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20 April 2021

Ancient and Modern Cereals as Ingredients of the Gluten-Free Diet: Are They Safe Enough for Celiac Consumers?

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Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy
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Foods2021, 10(4), 906;https://doi.org/10.3390/foods10040906
This article belongs to the Special Issue Food, Environment and Health Challenges
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Abstract

Celiac disease is an autoimmune disorder that occurs in genetically predisposed individuals after consuming prolamins from some cereals. Although the products available for celiac subjects have increased significantly in quality and quantity over the last few decades, research still focuses on identifying new ingredients to improve the nutritional, sensorial and functional qualities of gluten-free products. In terms of toxicity for people with celiac disease, there is a wide variability between ancient and modern grains. The most contradictory results are related to the role of oats in the gluten-free diet. In order to clarify the role of minor cereals (such as oat) and ancient grains in the diets of celiac patients, this review discusses recent in vitro and in vivo studies performed on those cereals for which the toxicity for celiac subjects is still controversial. According to in vivo studies, selected oat varieties could be tolerated by celiac patients. On the other hands, although some wheat-ancient grains (Triticum monococcum, Triticum aestivum ssp. spelta and Kamut®) showed a reduced in vitro toxicity, to date, these grains are still considered toxic for celiac patients. Contradictory results underline the importance of studying the safety of “unusual” cereals in more detail.

1. Introduction

Cereals are widely available in diets all over the world. Most cereals contain gluten, a protein complex that plays an important role in the technological properties of cereal-based products. The cereals with the highest content of gluten-like proteins are wheat, barley and rye. Wheat provides up to 50% of the caloric intake in both industrialized and developing countries, representing one of the world’s primary sources of energy [1]. Recently, pseudo-cereals (e.g., buckwheat, quinoa) have received considerable attention, since they are a good source of macronutrients, such as carbohydrates and proteins, but also of fibers, vitamins and minerals.
Gluten-related disorders (GRDs) are becoming increasingly common. The main GRDs are celiac disease (CD), non-celiac gluten sensitivity (NCGS) and wheat allergy (WA). WA is an adverse reaction that involve the immune system mediated by immunoglobulins E (IgE) [2]. NCGS is a condition characterized by intestinal and extra-intestinal symptoms associated with the consumption of gluten-containing foods in subjects who are not affected by CD or WA. The prevalence of NCGS is not clearly defined; no specific biomarkers are available for the diagnosis of NCSG. Currently, the diagnosis is based on exclusion criteria (absence of CD and WA) and positive diagnostic challenges (double-blind, placebo-controlled gluten challenge) [3].
The role of gluten is well documented in celiac disease (CD), including dermatitis herpetiformis. CD, one of the most common lifelong diseases worldwide, showed a global prevalence of 1.4%, based on serologic tests, and 0.7%, based on in vivo tests (biopsy) [4].
CD is an autoimmune disorder, occurring in genetically predisposed subjects, having the necessary co-factor of the consumption of toxic prolamins [5,6]. Of these, the most toxic proteins are wheat gliadins (a portion of gluten); however, rye secalin and barley hordein show similar toxicities in celiac subjects [6]. After deamidation, due to the action of transglutaminase, peptides stemming from the proteolysis of gliadin and other toxic prolamins, bind human leukocyte antigen (HLA)-DQ2 or DQ8, thus leading to inflammation [5]. These complexes are associated with the production of auto-antibodies generally belonging to the immunoglobulins A (IgA) class [7].
Celiac disease is characterized by a condition of malabsorption correlated with enteropathy characterized by small-intestinal villous atrophy. In addition to the intestinal symptoms, CD could be characterized by different extra-intestinal complications, such as bone and skin diseases, microcytic anemia (due to iron deficiency), endocrine disorders, and neurologic deficits [5].
At present, the total exclusion of toxic prolamins from the diet is the only accepted treatment for patients with CD. Gluten is an important agent in baking products, contributing to dough viscosity and elasticity [8,9]. As a consequence, different studies underline the limitations of gluten-free products (in particular, gluten-free bread), in terms of technological and sensorial properties [8]. In this contest, the research still focuses on identifying new ingredients to improve the nutritional, sensorial and functional qualities of gluten-free products. The safety of cereals used in gluten-free products, thus, need to be monitored continuously, since in some cases, it depends on the variety considered (as discussed in paragraph 2.4. for oat) [10,11,12,13].
Figure 1 shows the botanical classification of cereals. All cereals belong to the Poaceae family. The main toxic cereals (e.g., wheat, rye, and barley) belong to the subfamily of Pooideae and contain CD-eliciting epitopes. On the other hand, rice, millet and corn are safe for CD patients.
Figure 1. Botanical classification of cereals [14,15].
Table 1 summarizes the main cereals and pseudocereals currently allowed or not allowed in the gluten free diet (GFD) [16].
Table 1. Cereals and pseudocereals and their inclusion in the GFD.
Rice and corn are the most common alternatives to gluten-containing grains in the GFD. Among the minor cereals, particular attention has been given to oat, which has been widely used in Northern Europe. Avena sativa L. has interesting nutritional properties [17]; it presents a high fiber content and a low glycemic index compared to other cereals or pseudocereals (e.g., buckwheat, quinoa, sorghum, and teff) [18] and could improve the palatability of gluten-free products. Oat was once excluded from the GFD in Mediterranean countries but recently the EU included oat as a gluten-free ingredient [19], although its inclusion in the CD diet is still a matter of debate.
Table 1 includes Kamut®, a patent referring to Triticum (T.) turgidum, spelt (T. aestivum ssp. spelta) and einkorn wheat (T. monococcum) as toxic cereals.
Interest in the consumption of ancient grains has recently increased and various in vitro and ex vivo methods have been used to evaluate the safety of these cereals for celiac patients.
Table 2 shows the main tests used to assess the toxicity of cereals in CD. K562(S) and Caco-2 cells are the principal cell lines used, and various outcomes (such as the agglutination ratio, transepithelial electrical resistance and expression of tissue transglutaminase) are considered.
Table 2. In vitro and ex vivo tests most frequently used to evaluate the toxicity of cereals in CD.
These tests often provide conflicting information on the safety of these grains for celiac patients. For example, studies on spelt underline the large variations among accessions, in terms of toxicity for celiac subjects [20,21,22]. Although still excluded from the GDF diet, recent studies have suggested that the wheat T. monococcum presents a lower number of immunogenic peptides and a higher in vitro digestibility compared to the hexaploid common wheat [23]. All these findings have led to an increasing interest in the study of ancient grains in terms of safety for celiac patients.
The present paper reviews the recent in vitro and in vivo studies performed on those cereals whose toxicity for CD is still controversial.

