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.
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.