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  • Jefferson Adams
    Jefferson Adams

    AN-PEP Digestive Enzymes Degrade Gluten Better Than Most Other Digestive Enzymes

    Reviewed and edited by a celiac disease expert.

    The pure enzyme AN-PEP effectively degraded all nine epitopes in the pH range of the stomach at much lower dose.

    AN-PEP Digestive Enzymes Degrade Gluten Better Than Most Other Digestive Enzymes - Photo: CC--SuperFantastic
    Caption: Photo: CC--SuperFantastic

    Celiac.com 06/22/2015 - Currently available digestive enzymes do not fully degrade gluten, and are thus of questionable use for people with celiac disease or gluten intolerance, say a team of researchers. Prior research had shown that post-proline cutting enzyme effectively degrade the immunogenic gluten peptides. Several existing digestive enzyme supplements claim to promote gluten degradation.

    The research team set out to assess the degradation of immunogenic gluten epitopes by currently available digestive enzymes. The team included G. Janssen, C. Christis, Y. Kooy-Winkelaar, L. Edens, D. Smith, P. van Veelen, and F. Koning. They are variously affiliated with the Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands, DSM Food Specialties in Delft, The Netherlands, and DSM Food Specialties in South Bend, Indiana, USA.



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    For their study, they assessed five commercially available digestive enzyme supplements along with purified digestive enzymes. They assessed these enzymes using enzyme assays and mass spectrometric identification. They monitored gluten epitope degradation using R5 ELISA, mass spectrometric analysis of the degradation products, and T cell proliferation assays. 

    They found that the enzyme supplements leave the nine immunogenic epitopes of the 26-mer and 33-mer gliadin fragments largely intact. This is due to the high proline content of gluten molecules, which prevents gastrointestinal proteases from fully degrading them, leaving large proline-rich gluten fragments intact, including an immunogenic 33-mer from α-gliadin and a 26-mer from γ-gliadin.

    These latter peptides can trigger pro-inflammatory T cell responses resulting in tissue remodeling, malnutrition and a variety of other complications.

    In contrast, the pure enzyme AN-PEP effectively degraded all nine epitopes in the pH range of the stomach at much lower dose.

    From these results, the team concludes that most of the currently available digestive enzyme supplements are ineffective in degrading immunogenic gluten epitopes, but the AN-PEP do effectively degrade gliadin fragments.

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  • About Me

    Jefferson Adams

    Jefferson Adams is Celiac.com's senior writer and Digital Content Director. He earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,500 articles on celiac disease. His coursework includes studies in science, scientific methodology, biology, anatomy, medicine, logic, and advanced research. He previously served as SF Health News Examiner for Examiner.com, and devised health and medical content for Sharecare.com. Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book "Cereal Killers" by Scott Adams and Ron Hoggan, Ed.D.


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  • Related Articles

    Jefferson Adams
    Celiac.com 10/14/2013 - A team of researchers recently set out to assesses the safety and efficacy of Aspergillus niger prolyl endoprotease (AN–PEP) to mitigate the effects of gluten in celiac patients.
    For their study, the researchers included celiac patients with positive serology and subtotal or total villous atrophy on duodenal biopsies, who follow a strict gluten-free diet (GFD) resulting in normalised antibodies and mucosal healing classified as Marsh 0 or I were included.
    Prior to this randomized double-blind placebo-controlled pilot study, the team measured complaints, quality-of-life, serum antibodies, immunophenotyping of T-cells and duodenal mucosa immunohistology.
    They then had patients consume approximately 7 grams of gluten per day as toast, along with AN-PEP for a two week safety phase. The team put subjects through a two week washout phase where they followed their usual gluten-free diets. The team then randomly assigned 14 patients to receive gluten, with either AN-PEP or placebo, for a two week efficacy phase.
    They also collected patient questionnaires on serum and quality of life during and after the safety, washout and efficacy phase. They conducted duodenal biopsies after both the safety phase and the efficacy phase. Change in histological evaluation according to the modified Marsh classification served as the primary endpoint.
    In all, 16 adults participated in the study. No serious adverse events occurred during the trial and no patients withdrew during the trial. The average score for the gastrointestinal subcategory of the celiac disease quality (CDQ) was relatively high throughout the study, indicating that AN-PEP was well tolerated.
    In the efficacy phase, the team saw no significant deterioration in the CDQ scores of patients consuming gluten with placebo or gluten with AN-PEP, nor did they observe any other differences between the groups. During the efficacy phase, neither the placebo nor the AN-PEP group showed significant antibody titers. IgA-EM concentrations remained negative in both groups.
    The team excluded two patients from entering the efficacy phase because their mucosa showed an increase of two Marsh steps after the safety phase, yet with undetectable serum antibodies. A total of 14 patients were considered histologically stable on gluten with AN-PEP.
    Also, after the efficacy phase, the team saw no significant deterioration in immunohistological and flow cytometric evaluation in the group consuming placebo compared to the group receiving AN-PEP.
    Furthermore, in four out of seven patients on placebo, IgA-tTG deposit staining increased after two weeks of gluten intake compared to baseline.
    In the seven patients receiving AN-PEP, one patient showed increased and one showed decreased IgA-tTG deposits.
    AN–PEP appears to be well tolerated. However, the primary endpoint was not met due to lack of clinical deterioration upon placebo, impeding an effect of AN–PEP.
    The research team included Greetje J Tack, Jolanda MW van de Water, Chris J Mulder of the Department of Gastroenterology and Hepatology, VU University Medical Centre in Amsterdam, The Netherlands; Engelina MC Kooy-Winkelaar, Jeroen van Bergen, and Frits Koning of the Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre in Leiden, The Netherlands; Petra Bonnet, B Mary E von Blomberg, and Marco WJ Schreurs from the Department of Pathology, VU University Medical Centre, in Amsterdam, The Netherlands; Anita CE Vreugdenhil, with Department of Paediatrics, University Hospital Maastricht in Maastricht, The Netherlands; and Ilma Korponay-Szabo, with the Department of Paediatrics, University of Debrecen in Hungary, and the Paediatric Research Centre, University of Tampere, in Tampere, Finland.
    Source:
    World Journal of Gastroenterology, 10/03/2013


