Award details

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

Reference	BB/G005591/1
Principal Investigator / Supervisor	Professor John McLaughlin
Co-Investigators / Co-Supervisors	Professor Richard Case, Professor Emeritus Stephen Williams
Institution	The University of Manchester
Department	Medical and Human Sciences
Funding type	Research
Value (£)	569,143
Status	Completed
Type	Research Grant
Start date	30/03/2009
End date	29/09/2012
Duration	42 months

Abstract

Our objectives are to determine: (i) the role of sweet 'taste' receptors in the gut in the initiation of gut-to-brain signalling (ii) the effect of regional variations in small intestinal exposure to sweet tastants (ii) the role of endogenous cholecystokinin and glucagon-like peptide-1 in mediating these responses. (iv) the brain correlates of oral versus intragastric nutrients, determined by functional MRI scanning. Gastric emptying will be used as a proxy measure of signalling activity in this system. The medulla houses the sensory and motor nuclei of vago-vagal enteric control circuits. Therefore, determining changes in gastric emptying permits a highly effective measure of signalling in these pathways. Gastric emptying will be evaluated using a reproducible, high-throughput, non-radioactive, 13C-acetate breath test. This is absorbed only when it enters the duodenum, then metabolised and exhaled in breath samples as 13CO2, quantified in real-time using an IRIS spectrophotometer. Perceptions will be assessed using validated visual analogue scale questionnaires. The potential role of key regulatory peptides (CCK, GLP-1, insulin) will be assessed by assaying changes in circulating concentrations in response to the presence of sweet tastants in the gut, and functionally explored using highly specific antagonists to CCK and GLP-1. Glycaemic responses to the experimental interventions will also be monitored since glucose can exert post-absorptive effects on stomach and brain. Where appropriate, intravenous glucose infusion experiments will also be performed as control studies. Regional brain activation will be evaluated using a high-resolution fMRI protocol on the 3T scanner in the Translational Imaging Unit. This assesses changes in blood oxygen level dependent (BOLD) signal in brain areas activated in response to signals from the gut. We will initially focus on areas associated with appetite and energy intake (brainstem/hypothalamus).

Summary

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.

Committee	Closed Committee - Agri-food (AF)
Research Topics	Diet and Health, Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	Diet and Health Research Industry Club (DRINC) [2008-2014]
Funding Scheme	X – not Funded via a specific Funding Scheme

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