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Gut microbiota and atherosclerosis: a bacterial perspective

Principal Supervisor: Dr Yin Chen, School of Life Sciences

Co-supervisor: Dr Kumar Rajakumar, University of Leicester

PhD project title: Gut microbiota and atherosclerosis: a bacterial perspective

University of Registration: University of Warwick

Project outline:

Research in the past two decades has now convincingly demonstrated that human is a “super-organism”. We coexist with trillions of microorganisms, collectively termed the microbiota. Our microbiota impact dramatically on our development, health and wellbeing. However, besides our understanding the potential of the microbiota to cause infections, our knowledge pertaining to human-centric functional contributions of this community is very limited.

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 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.

References:

  1. Wang et al 2011 Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472:57-63.
  2. Koeth et al., 2013 Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine. 19, 576–585.
  3. 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.

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

  • Cutting edge omics and bioinformatics, e,g. RNA-seq, proteomics;
  • Cloning and construction of expression vectors in E. coli;
  • UV-Vis spectrometry;
  • Marker exchange mutagenesis;
  • Complementation of targeted mutants;
  • Analytic skills, e.g. gas and ion chromatography;
  • Protein overexpression and purification;
  • Batch and continuous culture and mathematic modelling.

Contact: Dr Yin Chen, University of Warwick