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Identifying the microbes at the heart of disease

Principal Supervisor: Dr Eleanor Jameson, School of Life Sciences

Co-supervisor: Dr Yin Chen, School of Life Sciences

PhD project title: Identifying the microbes at the heart of disease

University of Registration: University of Warwick

Project outline:

Collectively the bacteria in the human gut form a complex community known as the gut microbiome. The metabolic capacity of the gut microbiome is immense and has been linked to a wide variety of diseases. There has been huge research focus high-throughput sequencing the whole gut microbiome through 16S rRNA and metagenome sequencing allowing an insight into the community structure of the microbiome in health and disease (Wang 2011, Bennett 2013, Koeth 2013). This work is still in its infancy and this approach may miss essential, fine details. There is a need to understand the roles of key gut microorganisms in greater detail to inform medical science how to treat gut-related diseases.

This PhD project will tackle the issue of which key organisms in the microbiome contribute to cardiovascular disease in response to dietary changes. Bacterial trimethylamine production from dietary precursors such as choline and carnitine is implicated in atherosclerosis. This bacterial trimethylamine is absorbed through the gut and oxidised by the liver to trimethylamine oxide, which promotes atherosclerotic plaque formation in blood vessels and consequently cardiovascular disease (Wang et al 2011; Koeth et al 2013). Gregory et al (2015) showed that gut microbiota from different mice vary in their potential to cause atherosclerosis and can transmit atherosclerosis. Using a range of bioinformatics, molecular and microbiology techniques we have identified the novel enzymes responsible for the formation of trimethylamine from human gut microbiota, including choline-TMA lyase, CutC (Craciun and Balskus 2012, Jameson et al 2016a), and carnitine monooxygenase, CntAB (Zhu et al 2014). Using knowledge of these enzymes we carried out data mining analyses of existing human gut metagenomes that showed a number of Enterobacteraceae, particularly Klebsiella were prevalent in human guts and contained both the choline and carnitine degradation pathways for TMA production (Jameson et al 2016b). However the presence of the machinery for trimethylamine production in these gut bacteria sequences is insufficient to prove they contribute to in situ trimethylamine production or cardiovascular disease.

The project will seek to understand overall changes to the gut microbiome with increased dietary intake of choline. This will involve analysis of the bacteria, archaea and viruses that respond to choline in gut microbiome microcosms and identify the metabolically active organisms with stable isotope probing. This PhD project will investigate which bacteria can use the carbon from choline for active growth and therefore produce trimethylamine, contributing to cardiovascular disease.

Reference:

  • Wang et al 2011 Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472: 57-63.
  • Koeth et al 2013 Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine 19: 576–585.
  • Bennett et al 2013 Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell metabolism 17: 49-60.
  • Gregory et al 2015 Transmission of atherosclerosis susceptibility with gut microbial transplantation. Journal of Biological Chemistry. 290: 5647-5660.
  • Zhu et al 2014 Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota PNAS 111: 4268-4273.
  • Jameson et al 2016a Anaerobic choline metabolism in microcompartments promotes growth and swarming of Proteus mirabilis. Environmental Microbiology 18: 2886-2898.
  • Jameson et al 2016b Metagenomic data-mining reveals contrasting microbial populations responsible for trimethylamine formation in human gut and marine ecosystems. Microbial Genomics 2 (9).

BBSRC Strategic Research Priority: Food Security & Molecules, Cells and Systems

Techniques that will be undertaken during the project:

  • Cutting edge omics and bioinformatics, e,g. metagenomics, proteomics
  • UV-Vis spectrometry
  • Stable isotope probing
  • Next generation sequencing
  • Analytic skills, e.g. gas and ion chromatography
  • Flow cytometry
  • Batch and continuous culture and mathematic modelling

Contact: Dr Eleanor Jameson, School of Life Sciences, University of Warwick