by Saul Geller
Celiac disease is currently treated with a strict and life-long gluten-free diet which can be very challenging and expensive. Alternative therapies to this diet are being researched, such as drugs that target and eliminate gluten on its way through the digestive tract and compounds that strengthen the intestinal lining to prevent gluten from getting into the body. A recent study, published by The American Journal of Gastroenterology has uncovered a new potential method for treating celiac disease.
The study, titled “Novel Role of the Serine Protease Inhibitor Elafin in Gluten-Related Disorders” was first published online on April 8th, 2014. It’s authors, doctors and scientists hailing from all over the world, looked at several different aspects of a protein called elafin and its effect on gluten-related disorders like celiac disease.
Shown above is a cartoon of the crystal structure of human elafin, colored in pink, complexed with an elastase protein.
In humans, elafin is a protein found in the gastrointestinal tract that inhibits certain other proteins. It has previously been found to be less expressed in patients with inflammatory bowel disease but if this is also true in patients with celiac disease had not yet been established. Elafin is also a substrate for tissue transglutaminase (tTG), a protein known to be involved in the pathogenesis of celiac disease.
In this study, the authors conducted three experiments investigating elafin. They first looked into elafin’s expression among three groups: 10 patients with active celiac disease, 9 patients with celiac disease but had been on a gluten-free diet for at least a year, and 11 patients without celiac disease but who were undergoing a gastroduodenal endoscopy. They found that elafin was less common in patients with active celiac disease compared to the the control group of patients without CD. The group of patients with CD but on a gluten-free diet had levels of elafin in between the other groups but the difference did not reach statistical significance.
Then they examined how elafin affected tissue-transglutaminase (tTG) in the lab. Gliadin, a component of gluten, gets cleaved into fragments after being digested and one of these fragments, a 33-amino acid-long peptide chain, is the primary immunogen for patients with celiac disease. This peptide becomes a stronger immunogen, meaning it more potently activates the immune system, after it undergoes deamidation by tTG. Test tubes of tTG and the gliadin fragment, along with varying levels of elafin, were incubated and liquid chromatography-mass spectrometry was used to see how much deamidation of gliadin had occurred. The results showed elafin was able to significantly slow down tTG’s deamidation of the immunogen.
Lastly, the authors explored the anti-inflammatory and barrier-enhancing characteristics of elafin in a living, breathing organism, a mice model of celiac disease. Elafin was inserted into the intestine via a bacterium called Lactococcus lacti. The L. lacti was genetically modified to produce the elafin, a method that had been used previously in mice models of colitis. In the gluten-sensitive mice treated with elafin, inflammation and barrier function were both improved compared to controls after being given gliadin.
The results of these three experiments suggests that the loss of elafin from the GI tract might play a role in celiac disease and that elafin may be a prime target for future therapies for gluten-related disorders, especially celiac disease. The next step would be to fully investigate how elafin improves inflammation and intestinal barrier function.