    Jefferson Adams
    Celiac.com 02/27/2014 - For many people with celiac disease, one of the numerous downsides of the condition is the constant threat of an adverse reaction triggered by accidental gluten consumption. Because reactions to gluten ingestion can be severe for some celiac patients, many clinicians are looking to see if anything can be done to lessen the effects gluten reactions in celiac patients once they have started.
    A team of researchers sought to provide at least one possible answer by looking into the safety and efficacy of Aspergillus niger prolyl endoprotease (AN-PEP) to lessen effects gluten reactions in celiac patients. The researchers included G.J. Tack, J.M. van de Water, M.J. Bruins, E.M Kooy-Winkelaar, J. van Bergen, P. Bonnet, A.C. Vreugdenhil, I. Korponay-Szabo, L. Edens, B.M. von Blomberg, M.W. Schreurs, C.J. Mulder, and F. Koning. They are all affiliated with the Department of Gastroenterology and Hepatology, VU University Medical Centre, 1007 MB Amsterdam, The Netherlands.
    For their study, the team enrolled 16 adults with celiac disease as confirmed by positive blood test and biopsy-confirmed subtotal or total villous atrophy. All patients were following a strict gluten-free diet, and showed normalized antibodies and mucosal healing classified as Marsh 0 or I.
    In their randomized double-blind placebo-controlled pilot study, the team had patients consume wheat toast, totaling about 7 grams of gluten per day, with AN-PEP for a two-week safety phase. After a two-week washout period with adherence of the usual gluten-free diet, 14 patients were randomized to receive gluten with either AN-PEP or placebo for there two-week efficacy phase.
    Baseline measurements included complaints, quality-of-life, serum antibodies, immuno-phenotyping of T-cells and duodenal mucosa immuno-histology. The team collected both serum samples and quality of life questionnaires during and after the safety, washout and efficacy phase. They conducted duodenal biopsies after both safety and efficacy phases. The primary endpoint was a change in histological evaluation according to the modified Marsh classification.
    None of the sixteen adults in the study suffered serious adverse events, and no patients withdrew during the trial. Overall scores for the gastrointestinal subcategory of the celiac disease quality (CDQ) remains fairly high throughout the study, indicating that AN-PEP was well tolerated. Through the efficacy phase, CDQ scores for patients consuming gluten with placebo or gluten with AN-PEP remained largely unchanged, and researchers observed no differences between the groups. Moreover, neither the placebo group nor the AN-PEP group developed significant antibody titers, and IgA-EM concentrations remained negative for both groups.
    The team excluded two patients from entering the efficacy phase because their mucosa showed an increase of two Marsh steps after the safety phase, even though their serum antibodies remained undetectable.
    A total of 14 patients were considered histologically stable on gluten with AN-PEP. Also after the efficacy phase, the team saw no significant deterioration in immunohistological and flow cytometric values between the group consuming placebo compared to the group receiving AN-PEP.
    Furthermore, compared to baseline, after two weeks of gluten four out of seven patients on placebo showed increased IgA-tTG deposit staining. In the seven patients receiving AN-PEP, one patient showed increased and one showed decreased IgA-tTG deposits.
    AN-PEP appears to be well tolerated. However, the primary endpoint was not met due to lack of clinical deterioration upon placebo, impeding an effect of AN-PEP.
    Source:
    World J Gastroenterol. 2013 Sep 21;19(35):5837-47. doi: 10.3748/wjg.v19.i35.5837.


