Celiac Disease and Safe Grains

Donald D. Kasarda, Ph.D.
Research Chemist (Retired)
U. S. Department of Agriculture
Albany, CA

July, 2003

Learning Objective: To review the relationship of wheat, rye, and barley, the harmful grains in celiac disease, to other grains that might suitably be included in the diet of celiac patients.

Celiac disease—Definitions

People with celiac disease (gluten-sensitive enteropathy) must avoid eating wheat, rye, and barley storage proteins in order to avoid adverse changes to their intestinal mucosa that can lead to serious malabsorption of almost all nutrients (Kasarda 2000; Feighery 1999; Maki and Collin 1997; Wieser 1995). The wheat, rye, and barley storage proteins are collectively called gluten proteins by celiac patients and their physicians, although, strictly speaking, gluten is derived only from the endosperm of wheat grain. Both celiac disease and allergy can be triggered by gluten proteins although these responses involve different immunological mechanisms. Celiac disease is sometimes classified as a Type IV hypersensitivity mediated by T-cell responses whereas allergy is usually classed as a Type I hypersensitivity mediated by E-type immunoglobulins (IgE antibodies). In a very broad sense of ‘disease following a response by the immune system to an otherwise innocuous antigen,’ however, both celiac disease and allergy could be accommodated under the definition of allergy (Janeway et al. 1999), but limitation of the term allergy to Type I hypersensitivy is the current, more usual practice.

Wheat and its close relatives, rye and barley

Since the discovery by W. K. Dicke in 1950 that wheat was a key environmental factor that triggered celiac disease in susceptible individuals, the relationship of the disease to ingestion of wheat gluten proteins has become an essential part of the definition. By and large, if wheat doesn’t trigger enteropathy (or at least, changes in the mucosa that presage enteropathy), it isn’t celiac disease. Most reviews of celiac disease tend to avoid the question of toxicity, or lack thereof, in grains, seeds, or foods other than wheat—possibly because studies are lacking or inadequate. This may be reasonable from a scientific standpoint, but patients, dietitians, and primary care physicians would like something more. Only wheat and, in recent years, oats have been extensively studied with modern approaches (such as measurement of intraepithelial lymphocyte infiltration and cytokine production) for their toxicity in celiac disease—with wheat obviously being toxic, whereas evidence for the lack of toxicity of oats has now become quite strong (see below). Rye and barley have many identical or nearly identical storage proteins to those in wheat. Although testing is rather minimal, these strong protein sequence similarities, combined with the experience of celiac patients over many years with these grains and what scientific investigations have been carried out, are supportive of some degree of toxicity for these grains in celiac disease. It is very difficult to quantify the toxicity of any given grain, but I think it is at least possible that the lack of a-type gliadins (one of the most studied fractions in wheat) in rye and barley results in lesser toxicity for these two grains in comparison with wheat, as does the generally lower protein percentages of rye and barley grain.

Rice and corn (maize)

Rice and corn have generally been considered safe grains for celiac patients, although once again there has been lack of rigorous, controlled, scientific study of these grains in relation to celiac disease, especially with up-to-date methods. I am not aware of any major evidence against their safety during the past 50 years. There are people who are sensitive to rice and corn and probably to any grain. Some have clearly allergic reactions, such as respiratory difficulties or skin wheals to these grains, but gastrointestinal symptoms, such as diarrhea, might result from allergy as well (Janeway et al. 1999). If we accept celiac disease as being properly classified predominantly as a Type IV hypersensitivity mediated by T cell responses, there is also the possibility that celiac disease might be combined in a given patient with immediate hypersensitivities, such as allergies (Type I), to wheat or to any other grains, including rice and corn. Intestinal biopsy might pick up the celiac disease, but not necessarily other sensitivities. As far as I know, these potential complications have not been well studied or well understood. It seems unreasonable, however, to suggest to a celiac patient who indicates that he or she responds badly to a particular grain or food other than wheat, rye, or barley, that he or she is imagining things. Adverse reactions to what I shall somewhat arbitrarily term safe grains for celiac patients may not be common, but they do exist. Such adverse reactions should be the subject of more research as to the mechanisms involved.


