Scientists discover major cause of inflammatory bowel disease

Micrograph showing inflammation of the large bowel in a case of inflammatory bowel disease. Colonic biopsy. Credit: Wikipedia

Researchers from the Francis Crick Institute, UCL, and Imperial College London have discovered a new biological pathway that is a major driver of inflammatory bowel disease (IBD).

This breakthrough could lead to better treatments for IBD, which includes Crohn’s disease and ulcerative colitis, and other related autoimmune conditions.

The findings were published in the journal Nature.

IBD affects about 5% of the world’s population, and one in ten people in the UK suffer from an autoimmune disease.

Over half a million people in the UK have IBD, nearly double the previous estimate of 300,000. Despite the rising number of cases, current treatments do not work for everyone, and new drug development often fails due to an incomplete understanding of the disease.

In their research, scientists explored a “gene desert,” an area of DNA that doesn’t code for proteins but has been linked to IBD and other autoimmune diseases. They found that this gene desert contains an “enhancer,” a section of DNA that boosts the activity of nearby genes.

This enhancer was active only in macrophages, a type of immune cell important in IBD, and increased the activity of a gene called ETS2. Higher levels of ETS2 were associated with a higher risk of the disease.

Using genetic editing, the researchers showed that ETS2 is essential for almost all inflammatory functions in macrophages, contributing directly to tissue damage in IBD. Increasing ETS2 levels in resting macrophages turned them into inflammatory cells similar to those found in IBD patients.

Specific drugs that block ETS2 don’t exist, so the team searched for drugs that might reduce its activity indirectly. They found that MEK inhibitors, drugs already used for other conditions, could switch off the inflammatory effects of ETS2.

Tests showed that these drugs reduced inflammation in both macrophages and gut samples from IBD patients.

Because MEK inhibitors can have side effects in other organs, researchers are working on ways to deliver these drugs directly to macrophages. This approach aims to minimize side effects while effectively treating IBD.

James Lee, who led the research, emphasized the importance of finding better treatments for IBD, which often develops in young people and can severely disrupt their lives. “Using genetics as a starting point, we’ve uncovered a pathway that appears to play a major role in IBD and other inflammatory diseases.

We’re now working on how to ensure this approach is safe and effective for treating people in the future,” he said.

Christina Stankey, a Ph.D. student at the Crick and one of the study’s first authors, highlighted the significance of the findings. “To find one of the central pathways and show how this can be switched off with an existing drug is a massive step forward,” she said.

The study involved volunteer participants from the NIHR BioResource, who provided blood samples for the research. Collaborators from across the UK and Europe also contributed to the study.

Ruth Wakeman from Crohn’s & Colitis UK praised the research, noting that more than 25,000 people are diagnosed with IBD each year. “This research is a really exciting step towards the possibility of a world free from Crohn’s and Colitis one day,” she said.

Interestingly, the disease variant in the ETS2 enhancer is very common, with about 95% of people with IBD carrying one or two copies of it. Researchers found that this variant is ancient, appearing at least 500,000 to one million years ago and was even present in Neanderthals. This variant likely played a role in early responses to bacterial infections, which may explain its persistence in human populations.

This groundbreaking discovery not only provides a new understanding of IBD but also opens the door to potential new treatments that could improve the lives of millions of people.

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