2. Methods

A literature revision was performed to summarize the data at our disposal and clarify the safety of some discussed cereals (ancient grains and minor cereals, such as oat) in the gluten-free diet. PubMed, MEDLINE, Embase, and CAB-Abstract were searched (from database inception to November 2020) using the terms “Spelt or Triticum aestivum ssp. spelta”, “Kamut® or Triticum turgidum”, “Einkorn or Triticum monococcum”, “Oat or Avena sativa” in combination with “celiac disease” and “gluten”.
The search by title and abstract produced 335 papers. The inclusion criteria were based on the selection of papers reporting in vitro and in vivo studies assessing the safety of the cereals considered for celiac patients. Reviews, duplicates or papers not focused on the required topic were excluded. A final total of 52 papers were selected (Table 3).
Table 3. Studies collected from database searches. Those selected are in brackets.

3. Results and Discussion

3.1. Triticum monococcum

Some studies suggest a possible difference in the number of T-cell stimulatory peptides in wheat varieties [24]. Due to its simpler genome and to the presence of prolamins that are more susceptible to gastrointestinal digestion [23], some authors have suggested that T. monococcum may contain a lower number of epitopes and toxic peptides. In vitro and ex vivo studies have provided contradictory results on the safety of T. monococcum for patients suffering from CD (Table 4), suggesting that its use in GFD should be excluded or at least considered with extreme caution.
Table 4. In vitro and ex vivo studies to evaluate the toxicity of Triticum monococcum for celiac subjects.
Most studies on the safety of cereals in celiac patients investigate the products after peptic–tryptic digestion (PTd) [25]. The outcomes most frequently considered are: agglutination, the secretion of cytokines or the alteration of transepithelial electrical resistance (TEER) in cell models, such as Caco-2 cells [26,27,28], K562 (S) cells [26,29], or gliadin reactive T-cell lines [23,30,31,32,33].
Although PTd products from T. monococcum may determine a T cell response [30,31], a more extensive proteolysis by the brush border membrane enzyme (BBM) seems to be responsible for a reduction in its immune stimulatory properties [23,32]. The ex vivo experiments, performed using duodenum biopsies, showed similar results: no morphological change was observed by Pizzuti et al. (2006) in biopsies cultured with T. monococcum [34]. On the other hand, a reduction in immunotoxic potential was observed when tests were performed in ex vivo organ culture after extensive digestion by BBM enzymes [32]. Gianfrani et al. (2012) tested two different varieties of T. monococcum on jejunal biopsies, and both samples caused intraepithelial T cell infiltration and lamina propria T cell activation [30].
The ability of T. monococcum to trigger toxic effects in CD was also studied in vivo (Table 5). In an intervention study aimed to evaluate the safety of the daily administration of T. monococcum for 60 days, the concentration of CD-related antibodies changed from negative to positive in 60% of patients [35]. Zanini et al. investigated the gastrointestinal events associated with T. monococcum consumption and concluded that one single low dose of this cereal is generally well tolerated by celiac patients [36]. Another study underlined that T. monococcum elicited a reduction in T-cell response compared to T. aestivum [36,37].
Table 5. In vivo studies to evaluate the toxicity of T. monococcum for celiac subjects.
Generally speaking, 75% of the in vitro and ex vivo studies listed in Table 4 suggest that T. monococcum is less toxic for celiac patients than traditional varieties. On the other hand, the intervention studies, considering both short and chronic administration of T. monococcum, produced negative or inconclusive results. In conclusion, although T. monococcum at present is not suitable for GFD, further studies are in progress which will produce data for further evaluation [35].

3.2. Triticum aestivum ssp. spelta

In the scientific literature Triticum aestivum ssp. spelta was indicated as a cereal potentially tolerated by celiac subjects, thanks to its genotype being poor in prolamins [26]. At present, only the proteomic approach has been used for the assessment of this cereals; in vitro studies are needed before in vivo trials can be planned. On these bases, this review will list and discuss the papers that support tolerance using a proteomic approach.
Triticum aestivum ssp. spelta is usually considered toxic for celiac patients, although its high genetic variability in the germplasm could lead to the development of varieties with a lower toxicity for CD patients. Several studies, based on proteomic approaches, have investigated α-gliadin expression in spelt varieties (Table 6). They have underlined a high expression variability among varieties and epitopes [21,22,38]. In addition, no influence on these parameters by environmental factors, such as the harvest year and N fertilization was observed [20,22]. In a study by Asledottir et al. (2020) after an ex vivo digestion, the ancestral cereals (T. monococcum, T. aestivum ssp. spelta and T. diccocum) released fewer T-cell epitope-containing peptides than the common wheat varieties [25]. However, at present, ancestral wheat is considered toxic for celiac patients.
Table 6. Toxicity of spelt (T. aestivum ssp. spelta) based on proteomic approach.
Few in vitro studies have been conducted to evaluate the presence of cytotoxic prolamins for celiac disease in spelt. The potential immunogenicity of spelt and wheat accessions, evaluated using A1 and G12 monoclonal antibodies (A1 antibodies recognize the sequence QPQLPY and G12 recognizes the sequence QLPYPQP, which are present in DQ2.5-glia-α1a, DQ2.5-glia-α1b and DQ2.5-glia-α2 immunogenic epitopes), highlighted the great variability in terms of reactivity in both subspecies: accessions with a lower reactivity were found in both subspecies [20]. Regarding cellular tests, spelt wheat showed toxic effects on Caco-2 and K562 (S) cells. Increasing amounts of nitric oxide and transglutaminase-2 (TG-2) were observed in Caco-2 cells after treatment with spelt prolamins [26].
In summary, although a high expression variability among epitopes and Triticum aestivum ssp. spelta accessions has been found, the in vitro studies showed toxic effects and, for the moment, spelt wheat cannot be considered safe for celiac patients.