In the case of oats, some early work in which patients were not biopsied indicated toxicity for oats. Dicke et al. (1953) stated that rice flour, maize starch, wheat starch, and potatoes were safe, but that wheat, rye, and oats were harmful. More recent work that may be accorded greater confidence because analyses of biopsies were included provides impressive evidence for a lack of oats toxicity in celiac disease (Kilmartin et al. 2003; Picarelli et al. 2001; Janatuinen et al. 2000; Hoffenberg et al. 2000; Hardman et al. 1999; Srinivasan et al., 1999; Reunala et al., 1998; Janatuinen et al., 1995; Hardman et al. 1997; Srinivasan et al., 1996; Dissanayake et al. 1974). The cross-reactions between antibodies to oat or wheat storage proteins has muddied the waters at times. It now seems likely that the region of the gliadin molecule that cross-reacts with oats is not the region responsible for toxicity in celiac disease (Arentz-Hansen et al., 2002; Anderson et al., 2001). Avenins are related to the C-terminal half of a- and g-gliadins, but lack the large proline-, glutamine-rich repetitive domain most strongly associated with toxicity (Kasarda 1997). Consequently, it appears that a patient might have, for example, an allergic reaction to oats or have circulating antibodies to the avenin proteins of oats without having celiac disease. The question of whether the amount of contamination of oats by wheat, barley, or rye is sufficient to be of concern to celiac patients remains to be answered.

Plant classification, protein sequences, and grain safety

We do not have a unifying theory based on rigorous scientific investigation that will include or exclude various bad reactions to the ‘safe’ grains in celiac disease, but I suggest that it is unhelpful at this time to try to include responses to grains or other foodstuffs that occur in some people with celiac disease, but not in others, as part of the celiac disease syndrome. Here, in the absence of solid scientific studies of the toxicity of most grains or seeds, I attempt to combine our knowledge of wheat and oats, which is fairly solid, with plant classification or taxonomy, and with protein sequence data to provide recommendations concerning which grains or grain-like seeds are likely to be harmful to celiac patients and which are likely to be safe (Kasarda 2001). We have learned a great deal during the past 50 years, yet I emphasize that our knowledge is far from complete. As scientific investigation continues, perhaps some of my conclusions will have to be modified. Nevertheless, I feel reasonably confident in my recommendations, which seem to have gained significant, although not universal, support from several celiac patient organizations over the past dozen years. Some of what I have to say is opinion, but I hope it may be received as somewhat educated opinion on the basis of my having been involved in research on grains in relation to celiac disease for more than 25 years

Because studies of food reactions in celiac disease usually require human subjects, and biopsies (before and after challenge) are usually also required, it is extremely difficult and expensive to carry out such studies—first of all, to recruit a reasonable number of clearly diagnosed celiac patients is quite a challenge . It is not likely that studies will be carried out in the foreseeable future on many of the grains, seeds, or foods of possible interest to celiac patients. Considering this, I suggested in 1991 (see: Kasarda 2001) that plant classification might provide useful guidance in separating safe grains from unsafe grains. I will update that approach here.

Given that wheat is toxic and assuming that oats, rice and corn (maize) are not toxic, I suggested that grains that were closer in their taxonomic relationships to corn or rice than to wheat would not be toxic in celiac disease. Such grains included millet, sorghum, Job’s tears, ragi, teff, and wild rice. Furthermore, in plant classification, wheat, rye, and barley are included in the tribe of the grass family called the Hordeae or Triticeae, while oats falls in a separate tribe. There is, however, a significant similarity in protein sequence between oat avenins and the major wheat gliadin proteins, indicating relative closeness of the two tribes. The lack of toxicity in oats led me to the further conclusion that all toxic grains would be found in a single tribe, the Triticeae (see attachments I and II). Such grains include bread wheat, durum wheat (used in pasta), spelt wheat, polonicum (Polish wheat), Kamut, monoccum (einkorn), farro, triticale (a cross between wheat and rye), and many wild grass species not usually consumed by man. All grasses not in the tribe, Triticeae, were consequently classified as safe, including rice, corn, various millets, ragi, teff, Job’s tears, wild rice, and oats (see attachment III). Plants that did not fall in the grass family, such as the dicotyledenous plants, which are very distantly related to the grass family, would be highly unlikely to have seed proteins toxic in celiac disease. Some of the dicot seeds of interest include all beans, buckwheat, quinoa, and amaranth. These relationships are summarized in Attachment III. Rigorous studies of the safe grasses (and of grain-like seeds from various dicots) that would be desirable remain undone for the reasons I suggested above. The approach I have suggested as the best available in the absence of the pertinent scientific studies has been growing in use among celiac patients. I have not received any clear evidence that this is causing harm and have heard many favorable comments to the contrary. Some people do not tolerate these grains and I would recommend that a celiac patient avoid any food that he or she associates with adverse reactions. I emphasize again, however, that because some patients seem to tolerate the grains I have put in the safe category, it seems to me unreasonable to recommend that they be avoided by all celiac patients.

