Understanding how the bitter taste receptor, T2R38, regulates the intestinal epithelium - a study from microbiota to the intestinal epithelium

Research Group

Biomedical Research Group

Proposed supervisory team

Dr Havovi Chichger

Theme

Cardiovascular

Summary of the research project

Increased gastric permeability is associated with metabolic diseases such as diabetes and obesity. Maintenance of a healthy, intact intestinal epithelial barrier is vital to prevent inflammation and septicemia seen in these diseases. The intact barrier is preserved through the formation of junctional complexes between intestinal epithelial cells. We have recently shown that the activation of sweet taste receptors, by sweeteners, increases leak across the intestinal epithelium by breakdown of these junctional complexes. We have further demonstrated that sweeteners increase the ability of model bacteria, in the gut microbiota, to damage intestinal epithelial cells. In contrast, far less is understood about bitter taste sensing in the intestinal epithelium, despite the high number of bitter taste receptors in the G-protein coupled receptor family. Interestingly, increased expression of bitter taste receptor T2R38 observed in the specialized gastrointestinal tract cells of obese patients. Preliminary studies from the laboratory, using intestinal epithelial cells, show that stimulation of T2R38, by phenylthiourea, increases breakdown of tight junctions maintaining the epithelial barrier and increased leak. The research project will therefore address the hypothesis that bitter taste sensing regulates the intestinal epithelium through acting on microbiota and intestinal epithelial cells. By understanding the mechanisms regulating these processes, we aim to develop novel therapeutic targets to improve intestinal epithelial barrier function and therefore reduce inflammation and septicaemia in patients with metabolic disease.

Methodology

To test this hypothesis, studies will be performed using a combination of microbiology and cell culture studies using two model gut bacteria (E.coli NCT, E. faecalis) and a transformed cell model of the intestinal epithelium (Caco-2 cells). These two models, currently used in the laboratory, will be studied as a co-culture using bitter taste agonists to study the functional response. Key outcomes are changes in metabolism or pathogenic effect of bacteria on the epithelium and breakdown of the intestinal epithelial barrier.

Expected outcomes

Findings from the project will demonstrate the molecular mechanisms through which activation of bitter taste receptors can regulate function of the intestinal epithelium. This investigation is anticipated to demonstrate that taste receptors represent novel therapeutic targets in the treatment of inflammation and septicaemia in patients with metabolic diseases.

Where you'll study

Cambridge

Funding

This project is self-funded.

Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website as they become available.

Next steps

If you wish to be considered for this project, you will need to apply for our Biomedical Science PhD. In the section of the application form entitled 'Outline research proposal', please quote the above title and include a research proposal.