3.3. Kamut®

The taxonomy of Kamut® is controversial, and it has been classified as T. turgidum polonicum, T. turgidum turanicum, or T. turgidum durum. However, recently, Khlestkina et al. defined Kamut® as a hybrid between T. durum and T. polonicum [39]. Today, Kamut® is generally considered an ancient cereal correlated to the durum subspecies [40]. In the last few years, ancient wheats have been re-introduced into agriculture practices in order to maintain biodiversity. It has also been suggested that some ancient varieties may be less toxic for people suffering from food intolerances or allergies [24,33]. In order to evaluate this controversial hypothesis, several authors have tested the ancient wheat Kamut® in terms of its CD-immunogenic properties.
Various peptides, derived from Kamut® α-gliadins (such as the peptides p56–75), stimulate the T cell response [42,43]. In addition, other peptides (e.g., p31–49) activate the innate immune system [44]. In this context, several ELISA and western blot analyses have been carried out using specific monoclonal antibodies (mAbs—anti-p31–49 and mAbs anti-p56–75). Kamut® samples always showed an antibody–antigen positive reaction resulting in a similar toxicity to that obtained with modern wheats [40,44].
Small intestinal gluten-specific T-cell lines from celiac patients were tested with ancient and modern varieties in proliferation assays to evaluate whether the different varieties of wheat (including Kamut® ) were equally toxic to celiac patients. All the wheat varieties tested caused heterogeneous small intestinal T-cell responses, independent of their ancient/modern origin or ploidy [31].
In addition, the analysis of ancient grains, such as einkorn, emmer, Kamut®, rye, teff and sorghum, using an untargeted mass spectrometric method and a reverse phase-HPLC highlighted the presence of celiac epitopes in wheat-related ancient grains (e.g., einkorn, emmer, and Kamut®). Although differences in gliadin protein composition were found between ancient grain species [45], on the basis of the current data, Kamut® is toxic for celiac patients and should be excluded from the diet of celiac subjects.

