REVIEW published: 17 March 2020 doi: 10.3389/fnut.2020.00029 Recent Progress and Recommendations on Celiac Disease From the Working Group on Prolamin Analysis and Toxicity Katharina A. Scherf 1, Carlo Catassi 2, Fernando Chirdo 3, Paul J. Ciclitira 4, Conleth Feighery 5, Carmen Gianfrani 6, Frits Koning 7, Knut E. A. Lundin 8, Detlef Schuppan 9, Marinus J. M. Smulders 10, Olivier Tranquet 11, Riccardo Troncone 12 and Peter Koehler 13* Edited by: 1 Department of Bioactive and Functional Food Chemistry, Institute of Applied Biosciences, Karlsruhe Institute of Technology Jun Lu, (KIT), Karlsruhe, Germany, 2 Department of Pediatrics, Polytechnic University of Marche, Ancona, Italy, 3 Instituto de Estudios Auckland University of Technology, Inmunologicos y Fisiopatologicos- IIFP (UNLP-CONICET), Universidad Nacional de La Plata, La Plata, Argentina, 4 Norwich New Zealand Medical School, University of East Anglia, Norwich, United Kingdom, 5 St. James’s Hospital, University of Dublin, Dublin, 6 7 Reviewed by: Ireland, Institute of Biochemistry and Cell Biology, Italian National Council of Research, Naples, Italy, Leiden University 8 Sachin Rustgi, Medical Centre, Leiden, Netherlands, Department of Gastroenterology, Oslo University Hospital Rikshospitalet and Stiftelsen 9 Clemson University, United States KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway, Institute for Translational Medicine, 10 Govind K. Makharia, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany, Plant Breeding, Wageningen 11 12 All India Institute of Medical University & Research, Wageningen, Netherlands, INRAE, UR BIA, Nantes, France, European Laboratory for the Sciences, India Investigation of Food Induced Diseases (ELFID), Department of Medical Translational Sciences, University Federico II, Naples, 13 Emanuele Zannini, Italy, biotask AG, Esslingen, Germany University College Cork, Ireland Luis Rodrigo, Celiac disease (CD) affects a growing number of individuals worldwide. To elucidate the Central University Hospital of Asturias, Spain causes for this increase, future multidisciplinary collaboration is key to understanding *Correspondence: the interactions between immunoreactive components in gluten-containing cereals and Peter Koehler the human gastrointestinal tract and immune system and to devise strategies for CD [email protected] prevention and treatment beyond the gluten-free diet. During the last meetings, the Specialty section: Working Group on Prolamin Analysis and Toxicity (Prolamin Working Group, PWG) This article was submitted to discussed recent progress in the field together with key stakeholders from celiac Nutrition and Food Science Technology, disease societies, academia, industry and regulatory bodies. Based on the current state a section of the journal of knowledge, this perspective from the PWG members provides recommendations Frontiers in Nutrition regarding clinical, analytical and legal aspects of CD. The selected key topics that require Received: 15 December 2019 future multidisciplinary collaborative efforts in the clinical field are to collect robust data Accepted: 26 February 2020 Published: 17 March 2020 on the increasing prevalence of CD, to evaluate what is special about gluten-specific Citation: T cells, to study their kinetics and transcriptomics and to put some attention to the Scherf KA, Catassi C, Chirdo F, identification of the environmental agents that facilitate the breaking of tolerance to Ciclitira PJ, Feighery C, Gianfrani C, Koning F, Lundin KEA, Schuppan D, gluten. In the field of gluten analysis, the key topics are the precise assessment of Smulders MJM, Tranquet O, gluten immunoreactive components in wheat, rye and barley to understand how these Troncone R and Koehler P (2020) are affected by genetic and environmental factors, the comparison of different methods Recent Progress and Recommendations on Celiac Disease for compliance monitoring of gluten-free products and the development of improved From the Working Group on Prolamin reference materials for gluten analysis. Analysis and Toxicity. Front. Nutr. 7:29. doi: 10.3389/fnut.2020.00029 Keywords: barley, celiac disease, gluten, gluten-free diet, Prolamin Working Group, rye, wheat Frontiers in Nutrition | www.frontiersin.org 1 March 2020 | Volume 7 | Article 29 Scherf et al. Prolamin Working Group INTRODUCTION only effective treatment so far is a GFD that essentially relies on the consumption of naturally gluten-free foods such as animal- About 60% of agricultural land worldwide is used to grow based products, fruits, vegetables, legumes and nuts as well as 6 cereals, with maize (1,135 × 10 metric tons), wheat (772 × dietary gluten-free products that may not contain more than 6 6 10 metric tons) and paddy rice (770 × 