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Peer-reviewed │ Manuscript received: December 09, 2015 │ Revision accepted: May 13, 2016

Wheat and : Technological and health aspects

Katharina Anne Scherf, Peter Köhler, Freising

Summary Among the gluten-containing cereals only contains gluten that converts into a cohesive, viscoelastic dough after mixing with water. Due to its high gas holding capacity, wheat dough is the basis for with high volume and typical crumb structure as well as for a variety of different baked goods. On the other hand, in some individuals, the consumption of wheat and gluten-con- taining cereals, such as and , triggers hypersensitivity reactions; these Citation: include , or non-coeliac gluten sensitivity (NCGS). Scherf KA, Köhler P (2016) Wheat The only effective therapy for these individuals is to avoid exposure by strictly and gluten: technological and following a gluten-free diet. The great majority of the population (90–95%) do health aspects. Ernahrungs Um- not exhibit hypersensitivities and have no scientific reason to avoid products from schau 63(08): 166–175 gluten-containing cereals. This article is available online: Keywords: gluten, baking properties, non-coeliac gluten sensitivity, wheat allergy, coeliac disease DOI: 10.4455/eu.2016.035

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Cereals and cereal alcohols. Common names for these also known as gluten (“corn storage proteins are (pro- gluten meal”), which gives the false Cereals are among the most import- lamins) and glutenins (glutelins) impression that maize also contains ant raw materials in the world and from wheat, hordeins from bar- gluten. are grown on about 60% of agricul- ley, secalins from rye and avenins The term “gluten” is defined in the tural land. In 2014, more than 2.5 (only ) from oats. Both Codex Alimentarius – in the context billion tons of cereals were harves- the and glutelin fractions of hypersensitivity to cereal food ted, the main ones being maize (986 contain numerous compo- proteins. According to this, “gluten million tons), wheat (727 million nents; these can be classified as high is defined as a protein fraction from tons) and (714 million tons) [1]. molecular weight (HMW), medium wheat, rye, barley, oats or their Cereal products are among the most molecular weight (MMW) and low crossbred varieties and derivatives important staple foods, particularly molecular weight (LMW) groups on thereof, to which some persons are bread. With a mean content of only the basis of their homologous amino intolerant and that is insoluble in 10%, proteins are not the main in- acid sequences and similar molecular water and 0.5 mol/L NaCl” [4]. As gredient of bread. Nevertheless, ce- weights. Within the groups, close- oats is concerned, a footnote is added real proteins provide about 30% of ly related proteins are subclassified that permits special national regula- human protein requirements, due to into individual types (• Table 1) [3]. tions, as pure oats are tolerated by the high levels of consumption. most, but not all, individuals with coeliac disease. According to the extraction scheme Gluten developed by Osborne [2], cereal pro- teins can be classified into the frac- The term “gluten” means different and baking tions of albumins, globulins, pro- things, depending on the context. quality lamins and glutelins, depending on The classical definition of gluten their solubility in water, dilute salt is related to the baking quality of Wheat has a special position among solutions, 70% ethanol and dilute wheat flour. Gluten is also refer- the cereals, as, after kneading with acetic acid or alkali. The albumins red to as wheat glue and is a rub- water, only wheat flour forms a and globulins are metabolic proteins, ber-like proteinaceous mass, which dough with unique techno-func- with functions during grain de- remains after rinsing wheat dough tional properties. This is due to the velopment. Prolamins and glutelins with water or salt solutions (“wet so-called wheat gluten, which is are storage proteins, which make up gluten”) [3]. made up of the and glutenin about 70–80% of grain protein and In the industry, the term fractions. which occur in the starchy endo- gluten means something a little Gluten confers high water absorp- sperm of different cereal grains. Pro- different. During the production of tion to the flour and makes the lamins mostly occur as monomers, wheat starch, gluten is a by-product dough cohesive and viscous with whereas most of the glutelins are after starch has been separated and high capacity for gas retention. polymers linked through intermole- is used in dried and powdered form This gives bread of high volume and cular disulphide bonds which can be (so-called “vital gluten”) as a flour with the typical crumb structure. converted to monomeric subunits by improver, food texturiser or in ani- Wheat gluten is a decisive ingre- reduction. Like the prolamins, glute- mal feed. The by-product formed in dient for high quality bread, cakes lin subunits are soluble in aqueous the preparation of maize starch is and pastries. from all other

