, crucial species are effective at consuming and cross feeding on lactate and acetate to produce usually either butyrate or propionate.

To date there is a reasonably good understanding of primary short chain fatty acid metabolism from studies in cultures anaerobes, however there is considerable scope to increase our understanding using genomic information as it becomes available. This will also help to inform the development of our mathematical model (Kettle et al, 2014). Moreover, much less is known about secondary metabolites that may be formed by gut bacteria from short chain fatty acids, which is present in high levels in the human colon and may be used as building blocks for certain bacterial secondary metabolites and will be investigated in this project. Mining available genomes should allow us to discover novel secondary metabolites which may have biotechnological application.

Aims:

In this project we address the need to further understand the complex metabolic networks formed by bacteria in the human large intestine to promote health. The work proposed here will entail co-culture experiments between consortia of different human gut bacteria to investigate their metabolic interactions, as well as complete faecal microbiota studies in continuous culture fermentors. Molecular approaches will be employed to follow changes in microbiota composition and/or activity. A mathematical model of human microbiota metabolism that has recently been developed will be utilised to enable computer simulations of different scenarios to inform on design of laboratory-based experiments. We will also begin to investigate the microbial metabolic routes for gut bacterial secondary metabolites, which use short chain fatty acids as building blocks, as this may have the potential to identify novel metabolites with commercial application.

Approaches:

The project is multi-disciplinary and will embrace microbiology, biochemistry, advanced molecular biology techniques, bioinformatics and mathematical modelling approaches to understand the microbial metabolic networks that occur in the human large intestine.

Training:

Students will receive training in handling strict anaerobes, as the Rowett Institute of Nutrition & Health has an extensive and unique collection of representative gut bacteria, continuous fermentation, molecular microbiology techniques, bioinformatics and mathematical modelling.

Application:

Please select ’Degree of Doctor of Philosophy in Human Nutrition (Medicine)’ from the list of programme options in the University of Aberdeen’s online postgraduate applicant portal to ensure that your application is passed to the correct school for processing. Then manually enter the name of the supervisor(s), project title and funder (Elphinstone) in the space provided.

Funding Notes

This project is part of a competition funded by the Elphinstone Scholarship Scheme. Successful applicants will be awarded full tuition fees (UK/EU/International) for the duration of a three year PhD programme. Please note that this award does not include a stipend.

This award is available to high-achieving students. Candidates should have (or expect to achieve) a minimum of a First Class Honours degree in a relevant subject. Applicants with a minimum of a 2.1 Honours degree may be considered provided they have a Distinction at Masters level.

References

(1) Flint HJ, Duncan SH, Scott KP, Louis P (2015) Links between diet, gut microbiota composition and gut metabolism. Proc Nutr Soc 74: 13-22.

(2) Louis P, Flint HJ (2017) Formation of propionate and butyrate by the human colonic microbiota. Env Micro 19: 29-41.

(3) Kettle H, Louis P, Holtrop G, Duncan SH, Flint HJ (2014) Modelling the emergent dynamics and major metabolites of the human colonic microbiota. Environ Microbiol 17: 1615-1630.

(4) Vernia P, Caprilli R, Latella G, Barbetti F, Magliocca FM, and Cittadini M (1988) Fecal lactate and ulcerative colitis. Gastroenterology 95: 1564–1568.

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