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

在英国，60%的成年人口超重或肥胖。这种情况令人担忧，因为过度储存脂肪的副作用会对心血管疾病、糖尿病甚至癌症造成健康风险。与肥胖相关的健康风险不仅与脂肪总量有关，还与脂肪在体内的储存位置有关。因此，了解饮食成分如何在一生中保持能量动态平衡成为当务之急。与我们远古的祖先狩猎采集人相比，现代饮食中存在的一个重要的饮食成分是可发酵的碳水化合物。从食用高纤维食物中获得的可发酵碳水化合物不会被消化，因此进入结肠，在那里它们可供肠道细菌发酵。在结肠中发酵的高含量不可消化碳水化合物的饮食对脂肪组织的结构及其在体内的分布有有益的影响。发酵过程的重要产物是短链脂肪酸(SCFA)，越来越多的证据表明，它们介导了饮食中可发酵碳水化合物的有益影响。我们将重点研究食物结构将如何影响肠道中的不同部位如何将碳水化合物(数量和物理形式)加工成单链脂肪酸。细胞之间通过发送和响应化学信息进行交流。单链脂肪酸是一组许多不同类型的信息，通过细胞表面受体作用，称为G蛋白偶联受体(GPCRs)，之所以被称为GPCRs，是因为这些受体如何将化学信息传递到细胞内的机制。SCFA激活两个不同的GPCRs，FFA2和FFA3。尽管目前许多处方药针对的是其中一些GPCR，但对治疗更具体、副作用更少、有效时间更长的药物的需求很高。要做到这一点，我们必须首先了解构成控制这些受体活动的细胞机制的分子。虽然已知SCFA可导致结肠的胃肠激素分泌细胞--肠内分泌细胞数量增加，但对于不同的SCFA如何通过其GPCRs在这些肠内分泌细胞中诱导信号以及这些受体的位置还知之甚少。因此，这个项目的另一个关键目标是了解这些受体在细胞内激活的信号通路，以响应SCFA的变化。我们还将开发新的生化工具来了解受体在肠道内分泌细胞中的位置。GPCR信号的时间和位置都将被研究，因为它对细胞编程至关重要，告诉它是否释放更多的激素，激活特定的基因，分裂，甚至死亡。利用食物结构在结肠的特定位置定位SCFA的产生可能是一种重要的全人群干预措施，以维持能量平衡。该项目不仅将使人们更好地了解单链脂肪酸对内分泌细胞的影响，而且还将确定潜在的营养和药物靶点。该项目将通过对人类的干预性研究，深入了解饮食碳水化合物结构如何影响结肠食欲信号。它将使用新的化学生物探针，并解开到不同SCFA的受体信号

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