Gut response to ageing immune cells

19 April 2024

Australians are developing inflammatory bowel disease (IBD) at an increasing rate and, in a majority of cases, at a younger age. The average age of onset is about 15-25 years. These IBD sufferers have a higher chance of later developing bowel cancer — the second deadliest cancer in the world.

In 2023, more than 15,000 Australians were diagnosed with bowel cancer. The AITHM Senior Research Fellow and intestinal immunology group leader, Dr Roland Ruscher, is charting the lifespan of a gut immune cell linked to the onset of bowel cancer and IBD. Seeking to identify when and how the immune cell’s protective efforts begin to flag, Dr Ruscher is hoping this research will help pave the way for a cancer vaccine and other targeted disease prevention strategies.

With a $600,700 Investigator Grant from the National Health & Medical Research Council (NHMRC), Dr Ruscher and his team plan to track the ageing process of crucial gut border guards known as intraepithelial lymphocytes (IELs), looking for age-related changes which may influence the onset of intestinal diseases.

IELs are a subset of immune cells found in the gut epithelium, a single-cell layer that separates the gut content from other tissues in the body. IELs patrol this fragile barrier, screening and tackling a range of threats, including pathogens, cancerous cells and inflammations.

The lifespan of cells in the body can range from days to years. IELs are believed to be long-living gut residents, but exactly how long they survive — and how well they age — is not completely understood.

“If an IEL is there in early life, and sticks around into later life, what is happening with the IEL in early life that allows inflammatory bowel disease to occur? And what is happening with it later in life that allows the onset of colorectal cancer?” said Dr Ruscher.

He theorises that IELs activated early in life to destroy pathogens can cause collateral damage by releasing molecules that actually exacerbate a pre-existing inflammation in the gut and thereby contribute to IBD. Add long life to the equation and IELs may eventually begin to suffer from cell exhaustion and become too tuckered to tackle bowel cancer cells later in life.

Dr Ruscher and his team are attempting to measure the lifespan of these cells in experimental models by tracking them throughout their life and monitoring any genetic changes to the IELs over time.

“If we find genetic changes, we are hoping to then learn what kind of molecular pathways within the cell could be affected, because that might inform us about how the IEL cells change functionally — and whether such alterations open the door to IBD and later, cancer,” said Dr Ruscher.

The next step will be to confirm the findings in human gut samples that were acquired through a collaboration with Yale University, which possesses a biobank containing a range of donated human gut samples from newborn to adult age.

“It will be harder to find what we are looking for, but our genetic data will provide a basic map, assisting us to pre-select certain genes for further investigation in our human samples.”

If his pioneering study yields a better understanding of the genetic and molecular pathway-level changes which could cause IELs to begin to fail in their protective duties, particularly as they grow older, the results could contribute to future efforts to design targeted intervention strategies to prevent the onset of both IBD and colorectal cancer.

“If we understand what actually goes wrong, that may allow us to develop certain strategies to fix the under-performance of these immune cells at different life stages,” said Dr Ruscher.

“That may involve the design of a vaccine to enable IELs to maintain a strong response to cancer cells later in life. Or even the provision of something as simple as a therapeutic supplement during childhood or elderly life to help restore the performance of these immune cells.”