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

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

In England, 60% of the adult population is overweight or obese. There is an urgent need to understand how dietary components effect appetite regulation. Research from our group, has demonstrated that increased dietary intake of fermentable carbohydrate promotes weight loss. We have also demonstrated that high intakes of carbohydrates enter the colon and are fermented by the microbiotia producing short chain fatty acids (SCFAs), stimulating the release of the anorectic gut peptides PYY and GLP-1 from enteroendocrine cells. Using a novel method to deliver the SCFA propionate to the colon we have shown release of PYY and GLP-1 with a reduction in food intake. However little is known how food structure influences SCFA production. It can be hypothesized that the form of diet could impact on the ileum content and subsequent SCFA production in the colon, and thus the release of PYY and GLP-1. The colon has the highest density of enteroendocrine cells that produce PYY with an increasing gradient from the ascending colon to the rectum. Therefore fermentation of carbohydrate in the transverse and descending colon may stimulate greater production of PYY and GLP-1 via altered SCFA production. SCFAs, acetate, propionate and butyrate, in the colon signal via two distinct G protein-coupled receptors, FFA2 and FFA3, whose activity in the gut is poorly characterized. Our data suggests that exposing the colon to SCFAs increases entroendocrine cell differentiation specifically via FFA2. Crucially, very little is known about both receptor distribution and the intracellular signaling pathways controlling enteroendocrine cell function. In this project we will employ both in vivo and in vitro human colon and organoid systems and multidisciplinary technologies to identify, i) the impact food structure makes on the site and production of SCFA and ii) mechanistic regulation of SCFA action in the human colon and its potential reprogramming by diet.

This project aims to address one of UKs major diet-related health challenges, obesity. In this project we want to understand the relationship between food structure and carbohydrate driven release of PYY and GLP-1 through change in colonic short chain fatty acid (SCFA) production. It therefore has huge potential long term impact on a wide range of stakeholders from consumers to policy makers. In addition to the academic beneficiaries, the outputs of the research will impact on the following stakeholder groups:-

Food Industry: Fermentable carbohydrates yield SCFAs, the endogenous agonists of SCFA receptors FFA2 and FFA3. Therefore the outputs from this project and the further research it will generate will enable the food industry to develop a new generation of foods targeted at body composition to reduce the incidence of type 2 diabetes. Foods with high nutritional impact is a growing sector of the food industry and robust scientific evidence of positive health benefits arising from this and future projects will support health claims and further growth, giving the UK food industry a competitive advantage. The generic knowledge produced will allow approaches to be developed to improve control over rates of nutrient delivery.

The human physiological studies will give new methodology. The project will develop new biological chemical tools to give a deep synoptic understanding. Both will be available to the scientific community.

Consumers: Individual consumers will have new knowledge regarding the health benefits of fermentable carbohydrate, together with a wider choice of manufactured foods with specific, proven health benefits. Although care has to be taken with the health communication aspects as consumption of these foods may only be effective as part of a healthy balanced diet. The foods ought to have comparable consumer acceptability, making it more convenient for consumers to adopt healthier options. The long term health benefits of reducing obesity and the risks associated with diabetes will benefit the lifelong health, wellbeing of individuals and improve the quality of life into old age.

National Health Service and Government: This project is the first step in understanding how dietary carbohydrate, which is fermented to SCFA's and the release of anorectic gut hormones, leads to changes in appetite regulation. The number of individuals diagnosed with type 2 diabetes in the UK has roughly doubled since 1996 to about 2.6 million. The direct costs to the NHS and other health care providers for treating obesity and related conditions is currently around £10 billion per year (approx. 10% of the NHS budget). The total costs of diabetes to the nation including direct care and indirect costs are estimated to be £23.7 billion due to subsequent loss of working days due to sickness and loss of productivity. Any reduction in the prevalence of diabetes would have a huge impact through fewer admissions, fewer surgical interventions and fewer prescriptions, which would clearly have an impact on health costs. The data produced by the project will also enable the development of dietary advice for ameliorating the health problems in those who have already developed the early signs of diabetes.