Decoding the Obese Duodenum
Lead Research Organisation:
King's College London
Department Name: Cardiovascular
Abstract
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.
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.
Technical Summary
Obesity and its related co-morbid diseases are major public health concerns. One billion people are projected to be obese by 2030. Developing novel effective treatments remains critically important. The goal of this project is to understand how the proximal small intestine, the duodenum, changes in response to obesity and how these changes may exacerbate metabolic diseases. Our pilot data suggests obesity generates a type 1 interferon like response in the duodenum and this may drive barrier dysfunction. Our working hypothesis is that a "leaky duodenum" aggravates whole body metabolic dysfunction. Understanding the pathological role of this duodenal response will identify new therapeutic targets for metabolic disease. To do this we will:
1) Map the obese human duodenum: We will use cutting edge bioinformatics to integrate data from single-cell RNA-sequencing, spatial transcriptomics and metagenomic data from duodenal samples from lean and obese participants.
2) Establish how key pathological pathways disturb gut epithelial function and whole-body metabolism: To determine how these responses shape gut epithelial function, we will genetically manipulate human organoids. Subsequently, we will determine whether the changes observed in the duodenal epithelium drive metabolic pathology in the whole animal.
3) Assess the therapeutic potential of restoring duodenal epithelial function to treat the metabolic dysfunction associated with obesity: Finally, we will identify whether correction of barrier integrity or blockade of the type 1 interferon response improves epithelial function and improves metabolism in high fat diet fed mice and determine whether this.
This programme of work will identify the major regulatory pathways involved in duodenal dysfunction in obesity, determine whether this dysfunction can drive further metabolic consequences, and provide proof of principle as to whether treating this dysfunction is useful in the treatment of metabolic disease.
1) Map the obese human duodenum: We will use cutting edge bioinformatics to integrate data from single-cell RNA-sequencing, spatial transcriptomics and metagenomic data from duodenal samples from lean and obese participants.
2) Establish how key pathological pathways disturb gut epithelial function and whole-body metabolism: To determine how these responses shape gut epithelial function, we will genetically manipulate human organoids. Subsequently, we will determine whether the changes observed in the duodenal epithelium drive metabolic pathology in the whole animal.
3) Assess the therapeutic potential of restoring duodenal epithelial function to treat the metabolic dysfunction associated with obesity: Finally, we will identify whether correction of barrier integrity or blockade of the type 1 interferon response improves epithelial function and improves metabolism in high fat diet fed mice and determine whether this.
This programme of work will identify the major regulatory pathways involved in duodenal dysfunction in obesity, determine whether this dysfunction can drive further metabolic consequences, and provide proof of principle as to whether treating this dysfunction is useful in the treatment of metabolic disease.