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New discovery about the gut’s immune defenses may reveal the causes of inflammatory bowel disease

August 25, 2014
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An important discovery about how our gut protects our bodies from dangerous infections may help scientists understand the causes of inflammatory bowel disease, a group of common disorders that cause painful abdominal cramps, diarrhea, vomiting and other debilitating symptoms.  

“We know that every food-borne bacterial pathogen that we encounter tries to infect the cells that line the gut, but until now it wasn’t clear how these cells defended against infection,” says Dr. Bruce Vallance, the senior and co-corresponding author on the study recently published in the journal Cell Host & Microbe. “We’ve discovered that these cells defend themselves against dangerous bacteria using groups of proteins called inflammasomes.”

Dr. Vallance is a CFRI scientist at BC Children’s Hospital, holder of The Children with Intestinal and Liver Disorders (CH.I.L.D.) Foundation Research Chair in Pediatric Gastroenterology, and Associate Professor with the UBC Department of Pediatrics.

Inflammasomes are groups of proteins that work together to trigger an immune response. Previously, scientists thought that the cells lining the gut weren’t able to make inflammasomes because these cells don’t produce a protein called caspase 1. Scientists believed caspase 1 was a necessary component of inflammasomes because all known inflammasomes used capase 1 as a building block.

In collaboration with U.S. colleagues, Dr. Vallance’s team discovered that the cells lining the gut do in fact make inflammasomes. Instead of caspase 1, inflammasomes in the human gut are made up of another protein called caspase 4.

The way inflammasomes in the gut protect us from infection is also unique. When inflammasomes in the gut encounter dangerous bacteria, they separate from the intestinal lining and pass out of the body as waste, taking the bacteria with them. Other inflammasomes in the human body fight off infection mainly by triggering inflammation.

This discovery has the potential to improve understanding of the underlying causes of inflammatory bowel disease (IBD). Scientists now suspect that many people with IBD develop the disease because their intestinal cells don’t properly activate inflammasomes, making them more susceptible to chronic bacterial infections. It’s also possible that inflammasomes help repair damage to the intestinal walls, and that this healing function is impaired in people with IBD.

IBD is an umbrella term for Crohn’s disease and ulcerative colitis. The painful and potentially embarrassing effects of IBD have a particularly traumatic effect on children, who often grow up all but confined to their homes, unable to play sports or participate in other normal childhood activities.

Every year at BC Children’s Hospital, approximately 100 children are diagnosed with IBD. Roughly 233,000 Canadians have IBD.

There’s no cure for IBD and about one-third of patients eventually become resistant to current therapies. Dr. Vallance’s lab was built and equipped with funding from the CH.I.L.D. Foundation. It is the first in B.C. dedicated to finding a cure for IBD.

In order to further explore how gut inflammasomes work and how they malfunction in patients, Dr. Vallance and his colleagues plan to grow “mini-guts” in the laboratory using donated intestinal tissue from children who have been diagnosed with IBD. These tissue samples will be collected by gastroenterologists at BC Children's as part of a patient's routine treatment and diagnosis.

“Once we understand how inflammasomes are involved in IBD, we can start to work on more targeted therapies,” says Dr. Vallance.

Read more:

Leigh Knodler, Bruce Vallance, et al, “Noncanonical Inflammasome Activation of Caspase-4/Caspase-11 Mediates Epithelial Defenses against Enteric Bacterial Pathogens,” in Cell-Host & Microbe, August 13, 2014.