Form of Crohn’s disease traced to disabled gut cells

Scientists report in a recent issue of Nature that they have linked the health of specialized gut immune cells to a gene associated with Crohn’s disease, an often debilitating and increasingly prevalent inflammatory bowel disorder.

The link to immune cells intrigued School of Medicine researchers because they believe Crohn’s disease is caused by misdirected immune responses in the intestine that damage gut tissue. In addition, cells in the mouse model scientists used for the study had altered genetic activity that could lead to increased production of certain hormones. Those same hormones are elevated in some Crohn’s patients.

“We now have a significant new piece of the puzzle that is Crohn’s disease, but not the solution just yet,” said senior author Herbert W. “Skip” Virgin, M.D., Ph.D., the Edward Mallinckrodt Professor and head of the Department of Pathology and Immunology. “As many as 30 different areas in human DNA have potential links to Crohn’s disease, and to develop new treatments, it’s going to be essential to find out how each of them, as well as environmental factors, contribute to the disorder.”

Crohn’s disease is one of the most common inherited bowel disorders, affecting an estimated 400,000-600,000 patients in North America. The condition can lead to partial or full intestinal blockages, which can require surgical treatment.

Research previously revealed that some Crohn’s disease patients have a mutation in a gene known as Atg16L1. The change increases risk but doesn’t automatically lead to Crohn’s disease. To learn more, Ken Cadwell, Ph.D., a postdoctoral student in Virgin’s lab, created two lines of mice with a genetic alteration that reduced their ability to make copies of the Atg16L1 protein.

The laboratory of co-senior author Thaddeus Stappenbeck, M.D., Ph.D., assistant professor of pathology and immunology and an expert in mouse models of inflammatory bowel disease, led the analysis of the genetic change’s results. Reduced Atg16L1 had pronounced effects on Paneth cells, immune cells in the lining of a portion of the small intestine. These cells make proteins and antimicrobial peptides that they package as granules and secrete into the intestine to defend the body against infection.

“When they have less Atg16L1, the Paneth cells survive, but their ability to secrete granules is significantly impaired,” Cadwell said.

The researchers consulted with Ellen Li, M.D., Ph.D., professor of medicine and associate professor of biochemistry and molecular biophysics. When surgery becomes necessary to repair a patient’s bowel, Li collects samples removed from the intestine for research. Selecting tissue from patients with mutated Atg16L1, scientists compared human Paneth cells to cells from their mouse model and found what Virgin calls “striking similarities.”

“We don’t yet know why having abnormal Paneth cells would predispose a person to Crohn’s disease or to what degree other genes linked to Crohn’s may affect the Paneth cell, but those are just a few of the very interesting questions to follow up on from these results,” Virgin said.