Mayo Clinic researchers have identified an immune-regulating molecule that may help explain why some patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, do not respond to commonly used therapies. The findings, published in Cell Reports, describe a previously uncharacterized role for the molecule ST8Sia6 in regulating immune activity in the gut.
In preclinical models, researchers found that the absence of ST8Sia6 led to a marked increase in inflammatory immune cells in the intestines. The results suggest the molecule plays a key role in maintaining immune balance and may represent a distinct biological pathway from those targeted by existing treatments.
IBD affects nearly 3 million people in the United States, and its prevalence continues to rise. While the source of IBD is not known, researchers believe it may occur due to a combination of genetic and environmental factors. Recently introduced medications target a pro-inflammatory molecule known as TNF-alpha to reduce the autoimmune response in the intestines and help with symptoms such as diarrhea, bloating and bloody stools, but the treatment is not effective in all patients.
Discovering the role of the enzyme ST8Sia6 has provided the research team with a new view of IBD. "The normal function of ST8Sia6 in the gut had not been previously described," says Mayo Clinic immunology researcher Virginia Shapiro, Ph.D., principal investigator of the study. "We found ST8Sia6 regulates the abundance of immune cells and keeps them in the steady state of homeostasis. When the molecule is not present or even is reduced, the presence of inflammatory immune cells increases dramatically."
An intriguing enzyme in the immune system
The study of ST8Sia6 and its interactions with the immune system extend recent discoveries in Dr. Shapiro's research lab. Her team previously showed that ST8Sia6, an enzyme that adds sugar molecules to cell surfaces, enables a tumor to evade destruction by the immune system. The lab also found that ST8Sia6 can be used as a tool to help reduce the body's autoimmune attack on insulin-producing beta cells, as occurs in diabetes.
The leap to gastrointestinal disease occurred when the team noticed on an international database that a single mutation in the gene for ST8Sia6 turns up with greater frequency in people with Crohn's disease.
"The ST8Sia6 molecule is expressed pretty widely in different immune cells, but we weren't sure of its connection to this disease which involves chronic inflammation," says Sydney Crotts, a graduate student at Mayo Clinic Graduate School of Biomedical Sciences and first author of the study.
The team looked at preclinical models that lacked the ST8Sia6 gene. In the models, an abundance of immune cells gathered in the small intestine. The team also found that lower ST8Sia6 led to increased levels of messenger molecules that prompt an immune response. Together, the attributes increased susceptibility to intestinal inflammation.
"We think this might be a model of what's happening in patients with Crohn's disease who have a baseline of immune cells and are basically fine until they encounter a trigger and have a flare," says Crotts. She notes that the inflammation did not abate with TNF-alpha medication, suggesting this pathway may be distinct.
The study illuminates yet another action of ST8Sia6 on the immune system and presents a new avenue that may help IBD treatment. Further studies will be necessary to move the discovery toward the clinic.
"These findings mean researchers have an approach to better understand the source of TNF-resistant Crohn's disease, the pathways and molecules involved, and now may be able to develop additional ways to intervene to treat this disease," Crotts says.
For a complete list of authors, disclosures and funding, review the study.
