Understanding the interplay between fermentable carbohydrate, colonic short chain fatty acid profile and gut hormone release

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In England, 60% of the adult population is overweight or obese. The situation is alarming due to the side effects of excessive fat storage which are health risks for cardiovascular disease, diabetes, and even cancer. The health risk associated with obesity is not just related to total amount of fat but the where in the body the fat is stored. There for it becomes a priority to understand how dietary components can maintain energy homeostasis across the lifespan.An important dietary component that is present at much lower levels in modern diets compared to that of our ancient ancestors, the hunter-gatherers, is fermentable carbohydrates. Fermentable carbohydrates, obtained from eating foods high in fibre, are not digested and so enter the colon, where they are available for fermentation by resident gut bacteria. Diets high in non-digestible carbohydrate that is fermented in the colon, has a beneficial effect on the structure of the fat tissue and its distribution in the body. Important products of the fermentation process are short chain fatty acids (SCFAs) and there is increasing evidence that they mediate the beneficial effects of dietary fermentable carbohydrate. We will focus our study on how food structure will impact on how the distinct sites in the gut processes carbohydrates (both amount and physical form) in to SCFAs. Cells communicate to each other by sending and responding to chemical messages. SCFAs are a set of many different kinds of messages that act through cell surface receptors called G protein-coupled receptors (GPCRs), so called due to the mechanism of how these receptors transmit chemical messages in to the cell. The SCFAs activate two distinct GPCRs, FFA2 and FFA3. Although many currently prescribed drugs target some of these GPCRs, there is a high demand for drugs where treatments are more specific, have fewer side effects, and that are active for longer. To do this we must first understand the molecules that make up the cell machinery controlling the activity of these receptors. Although it is known that SCFAs can cause the gut hormone-producing cell of the colon, the enteroendocrine cell, to increase in number, very little is known about the way different SCFAs induce signals via their GPCRs in these enteroendocrine cells and where these receptors are located. Therefore further key goals of this project is to understand the signal pathways in the cells that these receptors activate in response to alterations in SCFAs. We will also develop novel biochemical tools to understand location of the receptor across enteroendocrine cells. Both timing and location of GPCR signals will be studied as it is critical for programming cells, telling it whether to release more hormone, activate particular genes, divide, or even die. Using food structure to target SCFA production at a specific site of the colon could be an important population-wide intervention to maintain energy homeostasis. This project will lead to not only a greater understanding on the impact of SCFAs on entroendocrine cells but also identify potential nutrition and drug targets. The project will give a deep understanding of the how dietary carbohydrate structure impacts of colonic appetite signalling through interventional studies in humans. It will use novel chemical biological probes and to unpick receptor signalling to different SCFA