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Unpicking the role of bacteriophage in the gut microbiome in health and disease

Principal Supervisor: Dr Eleanor Jameson, School of Life Sciences

Co-supervisor: Professor Orkun Soyer, School of Life Sciences

Co-supervisor: Prof Arjan Narbad, Quadram Institute Bioscience

PhD project title: Unpicking the role of bacteriophage in the gut microbiome in health and disease

University of Registration: University of Warwick

Project outline:

The gut microbiome consists of viruses, bacteria, archaea and eukaryotes, this project seeks to understand the role of viruses. To date research effort has focused on bacteria, however the gut virome remains underexplored, even though the viral (bacteriophages) interactions are intrinsically linked to the dynamics of the gut microbiome. Bacterial metabolites from the gut are linked to diseases, including; cardiovascular disease, irritable bowel disease, diabetes, autism, and cancer. The metabolic capacity of the gut microbiome is immense and plays key roles in both health through host digestion and nutrition and disease. Recent advances in high-throughput sequencing is allowing an insight into the community structure of the microbiome in health and disease (Wang et al 2011, Marchesi et al 2015). Metagenomics has allowed correlations to be drawn between bacterial families and health. However, this work is still in its infancy andmisses essential, fine details. Often the bacteriophage, archaea and fungi are overlooked, yet they play key roles in the microbiome structure with bacteriophage numbers surpassing the number of bacteria present in the gut.

Phage therapy (the use of phages as antimicrobials) is a viable alternative to antibiotics and this project will help understand the impacts of phage therapy on the gut microbiome to inform future medical and farming practices. Phage therapy has been utilised in countries including Georgia, Poland and Russia since 1919. Due to the rise in global concern of antimicrobial resistance (AMR) phage therapy has undergone a resurgence in the West and is now being practiced for treatment of recalcitrant bacterial infections. Furthermore, the impact of daily dietary and environmental phages entering the gut and the use of phages as a prophylaxis against microbiome related diseases is poorly understood. This project will explore the use of natural and synthetic communities of phages to engineer a healthier microbiome. Natural communities of phages will be isolated from compost heaps, sewage, fresh, esturine and marine waters to cover a range of environments. Using stool sample cultures, the student will investigate the effects of natural phage communities, and characterised phages, on the microbiome and their metabolite profile, to further understand the roles of key phage.

The methods used during this PhD project will begin to unravel the importance of bacteriophage and how they influence microbiome community dynamics and metabolic function. A number of bacteriophage capable of infecting opportunistic pathogens are available at Warwick and can readily be isolated from water samples by plaque assay on lawns of host bacteria. The recovery of natural bacteriophages requires the removal of large cellular material by centrifugation and filtration, then concentration with protein centrifugation columns. The phage will be characterised through infect assays on a plate reader, electron microscopy to identify morphology and sequencing. Isolated and characeterised phages will be added to the validated in vitrocolon model system at at QIB (Mandalari et al 2008), which accurately replicates the microbiological and physiological conditions of the large intestine. Modulation of the gut microbiome structure and function will be assessed by shotgun metagenomic sequencing of eh gut microbiome and by metabolomics of the cell-free culture supernatants using 1H-NMR based metabolomics. These model systems have already been tested for evaluating the phage therapy against Clostridium difficile infections (Meader et al 2013). These techniques will shed light on the impact and roles of phages on the gut microbiome.

The project will seek to understand overall changes to the gut microbiome with increased phage loads. This will involve analysis of the bacteria, archaea, eukaryotes and viruses and their metabolites in response to phage treatments in gut microbiome microcosms.

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

  • Microbiology - class II work
  • Synthetic communities
  • Batch and continuous culture
  • Phage isolation
  • UV-Vis spectrometry
  • Electron microscopy, i.e. TEM
  • Analytic skills, e.g. gas and ion chromatography; flow cytometry
  • DNA extraction
  • Next generation sequencing
  • Bioinformatics – metagenomics and metabolomics

Contact: Dr Eleanor Jameson, University of Warwick