Group Wheat Barley Rye Oats HMW HMW-Glutenins (p) 11% D-Hordeins (p) 5% HMW-Secalins (p) 9% - MMW ω1,2-Gliadins (m) 4% C-Hordeins (m) 36% ω-Secalins (m) 18% - ω5-Gliadins (m) 3% - - - LMW LMW-Glutenins (p) 22% B-Hordeins (p) 27% γ-75k-Secalins (p) 48% - γ-Gliadins (m) 27% γ-Hordeins (m) 32% γ-40k-Secalins (m) 25% Avenins (m) 100% α-Gliadins (m) 33% - - -

Tab. 1: Classification of storage proteins from wheat, barley and ryewith the corresponding percentages of the total storage protein [3] HMW = high molecular weight, LMW = low molecular weight, m = monomer, MMW = medium molecular weight, p = polymer

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low volume, as the gas bubbles are their molecular weights are between either unstable and collapse, or 28,000 and 55,000 [6]. Glutenins cannot expand enough. consist of aggregated proteins, lin- ked by disulphide bonds. Their mo- lecular weights range from 500,000 Composition, structure to more than 10 million [7]. This and function of the gluten means that they are among the lar- gest proteins occurring in nature proteins [8]. In contrast to the gliadins, only Wheat gluten proteins consist of a very small fraction with the low- hundreds of protein components, est molecular weight is soluble in some are present as monomers and aqueous alcohols. some as more or less high molecu- The molecular weight distribution lar weight aggregates (• Table 1). of the glutenins is regarded as one They are poorly soluble in water or of the most important factors that aqueous salt solutions. Although influence dough and baking proper- some of the monomeric components ties. The largest polymers are called have been well characterised, little is glutenin macropolymer (GMP) known about their aggregation or or gel protein [9]. The content of the interactions between the protein GMP in wheat flour (20–40 mg/g) components. It is nevertheless well is highly correlated with dough established that the gluten proteins consistency and baking volume have a decisive influence on the ba- (• Figure 2) [6, 10]. It is known that king quality of wheat. the glutenins are made up of protein Wheat gluten is made up of two subunits linked by disulphide bonds. Fig. 1:  from different cereals and pseudocereals, prepared using a standard recipe with yeast and a functionally distinct groups of sto- Thus, when glutenins are treated procedure. 1: wheat, 2: rye, 3: barley, rage proteins: the monomeric glia- 4: oats, 5: rice, 6: maize, 7: buckwheat, 8: millet dins and the polymeric glutenins. 1 A material is viscoelastic when it exhibits Gliadins are present at higher levels both viscous and elastic properties. (gliadin/glutenin ratio: 1.5–2.7:1), 2 Deformation and flow properties of a subs- cereal species give bread of lower vo- soluble in aqueous alcohols and tance lume, smaller pores and less elastic crumbs – if they are prepared with a standard recipe (• Figure 1). During kneading, the flour first takes up water and mechanical energy is transmitted to the de- r = 0.80 veloping gluten. A continuous, p < 0.01 viscoelastic1 gluten network with embedded starch granules is for- med [5]. Both the quantity and the composition of the gluten pro- teins influence the behaviour of wheat flour during kneading and its mixing tolerance (= sensitivity to excessive kneading). Gluten is also responsible for the rheologi- cal2 properties of the optimally de-

veloped dough. In particular, the Specific loaf volume [mL/g dough] resistance to extension of a dough determines its gas retention capa- GMP-content [mg/g flour] city, and thus the bread volume and crumb structure. Low or ex- Fig. 2: Dependence of specific bread volume on the content of glutenin tremely high resistance to exten- macropolymer (GMP) in flours from various wheat cultivars(modi - fied from [10]) statistical test procedure: Pearson correlation sion leads to baked products with GMP = glutenin macropolymer, p = significance, r = correlation coefficient

