Gut Cells That Limit Inflammatory Bowel Disease Identified

A new study has characterized a specialized type of immune cell that plays a key role in protecting cells in the healthy human gut and are depleted in inflammatory bowel diseases (IBDs). The research, which could lead to better management and treatment options for IBD patients, is published in Science.

Understanding IBD

Approximately 1 in 100 Americans have a diagnosis of IBD, a collective term that covers 2 conditions – Crohn’s disease and ulcerative colitis.

These are chronic, incurable and often debilitating diseases characterized by gut inflammation, which leads to symptoms such as abdominal pain, diarrhea and fatigue. They often go through periods of relapse and remission where symptoms can reoccur after periods of inactive disease.

People with IBD are also more likely to develop colorectal cancer, especially when the disease is uncontrolled, and some patients may develop cancerous or pre-cancerous growths in their gut that require surgery to remove.

The study team has previously identified that a population of immune cells called V-gamma-4 (Vg4) T cells interact with butyrophilin-like molecules (BTNL) on the surface of cells that line the colon.

These immune cells belong to a group called gamma delta (γδ) T cells and help to maintain the health of the gut lining and repair it after damage.

In the current study, researchers from the Francis Crick Institute investigated whether a lack of these normal interactions could be responsible for disease – potentially influencing our understanding of the gut barrier in IBD.

Differences in Vg4 T-cell populations

The researchers collected colon tissue from patients treated at Guy’s and St Thomas’ NHS Foundation Trust – including 34 healthy controls, 42 uninflamed samples from IBD patients, 27 inflamed samples from IBD patients and 7 from IBD patients for whom samples of both inflamed and uninflamed tissue were collected. Intriguingly, they found that Vg4 T cells were significantly altered and often depleted in the inflamed IBD samples.

Examining tissue from relatively rare individuals who carry BTNL mutations that severely limit interactions with Vg4 T cells revealed that, while these genes didn’t increase the likelihood of developing IBD, they significantly increased the risk of disease progression and severe complications for those who had already developed Crohn’s disease.

Additionally, in people whose inflammation had improved, those with restored Vg4 T-cell function were less likely to relapse than those who did not. This suggests that the function of Vg4 T cells could represent a useful biomarker for disease progression.

“There’s currently no cure for IBD, and for a significant proportion of the patients I treat, persistent relapses are distressing, severely impacting their day-to-day lives,” said the study’s lead author Dr. Robin Dart, a postdoctoral clinical research fellow at King’s College London and gastroenterologist at Guy’s and St Thomas’ NHS Foundation Trust. “Treatments tend to focus on reducing inflammation, but despite improvements in therapy, relapse rates remain high. So, we need to start targeting other areas, such as repairing the gut barrier, and γδ T cells, particularly Vg4 cells, may offer a way to do this.”

Potential for IBD monitoring and drug targets

“I see gut γδ T cells as a vacuum cleaner clearing up damage done by infections and toxins coming in through a door that has to be kept open in order for food to pass through,” said Dr. Adrian Hayday, senior author of the study and Kay Glendinning Professor of Immunobiology at King’s College London. “If the γδ T cells aren’t working properly, damage accumulates, driving inflammation and potentially cancerous changes that can build to unchecked levels.”

The next steps for the researchers include investigating interactions between γδ T cells and the epithelial cells to identify potential drug targets. Additionally, refining approaches to monitor gut γδ T cells could pave the way for a much-needed marker for IBD progression versus recovery.

Reference: Dart RJ, Zlatareva I, Vantourout P, et al. Conserved γδ T cell selection by BTNL proteins limits progression of human inflammatory bowel disease. Science. 2023;381(6663):eadh0301. doi: 10.1126/science.adh0301

This article is a rework of a press release issued by the Francis Crick Institute. Material has been edited for length and content.