A new enzyme originally developed for commercial food processing turns out to also quickly and nearly-completely break down whole gluten molecules as well as the T cell stimulatory peptides that cause celiac disease, a digestive disease with no current effective treatment other than avoiding wheat, barley or rye products.
In addition, the enzyme operates best in just the kind of physiological environment found in the human stomach and works 60 times faster than an earlier promising enzyme, which was not effective in acidic conditions and was inactivated by pepsin, both of which are found in the stomach.
"On the basis of our results, there now is a realistic chance that oral supplementation with an enzyme can ensure gluten degradation in the stomach before reaching the small intestine, where it causes problems for people with celiac disease," according to Frits Koning, researcher at the Leiden University Medical Center, The Netherlands, who headed the team that has published a new research paper on its work.
The paper, "Highly efficient gluten degradation with a newly identified prolyl endoprotease: implications for celiac disease," is in the online American Journal of Physiology- Gastrointestinal and Liver Physiology, published by The American Physiological Society. Research was by Dariusz Stepniak, Liesbeth Spaenij-Dekking, Cristina Mitea, Martine Moester, Arnoud de Ru, Renee Baak-Pablo, Peter van Veelen and Frits Koning of Leiden University Medical Center, the Netherlands, and Luppo Edens of DSM Food Specialties, Delft.
Clinical trials are likely next step
The new prolyl endoprotease (PEP) that was studied is derived from Aspergillus niger (AN), a common fungus. Strains of A. niger are used in industrial production of citric and gluconic acid as well as producing several food grade enzymes.
Because there are no animal models of celiac disease, "the in vivo efficacy of AN-PEP for gluten detoxification will ultimately have to be addressed in clinical studies involving celiac patients. AN-PEP appears to be a prime candidate for such clinical trials," the paper concluded. As for the timing of any such trials, Koning said: "This is an option the team hopes to explore in the future."
A disease of many paradoxes
Celiac disease affects about 2 million Americans and is also found in Europe, India and parts of the Middle East. It's caused by an uncontrolled immune response to wheat gluten and similar proteins of rye and barley that cause diarrhea, malnutrition and failure to thrive because it inhibits nutritional uptake.
"It's a Caucasian disease with a wide spectrum of symptoms; not all patients are equally affected, but we do not understand why this is the case," Koning said. "It is known to be associated with the HLA-DQ2 gene," he noted, "but while about 25% of the white population has this gene, only about one in 100 get the disease, so it's really a quite puzzling disease in many ways."
Currently the only way to elude the disease symptoms is by avoiding wheat, barley and rye products. "It sounds easy, but gluten especially is widespread in Western diets," Koning said. Gluten is often used as a food additive because it adds protein content inexpensively and also gives dough its elasticity and stickiness, which helps in manufacturing. For instance, Koning said: "Celiac patients can eat potato chips, but not if they have added paprika or other spices because they're 'glued' to the chip with gluten."
AN-PEP outstrips earlier enzyme by 60-fold
Earlier attempts at finding non-human proteases for gluten detoxification (first proposed in the late 1950s) focused on prolyl oligopeptidases (POP), most notably FM-POP, which was able to break down gluten sequences in vitro. However FM-POP's optimal operating pH is between 7 and 8, so it didn't work well in the more acidic stomach pH that goes down to 2 at one stage. A combination of pH 2 and pepsin "immediately inactivated FM-POP," the paper said. AN-PEP, on the other hand, is active from pH 2-8, with optimum effect around pH 4. The combination of pH 2 and pepsin didn't affect AN-PEP activity.
"An effective enzymatic treatment for celiac diseases requires means of destroying all or at least the vast majority of gluten derived T cell stimulatory sequences," the paper said. The key to this is to break the large gluten molecules (large peptides and intact proteins) into smaller pieces before they leave the stomach. Because food stays in the stomach one to four hours, speed of protein degradation is also important. Mass spectrometry comparisons showed that "degradation of gluten peptides by AN-PEP was on average [about 4 minutes, or] 60 times faster than degradation by FM-POP," the paper reported.
In addition to its ability to perform as a potential oral enzymatic therapy because it "is capable of degrading intact gluten molecules and T cell stimulatory epitopes from gluten into harmless fragments" AN-PEP has several additional commercial advantages, the paper said: "The enzyme is extremely stable and can be produced at acceptable cost at food grade quality in an industry setting."
Celiac disease is an HLA-linked disease related to Type 1 diabetes and rheumatoid arthritis in which autoimmune reactions cause the disease; similarly, immune reactions can lead to organ transplant rejection. Koning said it "isn't likely that AN-PEP would be of any therapeutic value in any of these HLA-associated diseases" because Type 1 diabetes and rheumatoid arthritis are real autoimmune diseases, where the immune system attacks parts of the body. In celiac disease, it is the gluten that is the target, not the body.
Reminder warning on early introduction of gluten products
Koning said feeding wheat (or barley or rye) products to infants before they're 6 months old isn't recommended because once an immune response develops "immuno-memory builds up and it doesn't go away." Indeed, Koning noted that in Sweden some years ago gluten was introduced into baby food, which led to a five-fold increase in celiac disease. The problem disappeared when gluten was removed.
Mayer Resnick | EurekAlert!
Scientists discover species of dolphin that existed along South Carolina coast
24.08.2017 | New York Institute of Technology
The science of fluoride flipping
24.08.2017 | University of North Carolina Health Care
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
24.08.2017 | Life Sciences
24.08.2017 | Life Sciences
24.08.2017 | Medical Engineering