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with reducing agents (e.g. dithio- threitol, 2-mercaptoethanol), they Gliadins Flour form monomeric components (sub- - monomeric units), which are soluble in aqueous - viscosity alcohols. The structure of the poly- mers formed from the glutenin sub- Kneading units (= glutenins) is only partially Glutenins known and is currently shown in - polymeric models [3, 11]. - elasticity Kneading The technological function of gluten is essentially determined by two pa- rameters: the gliadin/glutenin ratio Gluten and the quantity of GMP. The rea- (Dough) son for the importance of the glia- din/glutenin ratio is that gliadins Fig. 3: Schematic representation of the functional effects of gliadins and and glutenins have different roles glutenins in wheat gluten in dough. As glutenins are high molecular weight polymers, they form a three-dimensional network, have a positive influence on elasti- protein. However, in a part of the which is responsible for the glue’s city and baking properties when population, this immune tolerance resistance to extension and elasticity they are above a specific size [5, to gluten is either only partially [12, 13]. Gliadins are regarded as 18]. The formation of these high present due to genetic predisposi- “softeners” in dough, responsible for molecular weight polymers (= tion or is lost in the course of life, viscosity and extensibility [14, 15]. GMP) depends on the available due to interactions with external It is, therefore, obvious that optimal GS. For example, the presence of cofactors, such as infections [20]. baking quality is based on a bal- specific combinations and concen- Hypersensitivities can be differen- anced ratio between viscosity and trations of HMW-GS leads to high tiated by their different patholo- elasticity and, thus, between glia- levels of GMP. The explanation for gical mechanisms [21]. During dins and glutenins (• Figure 3). this is thought to be that HMW-GS the adaptive immune response in The composition (qualitative and of the x-type and LMW-GS act as wheat allergies, B cells produce quantitative) of the glutenins is so-called “chain extenders”, i.e. immunoglobulin (Ig) E antibo- also important for the properties of they contain two or more free cys- dies and these trigger the release the gluten and the baking quality teine residues, which favour poly- of inflammatory substances (e.g. of flour and also reflects the con- merisation. In contrast, so-called histamine) from basophilic gra- tent of GMP. One important factor “chain terminators” reduce GMP nulocytes and mast cells. In coe- is the presence or absence of specific content. These are high or low liac disease, dermatitis herpetifor- subunits, their concentrations and molecular weight proteins with mis Duhring4 and gluten-induced their mutual relationships. For ex- only a single free cysteine residue, ataxia5, the IgA and IgG antibodies ample, each wheat cultivar contains which hinder or prevent polyme- of the adaptive immune response 3–5 HMW glutenin subunits (-GS) risation. are characteristic and are directed [16] and 7–16 LMW-GS [17]. As against the external antigen glu- more than 20 different HMW-GS ten, as well as the endogenous tis- are known and more than 40 dif- Hypersensitivities to sue transglutaminase (TG2) and ferent LMW-GS, a large number of gluten and wheat the endomysium (autoimmune combinations and concentrations reactivity). However, some gluten would be conceivable and this is one About 10,000 years ago, glu- reason for the enormous difference ten-containing cereals were intro- 3 in baking quality between different duced into human nutrition when Einkorn (a primitive cereal) is a diploid form of wheat (which is actually hexaploid). 3 wheat cultivars. diploid was grown See article in “Ernährungslehre & Praxis” Much less is known about how for the first time [19]. The- im in this issue from p. S29. the different types of GS are linked mune system was then faced with 4  Duhring is a skin within the glutenins. Studies on the challenge of developing tole- disease from the group of the blister forming the size of glutenin aggregates rance to gluten, which had previ- autoimmune dermatoses and is closely linked to coeliac disease. have shown that polymers only ously only been a rare source of 5 Disorder affecting movement

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Wheat Allergy Coeliac Disease NCGS Prevalence 0.5–4% ≈ 1% 0.6–6% Genetics - HLA-DQ2/-DQ8 - Time till start of minutes–hours days–weeks hours symptoms Symptoms intra-/extraintestinal intra-/extraintestinal intra-/extraintestinal Triggering Proteins gluten/other wheat proteins gluten gluten/other wheat proteins/ other components Immune response adaptive adaptive/innate innate Antibodies IgE IgA/IgG IgG (≈ 56%) Autoantibodies none yes none Intestinal damage none yes none/very slight Therapy wheat-free diet gluten-free diet wheat- or gluten-free or low diet

