�鶹��ý

Potential new target for treatment of inflammatory bowel disease

Immunofluorescence image from the ascending colon of a patient with ulcerative colitis shows patterns of SUMO1 (red) and SUMO2/3 (green). Duke University School of Medicine

More than 4 million people in the U.S. live with an inflammatory bowel disease (IBD). Ulcerative colitis and Crohn’s disease are the two major IBDs. They can be extremely painful, require multiple surgeries to control, and eventually shorten patients’ lifespans.

IBDs are thought to be triggered in part by the body’s immune cells reacting abnormally to bacteria that naturally live in the gut. Stress is one factor known to trigger IBD symptoms. Treatments can suppress immune cells in people with IBD. But current treatments have substantial side effects and eventually stop working, leading to relapse.

A better understanding of how the immune system goes awry in IBD could lead to more targeted treatments with fewer side effects. Previous research suggested that SUMOylation of certain immune system proteins may play a role in IBD. SUMOylation is a cellular process in which small ubiquitin-like modifier (SUMO) proteins are reversibly attached to other proteins, thereby changing their function. The SUMOylation process can be affected by stress.

In a new study, funded in part by NIH, a team of researchers led by Drs. Wei Yang and Luis Ulloa from Duke University tested whether manipulating SUMOylation could affect IBD in mice. Their results were published on November 20, 2024, in Science Translational Medicine.

The researchers first analyzed the body stress response in mice given an irritating chemical in their drinking water that causes a condition similar to human IBD. In stressed mice, they noted a drop in the function of the parasympathetic nervous system, which helps the body relax and control inflammation. Improving the function of the parasympathetic nervous system, they reasoned, might counteract stress to help restore normal levels of SUMOylation and reduce inflammation in the gut.

The researchers tested a treatment called vagal nerve stimulation, which boosts parasympathetic nervous system activity, in the mice with IBD. While control mice died, the mice that received the nerve stimulation survived, had reduced intestinal bleeding, and maintained a healthy body weight.

Three major SUMO proteins—SUMO1, 2, and 3—are involved in SUMOylation. The researchers tested their different contributions to IBD development. In mice engineered to lack SUMO1, IBD did not progress past a certain stage. In mice lacking SUMO3, development of IBD was delayed. (SUMO2 can’t be safely deleted). Interestingly, the use of vagal nerve stimulation in normal mice substantially decreased the levels of SUMOylated proteins, especially those altered with SUMO2 and 3.

To look at SUMOylation in people, the team took intestinal tissue samples from two people with ulcerative colitis, seven people with Crohn’s disease, and nine people without any IBD. Compared to people without IBD, the tissues taken from people with Crohn’s disease had substantially higher levels of SUMO2 and 3 alterations.

To see if blocking SUMOylation with drugs had a similar effect to vagal nerve stimulation, the team treated mice with IBD with an experimental compound called TAK-981 (subasumstat). TAK-981 inhibited SUMOylation in the intestines of mice. The treated mice didn’t develop inflammation in their colons and maintained a healthy body weight. The drug also blocked the development of IBD when given before exposure to an irritating chemical.

“Inhibiting SUMOylation appears to mimic the beneficial effects of vagal stimulation, resulting in improved clinical symptoms of colitis,” Yang says.

Translating these findings from lab studies to the clinic could lead to different outcomes. More work in animal models is needed before this strategy could be tested in people.

—by Sharon Reynolds