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

Lead Research Organisation: University of Manchester
Department Name: Medical and Human Sciences

Abstract

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.

Technical Summary

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).

Publications

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Little TJ (2010) Gastric emptying of hexose sugars: role of osmolality, molecular structure and the CCK1 receptor. in Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

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Little TJ (2009) Sweetness and bitterness taste of meals per se does not mediate gastric emptying in humans. in American journal of physiology. Regulatory, integrative and comparative physiology

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McLaughlin JT (2016) Human brain responses to gastrointestinal nutrients and gut hormones. in Current opinion in pharmacology

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Psichas A (2012) Colestyramine slows gastric emptying of liquids and reduces appetite in healthy subjects. in Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

 
Description 1) We discovered that 'artificial sweeteners' do not exert significant effects on gut function, gut-brain signalling or appetitive behaviour in healthy humans, in particular when used in dietetically realistic amounts. This contrasts with predictions from prior animal studies where large effects where shown: these may be species differences or perhaps due to unrealistically high quantities of these agents used in other studies.
2) We have mapped the human brain response to sweet substances placed in the gut and/or the mouth, and discovered evidence for a novel interaction between them.
Exploitation Route The food and beverage industry have become cogniscent of this and other lines of evidence, and the claims and apprach for artificial sweetners are changing in consequence.

We need to now take this forward into further studies of the regulation of brain-gut signalling and appetite control, particularly by combining aspects of physiology with psychology/hedonics (taste).
Sectors Agriculture, Food and Drink,Healthcare

 
Description 1) The key physiological findings have been negative, in that artifical sweeteners do not have major effects in humans in terms of gut function and appetitive behaviour: the food and beverage industry have adjusted their approach to use and claims for sweeteners, these outputs are a component of that. 2) The consequently developed functional brain imaging platform technology will find significant applications in understanding gut-brain signalling in humans, and is now being entered into a variety of clinical study contexts.
Sector Agriculture, Food and Drink,Other
Impact Types Economic

 
Description BBSRC Food Nutrition and Health Working Group
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description BBSRC DTP (University of Manchester)
Amount £75,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2014 
End 08/2018
 
Title fMRI 
Description A technique to map the spatiotemporal matrix of nutrient induced activation in the human brain, especially hypothalamus and brainstem. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact Publication to date: about to translate into clincical applications 
 
Title fMRI 
Description Dr Shane McKie has made significant advances in the analysis of human brain responses to GI nutrients, especially in small hindbrain strcutures 
Type Of Material Data analysis technique 
Provided To Others? No  
Impact Beyond publications, we are now setting up several local and collaborative projects to harness this platform technology 
 
Description Campden BRI 
Organisation Campden BRI
Country United Kingdom 
Sector Private 
PI Contribution Talk given to panel about gut-brain signalling, and an agreement reached to seek joint funding
Collaborator Contribution As above
Impact None yet
Start Year 2013
 
Description EFSA 
Organisation European Food Safety Authority
Country Italy 
Sector Public 
PI Contribution European Food Standards Agency Expert Working Groups 2013-14 o Non-IgE-mediated adverse reactions to foods o In vitro digestibility tests for allergenicity assessment of food and feed
Collaborator Contribution Expert gastroenterology input to working groups Led by Prof Clare Mills in Manchester
Impact Reports to EFSA. http://www.efsa.europa.eu/en/supporting/doc/529e.pdf http://www.efsa.europa.eu/en/supporting/doc/527e.pdf Multidisciplinary: medicine, food science, physiology, immunology
Start Year 2013
 
Description Manchester Metropolitan University 
Organisation Manchester Metropolitan University
Country United Kingdom 
Sector Academic/University 
PI Contribution We offered expertise in gastric emptying and access to clinical measurement equipment.
Collaborator Contribution Ongoing use of multiplex assay facility in MMU
Impact DOI: http://dx.doi.org/10.1016/j.nut.2014.03.023 Multidisciplinary: medicine and healthcare science
Start Year 2011
 
Description Campden BRI's Consumer Panel 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Stimulated discussion

Potential research collaboration with this consumer body
Year(s) Of Engagement Activity 2013
 
Description Food for the Future 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talks led to food industry players thinkin about their relationshio with diet and health research

Led to further discussions with food and drinks industry including major UK and International players (see other entries)
Year(s) Of Engagement Activity 2012
 
Description School visits to UoM 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 'Getting to grips with the guts': multiple visits to give talks to school groups, on their sites and ours

Helps attract students to choose careers in medicine or biomedicine hopefully.
Year(s) Of Engagement Activity 2012,2013,2014