A new study may have shed light on what causes Crohn’s disease, an inflammatory bowel disease in which the body’s immune defenses, which are supposed to attack invading microbes, instead attack the digestive tract. Norovirus is a common infection that causes diarrhea and vomiting. It is thought to be one of several viruses and bacteria that cause Crohn’s disease, but no one knows why.

One hint came from earlier research that showed the majority of people with the illness have a certain genetic alteration (mutation). This mutation renders intestinal lining cells more prone to injury. The riddle was compounded further when it was discovered that half of all Americans carry the same risk-inducing genetic mutation, yet only about 500,000 get Crohn’s disease.

The new research was published in the journal Nature today. It demonstrated for the first time that in healthy people, immune defense cells called T cells secrete a protein called apoptosis inhibitor five (API5), which instructs the immune system to stop attacking cells in the gut lining. This protein provides an additional layer of defense against immunological damage, allowing even those with the mutation to have a healthy digestive tract. In mice designed to develop a rodent type of Crohn’s disease, the researchers also discovered that norovirus infection limits T cell release of API5, destroying gut-lining cells in the process.

The study, led by experts from NYU Grossman School of Medicine, backs up the notion that API5 protects most people with the mutation from the sickness until a second trigger, such as norovirus infection, pushes some over the disease threshold.

In trials using mice engineered to have the human mutation that causes Crohn’s disease, half of the untreated mice died whereas all of those given an injection of API5 survived. According to the study’s authors, this supported the hypothesis that the protein shields gut cells. In human tissue, the researchers discovered that patients with Crohn’s disease had five to 10 times less API5-producing T cells than those without the condition.

Lead author Yu Matsuzawa-Ishimoto says: “Our findings offer new insight into the key role that apoptosis inhibitor five plays in Crohn’s disease.” 

“This molecule,” according to the author, “may provide a new target for treating this chronic autoimmune illness, which has proven difficult to manage over the long term.” 

Matsuzawa-Ishimoto, a postdoctoral research fellow at NYU Langone Health, asserts that available treatments, which work by suppressing the immune system, put patients at a high risk for infection and often stop working after a few years of use. He also says that these problems might not happen if there was a way to treat API5.

In a different series of studies, the team used tissue taken from people who had the mutation to build organ-like structures. Notably, only the cells of the gut lining made up these structures. After injecting API5 into these “mini guts,” the study team discovered that this treatment protected the gut-lining cells. T cells that produce API5 were also added, and they protected the gut lining.

“The results of our investigation help explain,” adds co-author Shohei Koide, “why the genetic links to Crohn’s are much broader than the actual number of people who have the disease.”

According to study co-senior author and microbiologist Ken Cadwell, the findings suggest “that when norovirus infects those with a weak ability to produce apoptosis inhibitor five, it the balance toward a full-blown autoimmune disease.”

Although the study’s authors obtained the API5 protein from human tissue rather than rodents, Cadwell warns that it is yet unclear whether the injection treatment can be used on people without causing harm.

The next step for the research team is to look into the long-term effects of API5 injections. This will help them figure out if the potential treatment can help people with Crohn’s disease, which can cause flare-ups over a long period of time.

Source: 10.1038/s41586-022-05259-y

Image Credit: Getty

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