The struggle against Celiac Disease

Development of safe foods for Celiac patients – A multidisciplinary approach

Introduction

Celiac disease (CD) is a common, food-related inflammatory disorder of the small intestine caused by the ingestion of gluten in genetically predisposed individuals. In children, the main symptoms are chronic bowel ache, diarrhea, and retardation of growth. In adults, chronic fatigue, headache, bowel complaints, reduced fertility, miscarriage, dermatitis herpetiformis, osteoporosis, and even, in rare cases, intestinal cancer (lymphoma) can occur. Currently, a lifelong gluten-free diet is the only treatment.

Around 1% of the Western population suffers from Celiac disease. Unfortunately, the vast majority of these people are not even aware of having the disease due to large-scale underdiagnosis and wrong diagnosis. For example, in the Netherlands, the Dutch Celiac Disease Patient Society has a membership of over 10,000 diagnosed individuals, which, according to epidemiological studies, accounts for only 10% of the total Dutch population that actually has this disease. In the US, this situation seems to be even worse: about 50,000 individuals have currently been diagnosed with CD, while the NIH estimates more than 2 million people actually suffer from the disease, which would correspond to 1 in 133 people (NIH, 2010; Fasano et al. 2003).

Furthermore, the incidence of CD seems to be increasing. An extended cohort study over the last 50 years, carried out in the US among undiagnosed populations of young, mostly male adults, revealed an over fourfold increase in the prevalence of CD over the last 50 years, and a nearly fourfold increased risk of death (Rubio-Tapia et al. 2009).

A Finnish cohort study over 20 years showed a statistically significant doubling of the prevalence of CD among both sexes, and in different age groups, to almost 2% of the population (Lohi et al. 2007). Moreover, the consumption of gluten has also recently been associated with the development of type 1 diabetes (Zhernakova et al. 2009). Seen from another perspective, the annual growth of the gluten-free market worldwide over the last six years is about 30%, which is much greater than the annual growth in CD-diagnosed individuals, and reflects a general trend in food consumption towards gluten-free (“pseudo-celiac”). Apparently, many people, not only CD patients, feel more comfortable on a gluten-free diet.

Gluten in foods

A gluten-free diet is a form of secondary prevention, i.e. prevention of the disease after it has been triggered. A gluten-free diet, which affects the quality of life of the patient, is not widely available, is more expensive, and has a lower palatability. It is also difficult to avoid wheat gluten in food products. A survey in Australia of more than 10,000 supermarket items detected wheat in almost 30% of labeled products (Atchison et al. 2010). In some of these products, the connection to wheat was visible and even proactively marketed; in other products, it was just invisible. The latter group contained not only processed foods, but also foods that are not commonly associated with wheat, such as canned vegetables, milk, meat and even seafood; obviously, a big problem for CD patients.

Gluten consumption, as a major factor of increased CD occurrence, also opens the way for primary prevention, i.e. intervening before the disease processes have been initiated, because not all gluten proteins are toxic to CD patients. A reduction of the toxic gluten load in all food products for all consumers could be a primary prevention method to reduce the initiation of the disease process. This is a goal on which the food industry can focus by reducing the total CD-toxic gluten load of cereals and cereal-derived products to the entire population, including the undiagnosed celiacs and the pseudo-celiacs. The starting point is that every reduction in total CD-toxic gluten consumption will contribute to an overall reduction of the prevalence of the disease and of symptom severity.

Taking the challenge

The Celiac Disease Consortium is a Dutch initiative that consists of the medical universities of Leiden, Groningen, Amsterdam, and Rotterdam, Wageningen University and Research Centre, an international seed company (Limagrain), and several food (DSM, De Halm) and diagnostics (Eurodiagnostica, Europroxima, Genome Diagnostics) companies. This consortium is actively dealing with the challenge of developing a scientific basis for safe foods for Celiac patients, as well as the development of effective diagnosis, prevention, and therapy of Celiac disease. At the heart of the Consortium is the Dutch Celiac Disease Patient Society. Characteristic of this consortium is the high degree of multi- and inter- disciplinarity. This enables it to create a unique platform in which medical, agronomical and industrial partners closely cooperate.

Here, we will focus especially on the research work carried out at Wageningen UR. Two strategies are followed to generate CD-safe food products. The first strategy, to obtain safe cereal crops, is directed towards elimination of intrinsic CD-toxic peptides from gluten proteins in wheat. The second strategy relates to the use of alternative grain species that do not contain CD-toxic gluten, where the main issue is the avoidance of cross-contamination of the alternative safe grains by gluten during agricultural production and industrial processing. The major focus in this strategy is on oats.

