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

如果我们要解决日益严重的暴饮暴食和肥胖问题，就需要更好地了解控制食物摄入的方法。这些都对人类健康和繁荣构成了重大威胁。体重增加涉及许多不同的因素，但膳食大小是一个重要因素。在用餐过程中和进食后，消化系统向负责控制食物摄入量以及进食者感觉饥饿或饱腹的大脑部分发送多种信号。这些信号是由小肠内层的专门细胞检测食物分子最有力地触发的。这些细胞然后释放“肠道信号”，信使分子向大脑发出信号。激素（如CCK，GLP-1）被认为主要通过作用于直接从肠道连接到大脑的神经纤维（称为迷走神经传入通路）来起作用。激素也可以通过血液进入大脑。这些潜意识的信号然后被控制食物摄入的大脑中心整合，最重要的是被称为髓质和下丘脑的区域。营养分子最初是如何在肠道中被检测到的，现在才变得清楚。最近一系列令人兴奋的发现表明，检测肠道中糖分子的传感机制可能与识别口腔中甜味物质的味蕾受体相同。众所周知，肠道中的糖会向大脑发出“饱”的信号，并减缓食物从胃中排空的速度。这两种反应从而限制了进一步的食物摄入。现在必须充分了解这些机制，因为它们可以通过重新设计食品的组成来实现，以诱导饱腹感并减少食物消费。我们将进行一系列的研究，旨在精确地确定所涉及的传感和信号通路。使用一组代表性的糖和甜味剂放置在肠道或口腔中，我们将评估整个“控制回路”。这将通过（i）确定甜味分子对胃排空速度的影响，（ii）测量关键肠道激素的释放并使用阻断其作用的药物，以及（iii）确定肠道和/或口腔中甜味分子激活的大脑区域来实现。这些研究都将涉及监测整个过程中的饱腹感或饥饿感。我们拥有所有必要的研究基础设施和专业知识。一项关键技术涉及使用呼吸测试技术对胃功能的非侵入性测量。我们还拥有最先进的使用功能性磁共振成像的大脑成像设备：这使我们能够直接可视化大脑中响应营养物质而激活的精确区域。最后，我们希望通过与诺丁汉的同事合作来扩展这些研究的重要性，他们正在研究个体之间在关键甜味反应和口腔和肠道中存在的受体方面差异的遗传基础。了解这些途径将使科学研究人员和食品公司能够共同努力，设计和开发对人群具有积极健康益处的食品。

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.