Tab. 2: Overview of the characteristics of gluten-dependent hypersensitivities HLA = human leukocyte antigen; Ig = immunoglobulin; NCGS: non-coealic gluten sensitivity

peptides can also directly stimu- Wheat allergies Baker’s asthma and late an innate immune response. allergic rhinitis If neither allergic nor autoim- Wheat allergies are caused by speci- Baker’s asthma and allergic rhinitis mune mechanisms are involved, fic hypersensitivity to many different were already described in Roman the gluten-dependent symptoms wheat proteins, including gluten pro- times and are among the most fre- are caused by NCGS (non-coeliac teins. Wheat allergies can be classified quent occupational allergies. Up to gluten sensitivity), in which the as follows, depending on the path of 10-15% of millers, bakers and con- innate immune system is thought exposure to the allergens and the un- fectioners suffer an allergic reaction to play an essential role (• Table derlying pathological mechanism: when they inhale flour and dust, so 2) [22, 23]. - respiratory tract allergy (baker‘s that they may even have to change asthma, allergic rhinitis), their occupation if the symptoms Values on the prevalence of wheat - food allergy, are severe. α-Amylase inhibitors allergies are in the range of 0.5–4% - wheat-dependent exercise-induced (chloroform-methanol soluble [CM] of the population. The prevalence (WDEIA) and proteins) have been identified as the of NCGS lies within the broad - contact urticaria or dermatitis. main allergens. Many other proteins range of 0.6–6%. About 1% of the Sensitisation to wheat proteins can may also trigger allergic reactions, population is affected by coeliac take place through skin exposure including wheat germ agglutinin, disease. According to Codex Stan- or oral ingestion. Diagnosis is per- peroxidase, lipid transfer proteins dard 1-1985 [24], wheat and other formed through the skin prick test, the (LTPs), amylases, thioredoxin (Tri a gluten-containing cereals (rye, analysis of specific IgE serum antibo- 25) and gluten proteins [27]. barley, oats) are among the eight dies or functional assays, such as oral most important food ingredients provocation tests or in vitro basophil Contact urticaria and dermatitis that trigger hypersensitivity reac- activation tests (BAT). Although func- Contact urticaria and dermatitis tions and which therefore must be tional assays are regarded as the gold are allergic reactions, most often declared on packaged food. In the standard for diagnosis and can provide on the hands and face after contact European Union, the Food Infor- clarity if the results from skin prick with the allergen. As with baker’s mation Regulation (VO (EU) No. tests and IgE serum antibodies are un- asthma, employees in grain hand- 1169/2011) came into force on 14 clear, they are much more labour- and ling are most often affected by the December 2014. Since then, the 14 time-intensive and expose the patient different forms of these skin dis- most frequent triggers of allergies to the risk of a severe allergic reac- eases. For example, allergens from and food intolerance – including tion [26]. Therapy of wheat allergy wheat, rye, barley and other flours gluten-containing cereals – must depends on its form and is based on can trigger contact dermatitis, with be labelled on packed and loose either avoiding exposure to flour and rapid development (30–60 minutes) products [25], in order to make flour dust or of abstaining from foods of erythema, nodules and blisters. it easier for the customer to select containing wheat. In acute cases, anti- Cosmetics such as soaps, sham- suitable foods. histamines or corticosteroids can help. poos and creams may contain glu-

