Research led by the Institute of Molecular Biology of Barcelona of the Spanish National Council for Scientific Research (IBMB-CSIC), located in the Barcelona Science Park (PCB-UB), the Institute for Research in Nutrition and Food Safety (INSA) and the Faculty of Pharmacy and Food Sciences of the University of Barcelona (UB) has successfully designed and tested a gluten-degrading molecule that could be a promising ally for the management of celiac disease.

There is currently a complete lack of therapeutic alternatives beyond a gluten-free diet, which is difficult to maintain in Western societies based on wheat consumption. The major breakthrough is that the molecule is effective at very low concentrations and under pH 2 conditions—those of the stomach—something that none of the molecules currently available have been able to achieve to a relevant extent. Although these are marketed as nutritional supplements, they do not provide an effective alternative to gluten-free diets.

The study has been published in the journal EMBO Molecular Medicine and is led by researchers F. Xavier Gomis-Rüth, from IBMB-CSIC, and Francisco J. Pérez Cano, from INSA-UB. Its first authors are Marina Girbal-González and Arturo Rodríguez Banqueri, from INSA-UB and IBMB-CSIC, respectively. Teams from the Institute of Food Science Research (CSIC-UAM), the University of Salzburg (Austria), and the Technical University of Munich (Germany) also participated.

Counteract the “trigger” of coeliac disease

The trigger of coeliac disease is prolamins, a group of proteins found in most common cereals in our diet, such as gliadin in wheat gluten. When these proteins are digested in the stomach, they are broken down into smaller fragments (peptides). Some of these can be toxic, such as gluten immunogenic peptides (GIPs), which are able to resist gastric acids and reach the small intestine. Among them, the “33-mer” stands out—a fragment of α-gliadin from wheat gluten that is highly immunogenic.

This poses a problem for people with coeliac disease, because once they reach the small intestine, the 33-mer and other GIPs bind very readily to a receptor of the immune system (the human leukocyte antigen, or HLA), thereby triggering the inflammatory autoimmune response that leads to the characteristic manifestations of the disease.

Four years ago, the Proteolysis Group at IBMB-CSIC, led by F. Xavier Gomis-Rüth, reported in a Nature Communications article that neprosin—a molecule naturally found in the digestive fluid of the carnivorous plant Nepenthes ventrata—is able to cleave GIPs. In collaboration with the Autoimmunity, Immunonutrition and Tolerance group at the Faculty of Pharmacy and Food Sciences of the University of Barcelona, led by Francisco José Pérez Cano, they showed that neprosin can degrade the 33-mer peptide and other GIPs before they reach the intestine, thereby potentially preventing this inflammatory autoimmune response.

Designed through molecular engineering

In the new study, the team designed and tested a variant derived from neprosin. Named celiacase, this new molecule shows peak activity at the stomach’s gastric pH and, in synergy with pepsin from our digestive system, is able to break down cereal GIPs and wheat gliadin before they pass into the duodenum.

“There are other proteases, generally referred to as glutenases, that degrade gluten, but they are not fully active under pH 2 conditions—the stomach’s pH—rather at pH 7, that of the duodenum, when the predigested food has already left the stomach,” explains Gomis-Rüth. “This makes it necessary to increase the doses to levels that make them unviable for therapeutic use”.

The team tested the molecule in vivo using a mouse model developed by the University of Chicago, currently the one that best reproduces coeliac disease. The results show that celiacase is effective at very low doses and is able to attenuate the manifestations of the disease in mice receiving gluten, even in high amounts. “Intestinal atrophy, inflammation, the antibody response and dysbiosis—that is, alterations in the composition of the microbiota—were reduced,” says Pérez Cano. “In addition, immunoregulatory markers were restored to normal levels, as were microbial metabolic pathways.”

The results show that celiacase, a molecule stable under stomach acid conditions, could serve as an adjunct therapeutic alternative to a gluten-free diet.

Un altre avantatge de la celiacasa és que a partir del duodè ja no és activa. “Quan ha fet la seva funció, ja no interessa que segueixi activa, perquè no interfereixi amb cap altra proteïna de l’organisme”, afegeix Gomis-Ruth.

The molecule and its potential applications have been protected by a patent, and the team is taking the first steps to create a spin-off and move the development towards more advanced stages, for which they are interested in securing funding.

» Article of reference: Marina Girbal-González, Arturo Rodríguez-Banqueri, Hadeel Swaid, Soraia R. Mendes, Laura Garzón-Flores, Juan Sebastián Ramírez-Larrota, Carolina Cueva, M. Victoria Moreno-Arribas, Christof Regl, Christian G. Huber, Katharina A. Scherf, María José Rodríguez-Lagunas, Àngels Franch-Masferrer, Ulrich Eckhard, Francisco J. Pérez-Cano and F. Xavier Gomis-Rüth. Targeted enzymatic therapy for coeliac disease. EMBO Molecular Medicine. DOI: https://link.springer.com/article/10.1038/s44321-026-00430-8.

» Link to the news: CSIC Catalunya website [+]