10 metric tons) as 20 mg/kg of gluten according to Codex Alimentarius (Codex major crops in terms of global production (data from 2017, Standard 118-19792). There are several ongoing attempts to 1 FAOSTAT ). As an important source of dietary nutrients such develop non-dietary treatments of the disease—this is briefly as carbohydrates, proteins, dietary fiber, vitamins and minerals, discussed later. wheat is an essential cornerstone for food security. However, Founded in 1985 by Professor Wim Hekkens, University the consumption of products made of wheat, and the closely of Leiden, The Netherlands, the Working Group on Prolamin related cereals rye and barley, may cause adverse reactions Analysis and Toxicity (Prolamin Working Group, PWG) such as celiac disease (CD), non-celiac gluten/wheat sensitivity coordinates multidisciplinary research efforts primarily related (NCGS) and wheat allergy. With increasing evidence from to CD. The PWG currently has 13 executive members all of epidemiological studies pointing to a large number of affected whom are renowned experts in the fields of pediatric and adult individuals in many countries around the world, there is a gastroenterology, immunology, biochemistry, plant science, food strong need to understand the fundamental interactions between chemistry, and gluten analysis. Building upon this unique immunoreactive components in gluten-containing cereals and multidisciplinary knowledgebase, the PWG has made important the human gastrointestinal tract and immune system in order to achievements both in clinical research into CD and in improving develop strategies for disease prevention and treatment beyond food safety for CD patients by advancing analytical methods for the gluten-free diet (GFD). The term “gluten” includes the closely gluten detection. related storage proteins of wheat (gliadins and glutenins), rye Some of the highlighted clinical research work of the PWG (secalins), barley (hordeins), and oats (avenins). The part of include the assessment of the safety of oats in the GFD (10–12), gluten soluble in aqueous alcohols has been termed prolamins the establishment of 10mg of gluten intake per day as the safe and the insoluble part glutelins. gluten threshold for the vast majority of CD patients (13), the CD is defined as a lifelong small intestinal immune search for wheat species with a reduced content of immunogenic enteropathy with autoimmune features caused by ingestion of sequences for disease prevention (14, 15), and the study of the gluten from wheat, rye and barley in subjects with a dominant signals for T- and B-cell recruitment into the lamina propria and and necessary genetic predisposition [human leukocyte antigen epithelial compartment (16). (HLA)-DQ2 or -DQ8] (1). The main known environmental Having been granted observer status at Codex Alimentarius factor responsible for CD is the consumption of gluten, but in 1999, the PWG plays a leading role in the development there still needs to be a largely unknown factor as initial of enzyme-linked immunosorbent assays (ELISA) for gluten trigger of the disease. Certain viruses and bacteria are prime analysis (17) and the validation of such methods in collaboration suspects, and the idea is that virus infection can prime the with the Cereals & Grains Association [formerly known as AACC immune system in susceptible individuals so that not only the International; (18–20)], and AOAC International (21). It also virus is recognized and defeated but the intestinal immune produced the only well-characterized reference material, the so- system also misinterprets gluten as “dangerous” (vide infra). called PWG-gliadin (22) that is used to calibrate a variety of Patients develop characteristic mucosal (usually IgA) antibodies gluten analytical methods and is available in 100 mg batches to the autoantigen tissue transglutaminase [TG2, (2)]. TG2 can from the Association of Cereal Research (Arbeitsgemeinschaft deamidate gluten peptides, which improves their presentation by Getreideforschung e.V., Detmold, Germany). HLA-DQ2 or -DQ8 on antigen-presenting cells of the intestinal During its annual meetings, the PWG regularly unites a mucosa, and this increases their T-cell stimulatory potential (3, select group of about 60 international stakeholders including 4). While such gluten-specific T-cell responses are characteristic researchers, celiac disease societies, regulatory bodies, for CD, it is unclear which events cause the loss of mucosal manufacturers of gluten-free foods and raw materials, and tolerance to food antigens in CD. Many studies now imply a role manufacturers of test systems for gluten analysis in foods. This for additional environmental agents, including the exposure to paper will report the recent