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ten hydrolysates as foaming agent to avoid the combination of wheat In the symptomatic form, the pa- or emulsifier. They may also cause consumption and exercise or, to be tient suffers typical intestinal symp- allergic reactions, such as angio-oe- safe, to switch to a gluten-free diet toms (lower abdominal pain, chro- dema of the eyelids. For all these [30]. The main allergens are ω5-gli- nic diarrhoea, impaired digestion, skin diseases, exposure to allergens adins and HMW glutenins, although vomiting) and/or extraintestinal should be avoided with gloves, pro- other gluten proteins may be in- symptoms (anaemia, osteoporosis, tective creams or by totally avoiding volved in triggering the reaction, joint pain, chronic exhaustion). The contact. such as α- and γ-gliadins, LMW glu- principle characteristics of coeliac tenins or gluten hydrolysates. disease include damage to the mu- Food allergies cous membrane in the upper small Aside from milk and eggs, wheat is intestine, with loss of intestinal villi, Coealic disease, dermatitis her- one of the three most common food hyperplasia of the crypts and infil- petiformis Duhring and allergies that occur after ingesting tration of lymphocytes. Villous at- gluten-induced ataxia allergenic products [28]. The pre- rophy is accompanied by a reduction valence of wheat allergies is higher Coealic disease in intestinal surface and this leads to in children than in adults, because Coealic disease is a chronic disease of impaired absorption of nutrients in the allergy often subsides when the the small intestine that occurs in ge- the small intestine, with weight loss child reaches school age. Most chil- netically predisposed individuals and and signs of nutrient deficiencies. If dren with wheat allergy suffer from is due to lifelong intolerance to glu- the patient strictly complies with moderate to severe atopic dermatitis ten in food [23]. Although Samuel a gluten-free diet, these symptoms and wheat consumption can lead Gee already described the symptoms disappear in almost all cases and to typical IgE-mediated symptoms, of coeliac disease in 1888, the link be- the mucous membrane in the small such as urticaria, angio-oedema, tween coeliac disease and gluten – the intestine is normalised, entailing bronchial obstruction, dizziness and external factor triggering the disease only a slight risk of further com- pain in the lower abdomen, even – was established by the Dutch paedi- plications. In a few rare cases, the extending to anaphylactic shock. atrician Willem Karel Dicke not until small intestinal mucous membrane In adults, food allergy to wheat oc- the 1940s. Almost 97% of coeliac dis- does not regenerate and the coeliac curs irregularly. The most frequent ease patients are positive for the se- disease-specific intestinal symptoms form is wheat-dependent, exer- quences HLA-DQ2 and -DQ8. These remain or return, even though the cise-induced anaphylaxis (WDEIA). lie on human chromosome 6 and code gluten-free diet has been strictly ad- In contrast to coeliac disease and for human leukocyte antigens (HLA). hered to for more than 12 months. other food allergies, the dose nee- On the other hand, this genetic predis- Once unintentional ingestion of ded to trigger the reaction is rather position is also present in about 30 % gluten and other intestinal diseases high – namely about 1 g wheat pro- of the healthy population. For this have been excluded, refractory coe- tein. All gluten proteins can trigger reason, the absence of HLA-DQ2/8 is liac disease is diagnosed. wheat allergies, as can many other a relatively reliable exclusion criterion wheat proteins, such as α-amylase for coeliac disease, although its pre- Type 1 refractory coeliac di- inhibitors, germ agglutinin, peroxi- sence is not sufficient to trigger the sease is usually accompanied by dase, LTPs, β-purothionin, puroin- disease. It is still unclear which other intraepithelial lymphocytes of dolines A and B and starch synthase. factors ultimately trigger the disease normal phenotype. It can mostly [31]. Possibilities include other genetic be treated with the glucocorti- WDEIA factors, virus infections, changes in coids prednisolone or budesonide. WDEIA is a rare, but potentially intestinal bacterial flora, the hygiene If the phenotype of the intraepit- life-threatening form of wheat al- hypothesis6 and the time when gluten helial lymphocytes is shown to lergy. It only occurs when wheat was introduced to infant nutrition du- be abnormal, the diagnosis of consumption is combined with co- ring breast feeding [3]. type 2 refractory coeliac dis- factors, such as physical exertion, As a multifactorial clinical picture, ease is made. In the absence of an acetylsalicylic acid, alcohol, stress or coeliac disease may appear in symp- infections [29]. The typical symp- tomatic, asymptomatic, potential or toms include skin rashes, urticaria, refractory forms. The common fea- drop in blood pressure and breathing ture of all these forms is the positive problems, extending to anaphylactic genetic predisposition (HLA-DQ2/8) 6 According to the hygiene hypothesis, a fairly shock, and mostly occur during and the occurrence of coeliac-specific sterile environment in childhood may inhibit exercise 1–4 hours after ingesting IgA and IgG antibodies in blood. the development of the immune system, as the immune system is confronted with too wheat. It is therefore recommended few genuine pathogens.