3.4. Avena sativa L.

Among minor cereals, particular attention has been paid to oat. Avena sativa L. is a good source of vitamins (B complex), protein, fat, minerals and soluble fiber β-glucan. Oat (if considered safe) could, thus, increase the nutritional value of GFD and improve the palatability of gluten free products [17]. The Commission Regulation EU 828/2014 [19] allows the inclusion of oat in the gluten-free diet only if this cereal have been specially produced, prepared and/or processed in order to avoid contamination from other gluten-containing cereals (gluten content < 20 ppm). In addition, the regulation states that “Most but not all people with intolerance to gluten can include oats in their diet without adverse effect on their health”. For this reason, the inclusion of oat in GFD is still a matter of debate in the scientific community.
The different toxicities of cereals (wheat, barley and rye), non-toxic cereals (rice and corn) and oat (debated) for celiac subjects could be explained by the significant taxonomic differences between these cereals. Oat and toxic cereals belong to the same family of Poaceae but to different tribes (toxic cereals to Triticeae and oat to Aveneae) which may explain the different contents of toxic prolamins in these cereals. Oat prolamins (avenins) represent 10–15% of the total protein content, whereas prolamins of toxic cereals (wheat, barley and rye) constitute 30–50% of total protein.
In addition, the prolamins of toxic and non-toxic cereals show differences in amino acid composition: the percentages of proline and glutamine residues (both involved in the pathogenesis of CD) in toxic prolamins (from rye, barley and wheat) are 20% and 36%, respectively. Avenins contain a similar percentage of glutamine (34%) but a lower content of proline (10%) [46].
Contradictory results have been obtained regarding the role of oat in the GFD. Some studies have underlined the presence of different contents of oat immunoreactive epitopes in different varieties, while others explain the differences as a consequence of the contamination of oat products by other gluten-containing cereals [47,48]. Oat contamination has been tested using different in vitro techniques such as ELISA and immunoblotting. Several authors have reported that oat could be contaminated by gluten, and in a study performed on 133 commercial oat samples in Canada, 88% of the samples had a gluten concentration above 20 ppm [49]. Similar results were obtained in other studies for oat samples collected in Europe, the United States and Canada [50,51]. The origin of contamination may differ, depending on the field to the packaging [49]. All these studies underline that any oat varieties used for the celiac population must be free from gluten contamination.
Cross-contamination is not the only source of toxicity for celiac patients; in fact, oat avenins show a great variability which influences the immunoreactivity of peptides at the intestinal level [10].
To define the safety of oat for celiac subjects, several in vitro experiments have been performed. Some studies found no in vitro activities related to CD pathogenesis. Picarelli et al. (2001) examined the anti-endomysial antibody (EMA) production in supernatant fluid in cultured duodenal mucosa specimens from CD patients after oat and gliadin treatment [52]. EMAs were always detected after challenge with gliadin, but not after culture with digested avenins. The activities of two oat varieties (Avena genziana and Avena potenza) were tested in vitro in terms of the phosphorylation of extracellular signal-regulated kinase and TEER, in Caco-2 cells treated with PTd products from the two oat varieties and from gliadin. No negative in vitro activities related to CD were observed with these two specific varieties [53].
Other studies observed an in vitro toxicity of avenins [11,12,13,54,55,56]. Silano et al. (2014) evaluated the ability of different oat cultivars to activate the gliadin-induced transglutaminase-2 (TG2)-dependent events using in vitro models of CD [11]. They observed that some oat cultivars elicited these events, whereas other varieties did not [11].