The gluten proteins, as is typical of proteins, are made up of about 20 different amino acids strung together through peptide bonds like beads on a string into long polymer chains, called polypeptides. There are many gluten proteins, which vary in size, incorporating from about 250 to 850 amino acids in the polypeptide chain. The number of each type of amino acid and the sequence of incorporation of these amino acids into the polypeptide chain largely defines any given protein. When a gluten protein polypeptide is digested into smaller polypeptides (often called just ‘peptides’) by digestive enzymes, some of the peptides, incorporating from about 12-33 amino acids, are quite resistant to digestion by digestive tract enzymes (Shan et al. 2002; Bronstein et al. 1966; Frazer et al. 1959). A few of these peptides have been shown to be toxic to celiac patients by instillation studies of the equivalent synthetic peptides (Marsh et al., 1997; Marsh et al. 1995; Sturgess et al., 1994). It is unlikely that all toxic peptide sequences have been identified at this time. The amino acid sequences of the known toxic peptides do not seem to have exact duplicates in proteins other than those of grains falling in the tribe Triticeae, particularly when proteins that are likely to appear in organisms at more than trace levels are considered (Kasarda 1997). Thus, these sequences provide support for the taxonomic classification approach.

Sprouting and malting

Because enzymatic breakdown of gluten proteins often leads to small, difficult to degrade, toxic peptides, the partial breakdown of wheat, rye, or barley proteins during seed germination or in the malting process probably will not usually eliminate toxicity even when there is no trace of the large original proteins remaining. Thus, malt extracts and other hydrolysates of wheat, rye, or barley proteins (including beers) might retain some toxicity. Nevertheless, when such extracts are used in a product in very small proportions, as a flavoring, for example, the amount of toxic peptides present in the final product might be so small as to be negligible. Again, however, good scientific studies are lacking.

Alcohol derived from wheat

There has been concern expressed at times about products made from grain alcohol, when the alcohol might be derived from wheat. Because the toxic peptides (in fact all peptides) have low volatility, whereas alcohol produced by grain fermentation has a high volatility, properly distilled alcohol derived from wheat grain will contain no toxic peptides. Consequently, all vinegars made from a base of grain alcohol should be safe and this is true also for alcohol extracts as well, for example, alcoholic extracts of vanilla. In general, it appears that distilled liquors such as vodkas and whiskies should be safe, as well. Beer made from wheat, barley, or rye, as mentioned above, is a fermented, but not distilled, product and hence might have some toxic peptides in it. I suspect that beer has low toxicity, perhaps even none, but further scientific studies would need to be carried out to prove this.

Wheat starch

Products made from wheat starch are commonly eaten by celiac patients in some European countries. Wheat starch inherently is not harmful to celiac patients, but proteins adhering to the starch granules that make up a predominant part of wheat flour would be if the adherent proteins were gluten proteins, which is the case for some starch preparations.. Recent well done studies from Finland (Peraaho et al. 2003; Kaukinen et al.1999) indicate that use of the purified starches made in Europe for the purpose of producing "gluten-free" products are not causing harm to celiac patients. Such products are rarely used in the US, however, in part because the suitability of wheat starches readily available in the U.S. for gluten-free products hasn’t been evaluated.

Breast feeding and the introduction of wheat, rye, or barley to the infant diet

Recent epidemiological studies from Sweden (Ivarsson 2001) have indicated that environmental factors play an important role in determining how many children will develop celiac disease during the first two years of life. Introduction of small amounts of gluten at 4 months or older with ongoing breast feeding was favorable, decreasing the likelihood that children would develop celiac disease. The amount of gluten introduced was a complicating factor, with larger amounts being less favorable. There was also a correlation with the number of early infections experienced by young children—more infections during the first year of birth increased the likelihood that children would develop celiac disease. The correlation between infections and celiac disease provides some support for the role of one or more infectious agents as an environmental factor in the development of celiac disease (Kagnoff et al. 1984).

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