Defining the gut-to-brain signalling mechanisms underlying responses to nutrients

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The ways in which food intake is controlled need to be better understood if we are to combat the rising problem of over-eating and obesity. These are posing major threats to human health and prosperity. Many different factors are involved in weight gain, but meal size is an important factor. During the course of a meal and after eating, the digestive system sends multiple signals to the parts of the brain responsible for controlling how much food is eaten, and how hungry or full the eater feels. These signals are most powerfully triggered by the detection of food molecules by specialised cells in the lining of the small intestine. These cells then release 'gut hormones', messenger molecules which signal to the brain. The hormones (eg CCK, GLP-1) are believed to work principally by acting on nerve fibres linking directly from gut to brain, termed the vagal afferent pathway. The hormones may also travel in the bloodstream to the brain. These subconscious signals are then integrated by the brain centres which control food intake, most importantly by areas known as the medulla and hypothalamus. How the nutrient molecules are initially detected in the gut is only now becoming clear. An exciting series of recent discoveries has shown that the sensing mechanisms that detect sugar molecules in the gut may be identical to the taste bud receptors which recognise sweet tasting substances in the mouth. It is also known that sugars in the intestine send 'fullness' signals to the brain, and slow down the speed with which the meal empties from the stomach. These two responses thereby limit further food intake. It is now essential to fully understand these mechanisms, since they can potentially be targeted by redesigning the composition of food products in order to induce fullness and reduce food consumption. We will undertake a series of studies designed to precisely determine the sensing and signalling pathways involved. Using a representative panel of sugars and sweeteners placed in the gut or the mouth, we will assess the whole 'control circuit'. This will be achieved by (i) determining the effects of sweet molecules on the speed at which the stomach empties, (ii) measuring the release of key gut hormones and using drugs that block their effects, and (iii) identifying the regions of the brain that are activated by sweet molecules in the gut and/or mouth. The studies will all involve monitoring key sensations of fullness or hunger throughout. We have all the necessary research infrastructure and expertise required. A key technique involves a non-invasive measure of stomach function using breath testing technology. We also host a state-of-the art brain imaging facility using functional magnetic resonance imaging: this allows us to directly visualise the precise areas of the brain activated in response to nutrients. Finally, we hope to extend the importance of these studies by collaborating with colleagues in Nottingham who are conducting research into the genetic basis for differences between individuals in the key sweet tasting responses and receptors present in the mouth and gut. Understanding these pathways will permit scientific researchers and food companies to work together to design and develop food products with positive health benefits for the population.