Gluten intolerance: a new target for treating the disease

Celiac disease, or gluten intolerance, is a serious autoimmune disease that affects the gut. It occurs when people with it develop hypersensitivity to gluten, a substance found in wheat, rye and barley.

An international Franco-Italian research team has discovered a new molecular player involved primarily in the development of gluten intolerance, the mutation of the gene coding for “CFTR” was also present in cystic fibrosis, a disease where molecules targeting this anomaly are under development.

Their discovery, published in The EMBO Journalsuggests that a new target would be available for a therapeutic approach to celiac disease.

Gluten intolerance

Celiac disease can appear in genetically predisposed people in whom environmental factors trigger it. When people with celiac disease eat gluten, their immune system triggers an immune reaction against their own digestive cells, damaging the lining of the small intestine (the inner layer of the lining of the intestine).

Nearly one person in 100 suffers from celiac disease, but the frequency of this disease is about three times higher in patients who also suffer from cystic fibrosis. “This co-occurrence led us to wonder if there was a link between the two diseases at the molecular level,” said Luigi Maiuri of the University of Eastern Piedmont in Novara and the San Raffaele Scientific Institute, Milan, in Italy.

Common mechanism in cystic fibrosis

Cystic fibrosis is characterized by the accumulation of thick, sticky mucus in the bronchi of the lungs and intestines of patients. It is caused by mutations in the gene encoding the “transmembrane conductance regulator” (or CFTR).

CFTR is a protein that transports ions across cell walls and plays an important role in mucus retention. When it fails, the mucus thickens and builds up. Additionally, CFTR dysfunction triggers a number of associated reactions in the lungs and other organs, including the gut, via activation of the immune system. Since these effects are very similar to the responses triggered by gluten in intolerant patients, the research team took a closer look at the molecular underpinnings of these similarities.

Molecular mechanisms deciphered

Gluten is naturally difficult to digest, so relatively long proteins (peptides) penetrate the wall of the intestine. Using gluten-sensitive human intestinal cell lines, the researchers found that a gluten-specific peptide, P31-43, binds directly to CFTR and alters its function. This interaction then triggers cellular stress and inflammation, suggesting that CFTR plays a central role in mediating gluten sensitivity in intolerant patients.

Importantly, the interaction between P31-43 and CFTR can be inhibited by a “CFTR potentiator”, called “VX-770”. When samples of intestinal cells or tissues taken from patients with celiac disease were pre-incubated with VX-770 before being exposed to the P31-43 peptide, it no longer elicited an immune reaction. Thus, VX-770 would protect epithelial cells sensitive to gluten from the harmful effects of gluten. The researchers then verified that VX-770 could also protect gluten-sensitive mice against gluten-induced intestinal symptoms.

There is as yet no cure for celiac disease and the only current treatment strategy is to follow a strict gluten-free diet. This study is a promising step towards the development of a specific treatment for this disease. He suggests that “CFTR potentiators”, which are being developed for the treatment of cystic fibrosis, could also be used for the treatment of celiac disease.