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

在英国，60%的成年人超重或肥胖。这种情况令人担忧，因为脂肪储存过多的副作用是心血管疾病、糖尿病甚至癌症的健康风险。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整个生命周期中维持能量稳态成为当务之急。可发酵的碳水化合物是一种重要的饮食成分，与我们的古代祖先——狩猎采集者的饮食相比，现代饮食中的含量要低得多。从富含纤维的食物中获得的可发酵碳水化合物不被消化，因此进入结肠，在那里它们可以被常驻的肠道细菌发酵。饮食中富含在结肠中发酵的不易消化的碳水化合物，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（SCFAs），越来越多的证据表明它们介导了膳食中可发酵碳水化合物的有益作用。我们将重点研究食物结构如何影响肠道中不同部位如何将碳水化合物（数量和物理形式）加工成短链脂肪酸。细胞通过发送和回应化学信息来相互交流。scfa是一组多种不同类型的信息，它们通过称为G蛋白偶联受体（gpcr）的细胞表面受体起作用，之所以如此命名，是因为这些受体将化学信息传递到细胞内的机制。scfa激活两种不同的gpcr， FFA2和FFA3。尽管目前许多处方药都是针对这些gpcr的，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大。要做到这一点，我们必须首先了解组成控制这些受体活动的细胞机制的分子。虽然已知scfa可以导致结肠肠道激素产生细胞肠内分泌细胞数量增加，但对于不同的scfa通过其在肠内分泌细胞中的gpcr诱导信号的方式以及这些受体的位置知之甚少。因此，该项目的进一步关键目标是了解这些受体在响应scfa改变时激活的细胞信号通路。我们还将开发新的生化工具来了解受体在肠内分泌细胞中的位置。GPCR信号的时间和位置都将被研究，因为它对编程细胞至关重要，告诉细胞是否释放更多的激素，激活特定的基因，分裂，甚至死亡。利用食物结构靶向结肠特定部位的短链脂肪酸生产可能是维持能量稳态的重要人群干预措施。该项目不仅将使我们更好地了解scfa对内内分泌细胞的影响，而且还将确定潜在的营养和药物靶点。该项目将通过介入研究深入了解膳食碳水化合物结构如何影响人类结肠食欲信号。它将使用新的化学生物探针，并分离不同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