Decoding the Obese Duodenum

肥胖是一个主要的健康问题。了解肥胖是如何导致糖尿病和肝脏问题等疾病的，将有助于设计新的治疗方法。这个项目的目标是了解当一个人变得肥胖时，被称为十二指肠的小肠的第一部分是如何变化的，以及这是如何导致与肥胖相关的疾病的。目前对这些过程所知甚少。我们的早期数据表明，肥胖会引起十二指肠的变化，从而引起炎症，损害十二指肠作为保护屏障的功能。十二指肠的这些变化可能进一步恶化代谢，增加肥胖对肝脏等重要代谢器官造成的损害。通过研究这些变化是如何发生的，以及它们对十二指肠的影响，我们希望了解它们是如何加剧与肥胖相关的健康问题的，并确定治疗这些疾病的药物的新靶点。为此，我们将：绘制瘦人（非肥胖者）和肥胖者十二指肠差异的详细图。我们会看到不同类型的细胞和它们的活动，以及生活在十二指肠中的细菌。通过比较瘦人和肥胖者，我们将确定肥胖是如何影响十二指肠的，并找到导致代谢问题的重要途径。然后，我们将利用这些信息来研究这些变化如何影响十二指肠的功能。为了做到这一点，我们将在实验室中使用人类细胞培养被称为类器官的小型十二指肠模型。这些类器官将帮助我们了解十二指肠的变化如何影响肠道排除有害物质的能力，细胞如何自我更新，以及这些变化如何导致代谢问题。然后，我们将测试同样的机制是否会在老鼠变胖时恶化新陈代谢。最后，我们将探讨改善肥胖患者的十二指肠健康是否有助于减少肥胖对代谢的负面影响。使用类器官，我们将测试不同的治疗方法，找出最有效的。然后，我们将对肥胖的老鼠进行这种治疗，看看它是否能改善它们的新陈代谢，包括它们如何处理糖，以及组织中的损伤和炎症水平。这项工作计划将发现十二指肠如何受到肥胖的影响，确定这些变化是否会导致进一步的健康问题，并确定治疗或预防这些变化是否可以帮助患有代谢性疾病的人。

Obesity is a major health problem. Understanding how obesity causes diseases like diabetes and liver problems will help the design of new treatments. The goal of this project is to understand how the first part of the small intestine, called the duodenum, changes when someone becomes obese, and how this might drive diseases related to obesity. Little is known about these processes at present. Our early data suggests that obesity causes changes in the duodenum which can cause inflammation and compromise the function of the duodenum as a protective barrier. These changes in the duodenum may further worsen metabolism and increase the damage caused by obesity to metabolically important organs such as the liver. By studying how these changes occur and what they do to the duodenum, we hope to understand how they exacerbate the health problems associated with obesity and identify new targets for drugs to treat these diseases. To achieve this, we will:Create a detailed map of the differences in the duodenum of lean (non-obese) and obese individuals. We will look at the different types of cells and their activities, as well as the bacteria living in the duodenum. By comparing lean and obese people, we will determine how obesity affects the duodenum and find important pathways that contribute to metabolic problems.We will then use this information to investigate how these changes affect the function of the duodenum. To do this, we will grow small models of the duodenum called organoids using human cells in the laboratory. These organoids will help us understand how the changes in the duodenum affect the gut's ability to keep out harmful substances, how the cells renew themselves, and how these changes might contribute to metabolic problems. We will then test whether the same mechanisms worsen metabolism in mice as they become obese. Finally, we will explore whether improving the health of the duodenum in obesity can help reduce the negative effects of obesity on metabolism. Using the organoids, we will test different treatments to find which is most effective. We will then give this treatment to mice developing obesity see if it improves their metabolism, including how they process sugar and the level of damage and inflammation in their tissues.This programme of work will discover how the duodenum is affected by obesity, determine if these changes cause further health problems, and establish whether treating or preventing these changes may help people with metabolic diseases.