New take on how inflammatory bowel diseases can emerge and develop

A team of researchers has discovered the molecular trigger of inflammatory bowel disease.

Cells lining the intestinal tract form a critical barrier, protecting our bodies from the billions of bacteria living in the gut. Breaches in this barrier are driven largely by a single signaling molecule called tumor necrosis factor (TNF), elevated amounts of which are associated with inflammatory bowel diseases like Crohn's disease and ulcerative colitis.

Duke researchers now have discovered that a gene called uhrf1, which is involved in an epigenetic process known as DNA methylation, acts like a kind of molecular handbrake on TNF and in the absence of uhrf1, TNF rolls out a series of pro-inflammatory and immune signals that inflame and damage the digestive tract.

Researcher Michel Bagnat said that their findings provide a new take on how inflammatory bowel diseases can emerge and develop and they already knew that genetic susceptibility could play a part, but they've found that it is not just the immune genes themselves, but also the regulation of those genes (through epigenetics), that can cause problems.

The experiment yielded two big surprises. First, they found that TNF, originally thought to be produced mostly by immune cells, was also being made by the epithelial cells that line the gut and second, they discovered that one of the mutants actually pumped up the levels of TNF being produced in the digestive tract.

You can think about it in terms of a car parked in a driveway. If you get rid of the handbrake, the car is going to start rolling, Bagnat said. The results suggested that losing uhrf1's brakes was enough to head TNF on a course for destruction, even without that extra push from intestinal microbes.

Now the researchers are trying to translate their findings to higher organisms like humans by looking for similar methylation defects in patients with IBD. Ultimately, the defects they find could provide targets for new diagnostics or therapeutics for the disease.

The study is published in Proceedings of the National Academy of Sciences.