Using a Designer Receptor Exclusively Activated by Designer Drug to define the role of short chain fatty acids in metabolic disease and inflammation

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The relationship between diet, well-being and human disease is of considerable public interest and the subject of government health policy. Traditionally this has centred on the correct balance of nutrients where food was simply viewed as fuel or providing essential factors. It is now clear, however, that components of our diet can act as bioactive molecules in their own right, having a direct impact on biological processes. Prominent among the nutrients that act as bioactive molecules are short-chain free fatty acids (SCFAs). These are generated by the fermentation of non-digestible carbohydrates by the gut microbiota; and are proposed to control biological responses such as glucose homeostasis and inflammation. Thus, the SCFAs exemplify the relationship between diet, the microbiota and well-being and as such are of considerable interest to the public, government and pharmaceutical companies targeting obesity, type II diabetes, as well as metabolic and inflammatory diseases. The issue is, however, that we know very little about the modes of action of the SCFAs that act through two G-protein coupled receptors, FFAR2 and FFAR3. This is due to the fact that there are very few pharmacological tool compounds available to probe the in vivo function of these receptors together with the fact animal knockout models are inadequate. In collaboration with our industrial partner, AstraZeneca, we address these key issues by not only generating an array of novel tool compounds to FFAR2/3 receptors but also by generating a novel chemical genetic mouse model (FFAR2-DREADD) that will be used to probe the function of these receptors in glucose homeostasis, metabolism and inflammation. Thus, using the FFAR2-DREADD mice together with FFAR2-KO and FFAR3-KO mice and in conjunction with the novel FFAR2/3 ligands this study aims to not only define the physiological role of SCFAs in mouse but will also establish the therapeutic potential of targeting the FFAR2 and FFAR3 receptors.

Who will benefit from this research?
This programme addresses the relationship between diet, the microbiota and well-being; an area that is currently of general interest to the public where there is an understanding that controlling the microbiota with probiotics has an impact on health. Miller, Milligan, and Tobin are experienced in public engagement (press releases/popular media), hence dissemination of the results to the general public will facilitate the broad impact of our studies. Associated with this is the possibility that the data generated here might have impact on government health policy particularly in the area of diet and well-being. The most immediate beneficiaries from the research, however, will be our industrial partner AstraZeneca. Although the work detailed in the proposal will be made publically available, AstraZeneca will have immediate access to the results, in advance of public presentation. This is likely to provide AstraZeneca benefits commensurate with their contribution to the project both via direct funding and 'in-kind' contributions. Once the work has been made publically available then the next set of beneficiaries will be the wider pharmaceutical industry. There is considerable interest in whether acute or more sustained pharmacological manipulation of FFAR2 and/or FFAR3 might result in effective control of both gut inflammatory and metabolic diseases and the studies that will be performed are likely to shed considerable light on these topics. The third group of beneficiaries from this research are the neutraceutical and food industries. This reflects their interest in the potential effectiveness of both pre- and pro-biotic strategies to maintain or improve health and the developing concept of 'functional foods'.

How will they benefit from this research?
The general public and government agencies will certainly benefit from a clearer understanding of the impact of diet on well-being. This might affect public dietary habits and government policy on good nutrition. The results will certainly benefit the pharmaceutical industry as a whole, many of who are targeting free fatty acid receptors in the control of obesity, type II diabetes and inflammation. Thus, validation of FFAR2 and FFAR3 as targets in these indications will benefit these companies. The simple fact AstraZeneca have provided support to allow for an Industrial Partnership Award highlights the strategic decision of the company to invest in fully defining the therapeutic potential of FFAR2 and FFAR3. Rapid access to the research findings will allow more informed decisions at a corporate level about investment in efforts to identify lead and candidate molecules to target FFAR2/3. Other pharmaceutical companies will benefit in a similar way, although without such immediate access to the results. Any drug discovery programme targeting chronic diseases such as diabetes and inflammation of the lower gut is inherently a long term endeavour (8-12 years) but the work proposed certainly has the potential to impact on quality of life and healthy aging. It is generally easier to obtain regulatory clearance in some aspects of 'food and nutrition', so it is possible, therefore, that the research here would impact decisions in the food and nutrition industries in a 3-5 year time scale.
The project also has great potential in terms of staff training in that the PDRAs will benefit from opportunities to perform cutting edge research in a broad swathe of areas relevant to modern pharmacological studies, to enhance team working via the need to integrate work from two sites and three laboratories, and to interact directly with staff within a major international pharmaceutical company. This training is likely to be optimal to ensure the greatest range of subsequent career opportunities.