Some avenin-reactive T-cell lines (obtained from nine celiac patients) recognized avenin peptides in the context of HLA-DQ2 [55]. Some oat peptides also stimulated the circulating dendritic cells, which are an important connection between innate and immune responses in CD pathogenesis [54].
The different levels of toxicity observed with oat varieties [12,13] highlight the importance of screening oat varieties by in vitro tests, in order to assess their safety before starting clinical trials [11].
The sera reactivity of CD patients versus oat has also been investigated. The antibody responses of children with CD against oat prolamins were tested in 34 subjects and compared with 47 control sera. Children with CD had significantly higher levels of IgG and IgA versus avenins, compared to the control group [57]. Vainio and Varjonen (1995) also detected the reactions of CD patients’ serum to oat; however, some individual specificity was observed [58]. On the other hand, in a study by Guttormsen et al. (2008), using the serum of 136 CD adult patients (60% of subjects had consumed oat as part of their GFD), no significant differences were found in IgA against oat in oat-eating CD patients and the control group (non-oat-eating CD subjects) [59].
Some intervention studies (Table 7), performed on children (aged between 0.7–17.2 years) indicated that oat could affect the health of CD patients, leading to gut mucosal inflammation, with a possible risk for future complications [60].
Table 7. In vivo studies on the toxicity of A. sativa for celiac subjects with negative outcomes.
As indicated by the immune status of the intestinal mucosa, some pediatric CD patients seem to be reactive to oat [61]. Concerns regarding the safety of oat also remain for adult CD patients. After a 12-week intervention study conducted with 50 g oat/day, one patient developed villous atrophy and dermatitis after oat consumption, and 26% of patients showed positive levels of interferon γ mRNA after the oral challenge [62].
Other clinical trials have shown that patients with CD (both adult [63,64,65,66,67,68,69] and children [62,70,71,72,73,74,75]) can safely consume medium/high amounts oat when uncontaminated by gluten (Table 8).
Table 8. In vivo studies on the toxicity of A. sativa for celiac subjects with positive outcomes.
A double-blind, placebo-controlled, crossover study evaluated the long-term (15-month trial) consumption of oat in children (177 patients, 4–14 years of age) with celiac disease. Children were randomly assigned to Group 1 (six months of a GFD plus A products, three months of washout with a standard GFD, and six months of GFD plus B products) or Group 2 (six months of a GFD plus B products, three months of washout, and six months of GFD plus A products). A and B products consisted of gluten-free foods (such as pasta, flour and biscuits) containing either purified oat or placebo. For this study two oat varieties (“Irina” and “Potenza” Avena sativa) were selected, after a preliminary screening in vitro for immunoreactivity [13]. Clinical, serological and intestinal permeability data were collected at baseline and after six, nine and fifteen months.
No statistically significant effect was observed for clinical, serological, and intestinal permeability biomarkers after the treatment. This study highlights that the long-term consumption of pure non-reactive oat products is safe for children with CD [75].
In a large cross-sectional study, different outcomes were compared between celiac patients (n = 169) on a GFD with or without oat. A total of 82% of the participants interviewed consumed oat. Oat consumers and non-consumers did not differ in dietary adherence, prevalence of symptoms, positivity for antibodies, histological recovery after one year, osteoporosis/osteopenia, or fractures. The oat consumers showed better general health scores [76]. In addition, oat could improve the nutritional and sensory quality of a gluten free diet. In fact, patients that consumed oat had a significantly higher daily intake of fiber [66] and thiamine and Zn [68] than those who did not consume oat. Regarding the sensory quality of the diet, the majority of CD patients like oat in their diet [63,71].
Based on current evidence, celiac patients can safely consume oat, but only after appropriate screening in order to exclude the immunoreactivity of the selected varieties.