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established therapy, 40–58% of pa- tients suffer fatal intestinal cancer Pathomechanism of coeliac disease within the following 5 years [32]. Both the adaptive and the innate immune response are involved in the complex pathomechanism of coeliac disease. The gluten ingested in Asymptomatic coeliac disease food has very high contents of and glutamine. As a consequen- exhibits specific damage to the small ce, it is only partially hydrolysed by gastrointestinal enzymes and long intestinal mucous membrane, but peptides reach the epithelium of the small intestine. The gluten pep- the typical symptoms are missing. tides pass the epithelial layer, either trans- or paracellularly, and pass to the enzyme tissue transglutaminase (TG2) in the lamina propria. The In potential coeliac disease, the subsequent enzymatic de- or transamidation reactions give rise to de- typical symptoms are absent. In amidated gluten peptides or conjugates between TG2 and gluten pep- contrast to other forms, the small tides. Both these reactions enhance the immunostimulatory activity of intestinal mucous membrane is not the gluten peptides and their native, deamidated or TG2-conjugated damaged and exhibits normal vil- forms now bind to HLA-DQ2/8 heterodimers on antigen-presenting lous structure. Patients with poten- cells and stimulate CD4+ T cells through the corresponding receptors. tial coeliac disease have a greater risk After their activation, gluten-reactive T cells secrete pro-inflammatory of developing coeliac disease later in cytokines, such as interferon-γ, interleukins and tumour necrosis fac- life. Groups with particularly high tor-α, which stimulate the release and activation of matrix metallopep- risks include first degree relatives of tidases (MMPs). These break down extracellular matrix proteins and patients with coeliac disease, people thus lead to the destruction of the epithelium. On the other hand, glu- ten-reactive T cells also interact with B cells. These can differentiate into with genetically associated condi- plasma cells and produce IgA and IgG antibodies inducing an anti-in- tions, such as Down’s, the Ull- flammatory pathway. rich-Turner and the Williams-Beu- It is also known that gluten peptides stimulate the innate immune res- ren syndromes, as well as patients ponse and trigger the secretion of interleukin 15 by activating entero- with associated autoimmune dis- cytes, macrophages and dendritic cells. As a result, lymphocytes are eases, such as type 1 diabetes melli- stimulated to express the receptor NKG2D and epithelial cells to express tus, autoimmune hepatitis and au- MICA (major histocompatibility complex class I chain-related molecule toimmune thyroiditis. As patients A), the ligand for NKG2D. Once MICA has bound to NKG2D, intraepi- with asymptomatic or potential coe- thelial lymphocytes start to destroy epithelial cells [3]. liac disease do not suffer from the This new knowledge of the pathomechanism of coeliac disease shows typical symptoms of coeliac disease, the way to possible new therapeutic approaches. One of the most pro- mising is to break down gluten in the gastrointestinal tract with the help a long time may pass until the cor- of gluten-degrading enzymes [34]. rect diagnosis is made. Several spe- cialists may have to be consulted; patients at risk may have to be ac- tion of at least four small intesti- DH patients have additional antibo- tively screened for serum antibodies nal biopsies is regarded as the gold dies to epidermal transglutaminase typical of coeliac disease [33]. standard for the diagnosis of coeliac (TG3), which are useful in distin- disease [26]. The tests should be guishing between DH and other Diagnosis of coeliac disease includes performed while the patient is still skin diseases [35]. Most DH pa- the assessment of medical history ingesting gluten. If the symptoms tients show mild to moderate in- and symptoms, detection of speci- clearly improve after introduction of testinal damage, although the main fic IgA and IgG antibodies in serum, a gluten-free diet, this confirms both symptoms are intensely itching and taking biopsies from the small in- the success of the treatment and the burning blisters, erythema, eczema testine and possibly checking the correctness of the diagnosis. and wheals, mostly on the elbows, patient’s genetic predisposition with knees, shoulders and head. The respect to HLA-DQ2/8. It is recom- Dermatitis herpetiformis Duhring acute symptoms can also be medi- mended that the first step should be Dermatitis herpetiformis Duhring cally alleviated with dapsone7. to detect IgA anti-TG2 antibodies (DH) has a prevalence of about (TGA), as the specificity and sensi- 0.01% and is frequently described Gluten-induced ataxia tivity are both ca. 95%. This can be as the skin manifestation of coeliac Gluten-induced ataxia (gluten ata- confirmed by a test for IgA anti-en- disease, as both diseases are caused xia) is a form of idiopathic spora- domysium antibodies and – parti- by gluten, both can be treated with dic ataxia, which is characterised cularly if there is selective IgA defi- a gluten-free diet and both exhibit ciency – with tests for IgG TGAs and the genetic predisposition linked to IgG antibodies to deamidated gliadin HLA-DQ2/8 alleles. The serological 7 Dapsone is an anti-inflammatory drug with peptides. Histological characterisa- markers are also the same, although antibiotic activity.

