A recombinant protein, developed by researchers at the CSIC's Barcelona Institute of Molecular Biology, degrades gluten more effectively than current alternatives. It degrades the toxic peptides in the stomach before they reach the intestine, thus preventing the characteristic symptoms of coeliac disease. It can be administered orally and can be used as an agent or food additive, or as a food supplement for a low-gluten diet.
Researchers have developed a recombinant protein that effectively degrades immunogenic peptides derived from gluten in foods such as bread, thus preventing these peptides from reaching the gut. Image: Unsplash
Coeliac disease is a chronic autoimmune disorder that affects people with a sensitivity to dietary gluten. It is caused by partially degraded gluten peptides that, when they cross the wall of the small intestine, trigger a severe pro-inflammatory autoimmune response.
Peptides that reach the intestine and can be toxic
Cereals contain several prolamin-rich proteins. When these are digested in the stomach, they are broken down into smaller proteins (peptides) that can be toxic. Among them, one of the most immunodominant gluten peptid is the 33-mer, a fragment of alpha-gliadin, a wheat prolamin.
The 33-mer peptide is able to resist gastric acid in the stomach and reach the small intestine, where it passes through the intestinal mucosa. In people with coeliac disease, 33-mer binds particularly easily to a receptor of the immune system (the human leukocyte antigen), which triggers the autoimmune and inflammatory response that leads to the characteristic manifestations of the disease.
Patients with coeliac disease must follow a strict gluten-free diet for life. However, these diets do not always guarantee the total absence of gluten and many coeliacs suffer from intestinal symptoms even when they follow such dietary restrictions. This has created a demand for effective treatments.
Tests in a dynamic gastrointestinal simulator, which mimics the human gut, have confirmed that this new recombinant protein performs significantly better at degrading gliadin than other gluten-degrading enzymes
Based on studies with a natural protein, neprosin, researchers have developed a recombinant protein that is even more effective than the original natural molecule in degrading immunogenic gluten peptides in the stomach. In vivo experiments in a murine model have demonstrated its efficacy. They have also obtained the three-dimensional structure, the mechanism of action, as well as its thermal stability, pH profile, and latency period, among other characteristics.
They have also successfully performed tests in a dynamic gastrointestinal simulator, which mimics the human intestine, and have compared its activity with other gluten-degrading enzymes, which have shown that this recombinant protein offers significantly better results degrading gliadin.
In all trials, the protein drastically reduces the amount of toxic peptides, remains stable and active in the strongly acidic gastric environment, and can resist digestive enzymes. Another advantage is that it is effective at low doses when combined with pepsin during digestion. Although it is not possible to speak of a cure or treatment, the protein would allow better management of coeliac disease as it can prevent or reduce the inflammatory response in the case of voluntary or accidental gluten ingestion.
For larger-scale trials, the team has developed an efficient recombinant production system that allows the production of large quantities of pure protein.
Contact:
Xavier Gregori
Deputy presidency for Innovation and Transference