4. Conclusions

Although the EU 828/2014 reported that celiac subjects should avoid wheat (e.g., Triticum species, spelt and Kamut®), rye and barley [19], recent studies underline the presence of variability, in term of immunostimulating epitopes, between ancient and modern grains. Minor cereals (such as oat) and ancient cereals have received considerable attention as alternatives for the formulation of gluten-free products. However, their toxicity for celiac patients is still debated.
Some ancient wheat varieties would appear to be less toxic for celiac patients. For example, T. monococcum seems to contain a lower number of toxic peptides and its prolamins are more susceptible to gastrointestinal digestion. Although some wheat-related ancient grains, such as T. monococcum, Triticum aestivum ssp. spelta and Kamut®, show a reduction in in vitro toxicity, the studies presented in the literature highlight the presence of immunostimulating epitopes. Therefore, these grains are currently considered toxic for celiac patients. Some of these varieties, with a reduced ability to activate the immune response in CD mucosa, could be useful in reducing the incidence of CD, but future studies are needed to confirm this.
In 2009, oat was permitted in the EU as a gluten-free ingredient; however, the contamination of oat products by other gluten-containing cereals is only one of the problems associated with the safety of this cereal for celiac patients. In fact, some in vitro studies suggest that oat avenins show great variability that influences their immunoreactivity at the intestinal level. These results underline the importance of screening the safety of oat varieties by in vitro tests before starting clinical trials.
Although some trials describe the reduced tolerability of oat in a fraction of CD patients, the majority of in vivo studies highlight that selected uncontaminated and nonreactive varieties can be safely included in the GFD.
This paper has reviewed the main in vitro and in vivo studies performed on those cereals for which the toxicity for CD is still controversial. It is evident that this review shows limitations; among others, is the fact that the various experimental protocols were not compared. On the other hand, the aim was a collection of available data from the scientific literature without intervening on the significance or otherwise of the various experimental approaches.
Contradictory results remain which highlight the importance of studying the safety of “unusual” cereals in more detail in order to prevent adverse effects in celiac patients. Oat is an exception, as selected varieties of this cereal have proven to be well tolerated in a long-term clinical study.

Author Contributions

Conceptualization, F.C., C.D.L. and P.R.; investigation, F.C., C.D.L., S.B. and C.B.; writing—original draft preparation, F.C.; writing—review and editing, F.C., C.D.L., S.B., C.B. and P.R.; supervision, P.R. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Acknowledgments

This paper was prepared in the framework of the MIUR Progetto di Eccellenza.

Conflicts of Interest

The authors declare no conflict of interest.

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Rescuing Flavor Identity and Dynamic Perception in Puréed Dishes; A Restructuring Solution for the Purée Diet
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