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by gluten-specific antibodies. The very strong nocebo effect, the chal- dustries, where – also in modi- symptoms include nystagmus and lenge is performed blinded once with fied forms – it is used as thick- other visual disorders, ataxia when gluten and – after a one week inter- ener, emulsifier, filler or bread -im walking or standing and atrophy val with a gluten-free diet – once prover. Patients and their families of the cerebellum. About 40% of pa- with placebo [39]. The diagnosis of should seek detailed advice from tients with gluten ataxia also exhi- NCGS is regarded as positive if there doctors and dieticians, especially to bit changes in the small intestinal is a difference of at least 30% on the avoid any dietary deficiencies (B vi- mucous membrane that are typi- symptom rating scale between the tamins, D, folate, calcium, cal of coeliac disease. Antibodies challenges with gluten and with iron, magnesium, dietary fibre). It against brain transglutaminase placebo. is recommended to revise these ins- (TG6) can be detected in circula- The therapy consists of adhering to a tructions at least annually. ting blood, but accumulate in the wheat- or gluten-free diet, although Instead of gluten-containing cere- cerebellum and brain stem. The a low gluten diet may be sufficient als, gluten-free products made from white substance in the cerebellum in some cases. The individual steps in maize, rice, sorghum, teff, potatoes is infiltrated with T lymphocytes the pathomechanism of NCGS have and pseudocereals, such as ama- and there is irreversible loss of not yet been fully studied, so that ranth, buckwheat and quinoa serve Purkinje cells in the cerebellar cor- the triggering factor has not been as alternatives. The missing func- tex. For this reason, rapid diagno- unambiguously identified. There is tionality of wheat gluten in bread sis is essential, followed by ther- evidence that NCGS is triggered by and baked products must be com- apy with a gluten-free diet [36]. gluten and amylase trypsin inhi- pensated by adding proteins from bitors (ATIs) in gluten-containing e. g. milk, egg or soy, polysaccha- cereals, as these activate the innate rides, e. g. hydroxypropylmethyl- Non-coeliac gluten immune response. Thus both gluten cellulose, carboxymethylcellulose sensitivity (NCGS) and other wheat proteins may be re- or xanthan, enzymes and/or using NCGS is characterised by intesti- sponsible for triggering NCGS and it sourdough [39]. nal and extraintestinal symptoms must be clarified whether other pro- linked to the consumption of glu- teins or other components, such as Although gluten-free baked pro- ten-containing foods and affects FODMAPs (fermentable oligo-, di- ducts are still somewhat inferior to patients for whom wheat allergies, and monosaccharides and polyols) gluten-containing products with coeliac disease, irritable bowel syn- in gluten-containing cereals play a respect to aroma, flavour and tex- drome and other types of food in- role. ture, there have been substantial im- tolerances can be excluded. In some provements in recent years due to publications, this clinical picture is Gluten-free diet intensive research and the use of referred to as gluten sensitivity [22], new ingredients. The availability of wheat sensitivity or (non-allergy) A gluten-free diet is based on the tasty high-quality gluten-free pro- non-coeliac wheat sensitivity [37, strict elimination from the diet of ducts can greatly encourage the pa- 38]. Symptoms are observed some cereals containing gluten (wheat, tients to accept a gluten-free diet and hours or days after consumption of rye, barley, triticale, einkorn wheat, facilitate lifelong compliance. wheat (and possibly of other glu- , or khorazan wheat ten-containing cereals). The clini- and their hybrids), as well as their Conclusions cal presentation includes intestinal products. In almost all patients, the symptoms, such as flatulence, lower small intestinal mucous membrane The gluten proteins in wheat pos- abdominal pain and diarrhoea, as is regenerated within 6–12 months sess unique viscoelastic properties well as extraintestinal symptoms, if maximally 20 mg gluten is in- allowing the formation of dough such as exhaustion, impaired well- gested per day. According to the with high water absorption and being, headache, anxiety attacks, Codex Alimentarius Standard 118- gas holding capacities. After baking, a “foggy” feeling and pain in the 1979 [4], products labelled as glu- breads with high volume and the joints and muscles. ten-free by the manufacturer may typical crumb structure are formed. As there is no sensitive and specific contain a maximum of 20 mg glu- Wheat gluten also offers the possibi- biomarker for NCGS, the diagnosis ten per kg. lity to make a wide variety of other is based on a very thorough and It is a great challenge to com- products, including biscuits, cakes, standardised observation of the pa- ply with a gluten-free diet, in and , with good techno- tient during a switch to a glu- particular at the beginning, logical, functional and sensory pro- ten-free diet, followed by a renewed because gluten is widely used in perties (aroma, taste and texture). challenge with gluten. Due to the the cosmetic, drug and food in-

