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Understanding inhibition of the gut microbiota metabolism of carnitine by pomegranate (KROON_Q22DTP)


   Graduate Programme

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  Dr P Kroon  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

The human gut microbiota is actively involved in the metabolism of dietary compounds, often into metabolites that benefit the host (e.g. short chain fatty acids). However, the gut microbiota-dependent formation of trimethylamine (TMA) from L-carnitine and choline results in an atherogenic metabolite, TMA-N-oxide (TMAO). Plasma TMAO levels are strongly associated with several causes of death (e.g. heart failure) and with diseases such as diabetes, Alzheimer's and chronic kidney disease. There is no effective, sustainable treatment for reducing TMA(O) levels. But, we have recently shown substantial inhibition of gut microbial L-carnitine metabolism by a polyphenol extract. The aim of this studentship is to develop a mechanistic understanding of how the polyphenols interact with the gut microbiota and inhibit their ability to metabolise carnitine and generate TMA(O).

We have recently shown that an in vitro model of the human colon authentically replicates the metabolism of L-carnitine and choline observed in vivo (Day Walsh et al., 2021), and the student will use this to investigate (1) which compounds in the polyphenol extract inhibit L-carnitine metablism to TMA and (2) understand the mechanisms of action. The student will receive training in using colon models to investigate L-carnitine metabolism, shotgun metagenomics and bioinformatics analysis of gut microbiota communities, PCR and qRT-PCR assays for target microbial genes, and use of LC-MS/MS and LC-TOF-MS platforms for analysing polyphenol and L-carnitine metabolites.

This project will suit a student interested in fundamental research that links gut microbiota and health, and in undertaking pre-clinical work that is highly translational. The student will join the Kroon group in the Food Innovation and Health Programme and work closely with the Narbad group (expertise in gut microbial ecology). The Quadram Institute is part of the Norwich Research Park and is home to a large cohort of PGR students and researchers.

The Norwich Research Park Biosciences Doctoral Training Partnership (NRPDTP) is open to UK and international candidates for entry October 2021 and offers postgraduates the opportunity to undertake a 4-year PhD research project whilst enhancing professional development and research skills through a comprehensive training programme. You will join a vibrant community of world-leading researchers. All NRPDTP students undertake a three-month professional internship placement (PIPS) during their study. The placement offers exciting and invaluable work experience designed to enhance professional development. Full support and advice will be provided by our Professional Internship team. Students with, or expecting to attain, at least an upper second class honours degree, or equivalent, are invited to apply.

This project has been shortlisted for funding by the NRPDTP programme. Shortlisted applicants will be interviewed on Tuesday 25th January, Wednesday 26th January and Thursday 27th January 2022.

Visit our website for further information on eligibility and how to apply: https://biodtp.norwichresearchpark.ac.uk/

Our partners value diverse and inclusive work environments that are positive and supportive. Students are selected for admission without regard to gender, marital or civil partnership status, disability, race, nationality, ethnic origin, religion or belief, sexual orientation, age or social background.


Funding Notes

This project is awarded with a 4-year Norwich Research Park Biosciences Doctoral Training Partnership (NRPDTP) PhD studentship. The studentship includes payment of tuition fees (directly to the University), a stipend for each year of the studentship (2021/2 stipend rate: £15,609), and a Research Training Support Grant for each year of the studentship of £5,000 p.a.

References

Day-Walsh et al (2021) The use of an in-vitro batch fermentation (human colon) model for investigating mechanisms of TMA production from choline, L-carnitine and related precursors by the human gut microbiota. Eur J Nutr; https://doi.org/10.1007/s00394-021-02572-6.
Rajakovich et al (2021) Elucidation of an anaerobic pathway for metabolism of L-carnitine–derived γ-butyrobetaine to trimethylamine in human gut bacteria. PNAS 118 (32) E210149811. https://doi.org/10.1073/pnas.2101498118.
Israr et al (2021) Association of gut-related metabolites with outcome in acute heart failure. Am Heart J 234, 71-80. https://doi.org/10.1016/j.ahj.2021.01.006.
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