    Jefferson Adams
    Celiac.com 06/02/2014 - Despite following a gluten-free diet, many people with celiac disease continue to have symptoms, and to suffer from ongoing small intestinal inflammation. Can a drug be created to alleviate such symptoms and inflammation, and protect celiacs on a gluten-free diet against small amounts of gluten contamination?
    San Carlos California-based Alvine Pharmaceuticals is conducting a phase 2 trial to determine whether their drug, ALV003, an orally administered mixture of 2 recombinant gluten-specific proteases can protect celiac disease patients from gluten-induced mucosal damage. For this trial, Alvine is working with researchers Marja-Leena Lähdeaho, Katri Kaukinen, Kaija Laurila, Pekka Vuotikka, Olli-Pekka Koivurova, Tiina Kärjä-Lahdensuu, Annette Marcantonio, Daniel C. Adelman, and Markku Mäki.
    They are affiliated with the School of Medicine and Tampere University Hospital at the University of Tampere; the Department of Gastroenterology and Alimentary Tract Surgery at Tampere University Hospital and School of Medicine at the University of Tampere, and FinnMedi Oy in Tampere, Finland; the Department of Medicine at Seinäjoki Central Hospital in Seinäjoki, Finland; Liikuntaklinikka, Oulu Diakonissalaitos; and Terveys, Oulu Diakonissalaitos, Oulu, Finland.
    For their Phase 2 trial, the research team first established two grams of gluten per day as the optimal challenge dose for their 6-week gluten study. They then randomly assigned 20 adults with biopsy-proven celiac disease to receive ALV003, and twenty-one to receive a placebo. Both groups also received 2 grams of gluten each day. The team conducted duodenal biopsies at baseline, and after gluten challenge, focusing on the ratio of villus height to crypt depth and densities of intraepithelial lymphocytes.
    A total of seven patients dropped out due to adverse reactions. Four were receiving ALV003, and three were receiving the placebo. Sixteen patients given ALV003 and 18 given placebo were eligible for efficacy evaluation. Biopsies from subjects in the placebo group showed evidence of mucosal injury after gluten challenge, with average villus height to crypt depth ratio changed from 2.8 before challenge to 2.0 afterward. (P = .0007; density of CD3þ intraepithelial lymphocytes changed from 61 to 91 cells/mm after challenge; P = .0003).
    However, the team saw no significant mucosal deterioration in biopsies from the ALV003 group. The two groups showed no significant differences in symptoms, though they did show substantial differences in morphologic changes, and CD3þ intraepithelial lymphocyte counts differed significantly from baseline to week 6 (P = .0133 and P = .0123, respectively). This small, but important, step means that ALV003 did provide significant protection against gluten-induced gut damage for people with celiac disease on an otherwise gluten-free diet, which means that Alvine can continue to the next phases in the development process.
    If successful, glutenase ALV003 will be the first drug to protect people with celiac disease against gut damage from small amounts of gluten.
    Source:
    Clinicaltrial.gov, Numbers: NCT00959114 and NCT0125569


    Jefferson Adams
    Celiac.com 10/14/2014 - A new drug designed to prevent gluten uptake in the gut is showing some promise for the treatment of celiac disease.
    The drug, larazotide acetate, significantly reduced symptoms in a large double-blind, placebo-controlled trial. The drug prevents gluten uptake by closing tight junctions in the gastrointestinal (GI) tract.
    The drug is intended to supplement, rather than replace, the gluten-free diet that makes up the standard celiac disease treatment. Specifically, the drug is designed to help patients who continue to experience symptoms despite efforts to avoid gluten, and will not allow celiac patients to eat gluten with impunity.
    Some experts are cautioning celiac disease patients against high expectations. Joseph A. Murray, MD, of the Division of Gastroenterology and Hepatology at Mayo Clinic, in Rochester, Minnesota, said that, even if the drug is approved, it would not be a cure for celiac disease, but just another way to control symptoms for those already on a gluten-free diet.
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    Source:
    Gastroenterology and Endoscopy News. SEPTEMBER 2014 | VOLUME: 65:9


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