Towards reduced toxicity in wheat

Gluten is the water-insoluble, alcohol-soluble protein fraction that makes up the majority (80%) (Hamer, 2003) of the total seed protein of wheat. Generally, in gluten, two types of proteins are distinguished, glutenins and gliadins, with several subtypes (high- and low-molecular weight glutenins; α-, γ- and ω-gliadins). Gluten proteins have very specific characteristics due to the occurrence of repetitive domains, their high content of proline and glutamine, and the presence of several cystein residues with their specific SH (sulphide) groups. Through polymerization by disulphide bridges, glutenins form extended elastic molecular networks, to which the gliadins adhere, and provide the viscosity through water binding. These characteristics make gluten a highly useful and versatile group of proteins with numerous applications in the food industry, especially in bread making, and as a binder.

Gluten proteins are encoded by multigene families of genes. The estimated gene copy number for α-gliadins, for instance, may be as high as 150 genes (Van Herpen et al. 2006). Major and minor differences at the amino acid level make the individual gluten proteins specific in the context of CD. Recent research suggests that different gluten peptides (epitopes) are involved in the disease process. Currently, using molecular sequence information and epitope-specific T cells and antibodies, the heterogeneity of epitope occurrence has been shown at the protein level and at the plant variety and species level. Identification of more than one hundred different diploid, tetraploid and hexaploid wheat species and varieties has revealed a great variation in CD toxicity. For instance, the presence of the major Glia-α9 epitope in modern European wheat varieties was compared with landraces representing the wheat varieties grown up to a century ago. The intact epitope was found at higher frequencies in the modern varieties, suggesting that wheat breeding has led to an increased exposure to CD-toxic epitopes. On the other hand, some modern varieties as well as landraces have been identified with a lower content of the epitope, which can be used for breeding. In addition, there is clear evidence that also γ-gliadins contain CD-toxic peptides with comparable impact to those of the α-gliadins; γ-I is the major epitope. After screening about 1100 γ-gliadin sequences (see the dendogram), we discovered, at some loci, increased levels of variants of the epitope that do not trigger the disease. Such lines may serve as a start to breed wheat with “low CD-toxicity” as a new breeding target, either by classic breeding, or by genetic modification.

This requires the development of a new wheat breeding strategy. It will require cultivation of the less- or non-CD-toxic wheat varieties in separate production lines to avoid contamination with regular wheat cultivars. Marketable CD-safe wheat products will take at least ten years from now to develop. Recently, however, a short-term solution appeared: oats.

Safe oats

For CD patients, oats are a good replacement for wheat, rye and barley, and they serve as an important supplement of a patient’s daily diet. In fact, the consumption of oats can be recommended for the general population, since they are a good source of slowly degrading carbohydrates, and contain lots of unsaturated fats (with a good ratio between omega-3 and omega-6 fatty acids), beta-glucans (which contribute to the reduction of cholesterol and can help in the case of heart and vascular diseases), and polyphenols with antioxidant activity. The slow degradation might be beneficial with respect to obesity and diabetes issues, as well (Andon and Anderson 2008).

The most serious problem for CD patients in consuming oat products is the frequent occurrence of contamination with wheat gluten and gluten-containing cereal material during cultivation, harvest, storage, milling, baking, etc. In January of 2009 in Europe, EC-Regulation 41/2009 came into force on the content and labeling of foods for individuals with CD. Oat products containing less than 20 ppm gluten are now allowed to be sold as gluten-free and may carry the official logo of the Dutch Celiac Disease Patient Society. Countries such as Sweden and Finland have already, for several years, developed a separate oat production chain. In the Netherlands, such a CD-safe production chain from the field to the consumer is an initiative of Wageningen UR, in cooperation with the food industries, and the Dutch Celiac Disease Patient Society. Its first products will be on the market in 2010.

Epilogue

Large-scale culture and consumption of wheat varieties and their derived gluten, with strongly reduced and, in the long term, even completely eliminated CD-toxicity, would considerably aid in decreasing the prevalence of CD, and would largely increase the quality of life of undiagnosed CD patients. This prospect should become a new challenge as well as a new responsibility for wheat breeders, research organizations, food industries and governments, and create a new opportunity to contribute significantly to consumer health. Oats deserve a large-scale comeback as a healthy food in the diet of everybody, including the consumers that suffer from Celiac disease.

Authors of this article: Luud JWJ Gilissen, Hetty C van den Broeck, Wendy PC van’t Westende, Diana M Londono, Elma MJ Salentijn, Ingrid M van der Meer and Marinus JM Smulders

Contact Information:
Mr. Luud Gilissen, PhD
Plant Research International (PRI)
Wageningen University
luud.gilissen@wur.nl
http://www.pri.wur.nl/UK/
http://www.celiac-disease-consortium.nl/index.htm

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