Association of microbial bile acid metabolism with inflammatory bowel disease
The deadline for 2012 Doctoral College Studentships has now passed.
The Brighton Doctoral College is pleased to welcome applications from self-funded or externally sponsored students for programmes of research in this or a closely related area, beginning from September 2012. Applications are welcome from students wishing to study full time or part time, and applications are welcome from students in employment who have the support of their employers.
- Based in the Faculty of Science and Engineering
- Supervisors: Dr Brian Jones; Dr Lesley Ogilvie.
Application deadline
The university cannot guarantee that students can start at their requested date unless deadlines are met.
- UK/EU students: The deadline for the university to receive applications for an entry date of October is the 1 August, for January entry it is the 1 November and for May it is the 1 March.
- International students: The deadline for the university to receive applications for an entry date of October is the 1 June, for January entry it is the 1 September and for May it is the 1 January.
Bile acids (BA) are cholesterol derivatives synthesised in the liver and conjugated with either glycine or taurine.
The physiological functions of BA are diverse and include metabolic and immune regulation, via activation of the nuclear receptor Farnesoid-X-Receptor α (FXR), or the membrane receptor TGR5, for which bile acids are the natural ligands. Of particular significance to inflammatory bowel disease (IBD) are the recent findings that administration of synthetic FXR agonists affords multi-level protection against intestinal inflammation in mouse models of IBD. Bacteria resident in the human GI tract collectively encode a distributed pathway of BA modification. These modified BA display altered binding profiles for BA receptors, and microbial transformation could also influence BA bioavailability for receptor binding. Therefore, the capacity for bile acid modification in the gut microbiome has the potential to influence FXR signaling and mucosal immune regulation relevant to IBD pathogenesis. The well established dysbiosis of the gut microbiome in IBD, and the proposed role of the gut microbiota in IBD pathogenesis, highlight the need for further investigation of FXR modulating activities of this community in heath and disease.
The aim of this studentship is thus to identify any relationship that exists between the capacity for bile acid modification in the human gut microbiome and acquisition of Crohn’s disease (CD). In doing so, the studentship will explore the diagnostic potential of this activity, as well as examine the detailed genetic basis for bacterial bile acid modification and its impact on host cells. Based on the hypothesis that bile acid modification by bacteria resident in the human gut is important in the pathogenesis of inflammatory bowel disease, the specific objective are:
- Survey of community structure in the gut microbiomes of healthy individuals and those with CD.
- Determine the diversity and abundance of key genes involved in bile acid modification (Fig 1), and the capacity for bile acid modification in the gut microbiomes of healthy individuals and those with CD.
- Elucidate mechanisms involved in bacterial bile acid modification, identify accessory genes and assess impact on interaction with host cells and activation of FXRα.
The project will utilise a systems level approach to assess the capacity for bile acid modification in the gut microbiomes of patients with CD. This will include the construction and screening of gut metagenomic libraries, survey of community structure by 16S pyrosequencing, as well as the quantification of genes involved in bile acid modification by qPCR and amplicon-pyrosequencing approaches. The resulting data will be coupled with novel bioinformatic analyses of existing genomic and metagenomic data sets, as well as new sequence data generated here.
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