The genetic key that fast-tracks gut repair 

The cells that line our guts work hard – they absorb vital nutrients that sustain us and keep us healthy. But they’re also continuously exposed to pathogens and toxins, so are easily damaged. They need a process for fast recovery.

Thankfully, the gut wall can repair itself at incredible speeds. And researchers are learning that this rapid repair process is thanks to a carefully maintained balance of different cell types in our gut wall. 

“This is a finely-tuned balance which is crucial to repair the gut and keep it functional,” says the Crick’s Vivian Li, whose team is using cutting-edge techniques to identify the cells involved in maintaining the health of our gut lining. Her work has chiefly focused on the gut’s stem cells – specialised cells that generate new gut wall cells to replace those that get damaged.

A gut organoid, with stem cells in green and matured cells in red. Credit: The Francis Crick Institute.

As well as allowing us to understand the gut’s vital repair process, Vivian’s work is leading to crucial insights into diseases that affect the gut, such as inflammatory bowel disease (IBD) and bowel cancer.  

Vivian Li at the Crick. Credit: Dave Guttridge.

The key to gut repair

Recently, Vivian’s team found there is a carefully maintained balance between three types of cell – stem cells, gut wall cells, and a third type of cell that is essentially a transition between these two cell types, known as transit amplifying (TA) cells. Like stem cells, these seem to have the flexibility to turn into different cell types, a process called ‘differentiation’. TA cells turn into gut wall cells during normal tissue maintenance, but when stem cells are challenged and lost, TA cells can reverse to de-differentiate back to stem cells.

A key question has been to understand what governs the balance between these three types of cell, and how a cell ‘decides’ whether and when to differentiate. Vivian’s lab has recently highlighted a protein called ARID3A as a key player in this process.  

Without ARID3A, the balance between the cells is lost, and the gut cannot repair itself as quickly.

Mouse intestinal tissue, with cell nuclei in blue, ARID3A in red and specialised goblet cells in green. Credit: The Francis Crick Institute.

“We’ve identified the control gene for the decision moment of whether to keep producing more cells,” says Vivian. “Diseases affecting the gut in humans can involve a chronic state of injury, so next we plan to explore whether loss of ARID3A also plays a role in preventing the human gut from repairing itself in long-term conditions like IBD,” she adds.

In the future, Vivian’s lab plans to further expand on this work and map out all the genes and molecules that regulate this repair process and maintain the balance of a healthy gut.