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In many parts of the world, wheat is a basic food. In particular, whole- Conflict of Interest grain flour provides important nu- The authors declare no conflict of interest. trients, dietary fibre and minerals, such as iron, , magnesium and manganese, as well as B . Dr. Katharina Anne Scherf Prof. Dr. Peter Köhler1 On the other hand, some individuals Deutsche Forschungsanstalt für Lebensmittel- develop hypersensitivities when they chemie, Leibniz Institut consume products containing wheat Lise-Meitner-Str. 34 or gluten. Research is continuing to 85354 Freising 1 elucidate the underlying pathologi- E-Mail: [email protected] cal mechanisms, in order to iden- tify the genetic and environmental cofactors that are responsible for References the loss of immune tolerance to the triggering proteins. After diagnosis 1. Statista, das Statistik-Portal (2015) Ern- of coeliac disease, wheat allergy or temenge der wichtigsten Getreidearten welt- NCGS, it is essential for the patient weit in den Jahren 2008/09 bis 2015/16 to comply with a strict gluten-free (in Millionen Tonnen). http://de.statista. diet, in order to prevent symptoms com/statistik/daten/studie/28884/um and long-term complications. frage/erntemenge-von-getreide-weltweit/ However, there is no evidence that Zugriff 06.12.15 the great majority of the population 2. Osborne TB (1907) The proteins of the wheat (90–95%) suffer from gluten-depen- kernel. Carnegie Institution, Washington DC dent hypersensitivities and current 1907, Publ. No. 84 scientific knowledge indicates that 3. Wieser H, Koehler P, Konitzer K. Celiac dis- there is no reason for them to eli- ease and gluten – Multidisciplinary challen- minate wheat, rye or barley from ges and opportunities. 1., unveränd. Aufl., the diet. Academic Press Elsevier, London, Waltham, San Diego (2014) 4. Codex Standard 118-1979 (2015). Codex Standard for foods for special dietary use for persons intolerant to gluten. Codex Alimen- tarius Commission. Revision 1, Amendment 2 5. Singh H, MacRitchie F (2001) Application of polymer science to properties of gluten. J Cereal Sci 33: 231–243 6. Wieser H (2007) Chemistry of gluten pro- teins. Food Microbiol 24: 115–119 7. Wieser H, Bushuk W, MacRitchie F. The polymeric glutenins. In: Wrigley C, Bekes F, Bushuk W (Hg). Gliadin and glutenin: the unique balance of wheat quality. Ameri- can Association of Cereal Chemists Inter- national, St. Paul, MN, USA (2006), S. 213–240 8. Wrigley CW (1996) Giant proteins with flour power. Nature 381: 738–739 9. Graveland A, Bosveld P, Lichtendonk WJ, Moonen JHE (1980) Superoxide involvement in the reduction of disulfide bonds of wheat gel proteins. Biochem Biophys Res Commun 93: 1189–1195 10. Thanhaeuser SM, Wieser H, Koehler P (2014) Correlation of quality parameters with the

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