About the Project
This PhD project aims to explore a highly topical issue how diet is modified by microorganisms in the gut, affecting the health of the host organism. The human microbiota produces trimethylamine, which is oxidized by the liver. The resultant molecule, trimethylamine oxide, promotes atherosclerotic plaque formation in blood vessels and consequently cardiovascular disease (Wang et al. 2011; Koeth et al., 2013). Trimethylamine production is primarily governed by oral and intestinal microbes through degradation of dietary quaternary amines, such as choline and carnitine, both of which are also essential vitamins for human. Using molecular genetics, biochemistry and bioinformatics approaches, we have recently identified the carnitine-to-trimethylamine metabolic pathway exploited by gut microbiota, including commensal and pathogenic gut microbiota such as Escherichia coli (Zhu et al., 2014). However, several key questions remain. For example, what is the selective advantage for gut microbiota to possess this metabolic activity? Indeed, our comparative genome analyses predict that, in these microbiota, intra- and interspecies variation occurs in the capacity to produce trimethylamine, and that associated gene clusters have arisen through horizontal gene transfer. We hypothesize that beyond its impact on cardiovascular disease, carnitine metabolism contributes to wider bacterium–host interactions, and that this trait also offers yet to be defined evolutionary advantages to the bacterium. This PhD project aims to understand the role of carnitine degradation by gut microbiota from a bacterial perspective. Such information will be invaluable in developing interventions aimed at reducing gut microbiota-mediated trimethylamine production and the burden of cardiovascular disease.
BBSRC Strategic Research Priority: Understanding the rules of life: Systems Biology
Techniques that will be undertaken during the project:
• Cutting edge omics and bioinformatics, e,g. comparative transcriptomics, proteomics;
• Cultivation and maintenance of class 2 bacterial pathogens
• Tissue culture
• Marker exchange mutagenesis of bacterial pathogens
• Analytic skills, e.g. gas and ion chromatography; flow cytometry
• Batch and continuous culture and mathematic modelling.
Koeth et al., 2013 Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine. 19, 576–585.
Zhu et al., 2014 Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota Proceedings of the National Academy of Sciences USA 111: 4268-4273.
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