July 12, 2010

Crohn’s Disease Triggers May Include Viruses and Other Factors

Microscopic images with healthy finger-like structures in top panel and blunted, damaged ones in bottom panel In mutant infected mice, structures on the surface of the small intestine are damaged by a compound (right). In infected control mice given the compound, the structures remain undamaged (left). Cadwell et al., courtesy of Cell.

Mice with mutations in a Crohn's disease gene require a virus to trigger symptoms, according to a new study. The finding may give insight into why some people with genetic risk variants for complex diseases remain unaffected.

Crohn's disease arises from inflammation of the digestive tract. Symptoms include abdominal cramps, diarrhea, weight loss, malnourishment and rectal bleeding. In some cases, the intestine can become blocked or develop open sores, or ulcers.

As with many other complex diseases, Crohn's disease has been linked to several common gene variations. But even taken together, the over 30 variants that researchers have found still can't predict who will get the disease. Scientists believe that unknown environmental factors must trigger Crohn's disease in susceptible people.

A team led by Drs. Thaddeus S. Stappenbeck and Herbert W. Virgin at Washington University School of Medicine in St. Louis have been studying a variant of the ATG16L1 gene that's been tied to Crohn’s disease. About half of people of European descent have the variation. The team previously created mice with disruptions in the gene. They found abnormalities in Paneth cells—epithelial cells that are important in mucosal immunity. They also spotted similar Paneth cell abnormalities in people with Crohn’s disease who had 2 copies of the ATG16L1 risk variant. Their further studies were supported by NIH’s National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and others.

As the researchers explained in the June 25, 2010, issue of Cell, when they recreated the mutant mice in a more carefully controlled environment, they didn't see the Paneth cell abnormalities. This surprising finding suggested the abnormalities required something other than the gene mutation.

The scientists suspected a norovirus that they had previously identified in mice from their conventional mouse facility. Noroviruses cause vomiting, diarrhea and other severe intestinal problems in people. To test whether the mouse norovirus was involved, they orally infected the mice. A week later, the mutant mice displayed Paneth cell abnormalities. Infected control mice, in contrast, didn't. Paneth cells weren't directly infected with virus, but their gene expression patterns were altered. These findings show that a combination of the virus plus the gene mutation, but neither alone, causes abnormalities in the intestine.

When the researchers gave the mice a compound known to cause intestinal injury, mice carrying the Atg16L1 mutation and the virus, but not those carrying either alone, showed the hallmarks of human Crohn's disease. Blocking 2 molecules known to be involved in Crohn’s disease, TNFα and IFNγ, reduced the symptoms. These experiments show that the combination of the virus plus the mutation is the key to creating a Crohn's-like effect.

As bacteria are important in inflammatory bowel disease, the researchers tested broad spectrum antibiotics. They found that the antibiotics prevented the Crohn's-like response to intestinal injury in the virus-infected mutant mice.

"In Western society, about half of all copies of ATG16L1 contain the mutation linked to Crohn's," Stappenbeck says. "That means both copies of this gene are mutated in about 1 in every 3 persons. And yet Crohn's occurs in a small fraction of these individuals." This study shows how a virus, bacteria in the gut and other environmental factors might all interact to causes disease in someone carrying a genetic risk variant.

—by Harrison Wein, Ph.D.

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