A stomach virus is suspected to trigger inflammatory bowel disease - New Atlas

New research led by a team from New York University has found evidence a common viral infection can trigger inflammatory bowel disease in genetically susceptible people. Across a series of mouse experiments the researchers demonstrated how a norovirus infection can bring on Crohn's disease.

Crohn's disease is a chronic inflammatory condition that is generally diagnosed in young adulthood. The causes of Crohn's are unknown but it is strongly suspected to be triggered by a combination of genetic, environmental and microbial factors.

More than 30 different genetic variants have been linked to increased Crohn's disease risk. However, one particular variant, in a gene called ATG16L1, has been particularly associated with the disease.

This gene plays a role in cells that line the gut, but not everyone with this gene variant goes on to develop Crohn's. In fact, around half of all Americans carry this specific mutation, yet only a fraction will be diagnosed with the inflammatory disease.

So this new research set out to understand what other factors could be promoting the gut inflammation alongside this genetic susceptibility. The study focused on a type of gut cell known as Paneth cells. These cells are mostly found in the small intestine and they secrete antimicrobial molecules. Their role is to maintain microbial balance in the gut and those with the ATG16L1 genetic variant exhibit dysfunctions in these cells.

A key finding from the new research is that in healthy guts with the ATG16L1 variant, immune T cells produce a protein called apoptosis inhibitor 5 (API5). This protein makes sure the immune system doesn't attack and kill Paneth cells.

But in experiments with mice genetically engineered to develop Crohn's disease the researchers discovered infections with norovirus blocked T cells from secreting API5, leading to Paneth cell death and the onset of Crohn's disease. And in another experiment the researchers found injecting Crohn's mice with API5 increased survival rates linked to the disease.

"Our study suggests that when norovirus infects those with a weakened ability to produce apoptosis inhibitor 5, it tips the balance toward a full-blown autoimmune disease," explained co-senior author on the study Ken Caldwell.

While the study does specifically focus on norovirus infection as a particular trigger leading to API5 disruption and Paneth cell death, the researchers suggest other factors could also begin this chain of events. Salmonella has been found to interfere with API5 secretion, and smoking, a known risk factor for Crohn's, has been linked to Paneth cell defects. So it's possible a variety of factors could trigger this process in those with certain genetically susceptibility to Crohn's.

"Our findings offer new insight into the key role that apoptosis inhibitor 5 plays in Crohn's disease," said Yu Matsuzawa-Ishimoto, lead author on the new study. "This molecule may provide a new target for treating this chronic autoimmune illness, which has proven difficult to manage over the long term."

There is still a long road ahead for the research. Whether API5 administration can become a viable therapy for human patients is yet to be explored. The discovery of this mechanism does shed new light on how a common inflammatory bowel disease can develop and finding ways to maintain the API5/Paneth cell protective pathway could be a way to reverse the disease in some patients.

The new study was published in Nature.

Source: NYU Langone

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