Intestinal epithelium and gut health

Alastair Watson

Prof. Alastair Watson

Research Leader

Intestinal epithelium and gut health

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The Watson group is interested in finding out how the health and integrity of epithelial cells that line the bowel is maintained. The integrity of this barrier is essential for health, preventing the entry of microbes, toxins and allergens into the body. With a better understanding, we will help develop new treatments for major diseases that involve damage to epithelial cells, including Inflammatory Bowel Disease (IBD). Our work will also have an impact on the developing new treatments for bowel cancer based on a deeper understanding of how the microbiome influences the behaviour of bowel cancer when it starts to spread to distant tissues.

Some of the major diseases of the bowel, including IBD (comprising Ulcerative Colitis and Crohn’s Disease), gastroenteritis and bowel cancer involve damage to epithelial cells. For example, inflammation as occurs in IBD causes damage or loss of epithelial cells leading to bleeding and diarrhoea. The damage will also potentially allow the entry of microbes into the body. Cancer is caused by mutations to genes in epithelial cells leading to increased cell division, reduced death of defective cells and increased invasion. Our research into these processes will lead to both improved therapies and refining existing treatments by defining which patients will or will not respond to specific drugs, as well as new ways of diagnosing bowel disease and distinguishing patients with mild or severe disease.

In health, epithelial cells are constantly shed from the wall of the bowel. We have discovered how the barrier is maintained during this shedding process. When the bowel is inflamed, this shedding process increases damaging the wall of the bowel, breaking down the barrier, allowing the entry of bacteria and toxins which further increases the inflammation. We have found that a type of cell in the immune system called the gamma/delta intraepithelial lymphocyte plays an important role of controlling cell shedding. We are investigating how these intraepithelial lymphocytes controls the epithelial cell shedding. This line of research will lead to new treatments for inflammatory bowel disease.

We are also interested in studying the remarkable heterogeneity of human intestinal inflammation. Differences in clinical response to biologic agents highlight the importance of patient stratification for the success or failure of new treatments. Unfortunately, there are no biomarkers able to predict responsiveness to biologic therapy in inflammatory bowel disease (IBD). One mechanism of primary non-responsiveness to biologic agents in IBD may be represented by proteolytic degradation, triggered by increased mucosal levels of proteases. We are currently studying the contribution of proteolytic degradation as a possible mechanism of non-responsiveness to biologic therapy in IBD, and the use of serum levels of protease-cleaved IgG as predictors of response to biologic treatment in IBD.

We have a new project studying how the bacteria in the gut influence bowel cancer. Much research has been undertaken into how these initiate bowel cancer. However, it is also likely that bacteria will influence cancers at a later stage when they have started to invade and spread. This is a plausible idea as gut bacteria are on the surface of bowel cancers and the chemicals they generate drain to the liver along with spreading cancer cells. We are studying the behaviour of bowel cancers with defined genetic changes grown with and without bowel bacteria. This research will lead to bacterial and probiotic-based treatments for bowel cancer and potentially contribute to explaining why some cancers are more aggressive than others.

We use a wide variety of laboratory techniques including microscopy, gene sequencing and human sampling to undertake our research.

Barrier loss at the tip of an intestinal villus

Our Targets

Targeting cancer

Cancer

Targeting IBD

Inflammatory Bowel Disease (IBD)

Targeting the understanding of the microbiome

Understanding the Microbiome

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