Scientists Uncover Potential Major Cause of Inflammatory Bowel Disease

Scientists Uncover Potential Major Cause of Inflammatory Bowel Disease

Researchers in the UK appear to have discovered a pivotal genetic cause of inflammatory bowel disease. In a new study Wednesday, the team found evidence of a specific genetic flaw that seems to play a key role in driving immune cells to attack the guts of those with IBD—a flaw found in nearly all the cases they studied. The discovery could lead to new and existing treatments being repurposed for IBD, the authors say.

Inflammatory bowel disease is a debilitating and complex digestive condition. The two main types of IBD are known as ulcerative colitis and Crohn’s disease, both of which are characterized by damaging inflammation along the digestive tract. Symptoms tend to come and go as flare-ups and include abdominal pain, fatigue, diarrhea, rectal bleeding, and weight loss.

The root cause of IBD is a dysfunctional immune system that chronically harms the gut. But the exact reasons why this happens are still unclear and might vary from person to person. Genetics are thought to be an important factor, though, since IBD can run in families.

The new research was led by scientists from the Francis Crick Institute, as well as the University College London and the Imperial College London. They looked closer at a particular region of our genetic code that has been previously linked to IBD and autoimmune disorders. This region is one of many along our genome known as a gene desert, filled with genes that don’t actually code for any proteins. While scientists once thought these deserts contained nothing but “junk” DNA, we now know that they can have an significant influence on other, more plainly functional, genes.

Within this desert, the team identified a section of DNA important to macrophages—immune cells that normally protect us from germs but can also drive the inflammation found in IBD patients. The DNA snippet is known as an enhancer and it seems to directly affect the activity of a gene called ETS2.

The team’s gene-editing experiments found evidence that ETS2 is crucial to the macrophages’ ability to trigger inflammation, including the bad kind that leads to IBD. They also found that tweaking ETS2 to be more active could make macrophages in the lab resemble the ones seen in IBD patients. And when they looked at the genetic make-up of IBD patients, they found that 95% of patients in their sample carried at least one copy of a specific enhancer variant that seems to boost ETS2 activity. The team’s findings were published Wednesday in Nature.

“Using genetics as a starting point, we’ve uncovered a pathway that appears to play a major role in IBD and other inflammatory diseases,” said senior study author James Lee, group leader of the Genetic Mechanisms of Disease Laboratory at the Crick, in a statement from the institute.

More research will have to be done to confirm and better understand how important this variant and the ETS2 gene are to the development of IBD. But given how common it seems in those with the disease, the team’s work could point to an key step forward for IBD treatment. Current medications and lifestyle management around known triggers can help many, but around half of patients don’t respond to initial treatment, and fewer still experience a lasting remission.

There are no drugs specifically designed to target ETS2 right now. But the team did find evidence in lab macrophages and in gut cells taken directly from patients that an existing class of autoimmune drug, known as MEK inhibitors, should be able to quiet down the inflammation triggered by ETS2. The team is now planning to develop a way to deliver these drugs directly to macrophages, which should hopefully reduce their known side-effects. And with any luck, clinical trials with actual patients could happen in the next five years.

“This research is a really exciting step towards the possibility of a world free from Crohn’s and colitis one day,” said Ruth Wakeman, director of services, advocacy and evidence at Crohn’s & Colitis UK, a charity that helped fund the team’s work in a statement from the institute.


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