Decoding the Obese Duodenum

肥胖是一个主要的健康问题。了解肥胖如何导致糖尿病和肝脏问题等疾病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，小肠的第一部分，称为十二指肠，是如何变化的，以及这是如何驱动与肥胖相关的疾病的。目前对这些过程知之甚少。我们的早期数据表明，肥胖导致十二指肠的变化，这可能导致炎症并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，并增加肥胖对代谢重要器官（如肝脏）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，我们希望了解它们如何加剧与肥胖相关的健康问题，并确定治疗这些疾病的药物的新靶点。为了实现这一目标，我们将：创建一个详细的地图，在十二指肠的差异瘦（非肥胖）和肥胖的个人。我们将研究不同类型的细胞及其活动，以及生活在十二指肠的细菌。通过比较瘦人和肥胖人，我们将确定肥胖如何影响十二指肠，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称为类器官的十二指肠小模型。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抵御有害物质的能力，细胞如何自我更新，以及这些变化如何导致代谢问题。然后，我们将测试当小鼠变得肥胖时，相同的机制是否会恶化它们的新陈代谢。最后，我们将探讨改善肥胖者十二指肠的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，以找出最有效的方法。然后，我们将对肥胖小鼠进行这种治疗，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它们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.