Celiac disease, an inflammatory disease of the small intestine that affects 0.1% to 0.9% of the U.S. population and about 1% of the world population, is mainly triggered by storage proteins in wheat, barley, and rye in genetically predisposed individuals (Rubio-Tapia, 2012; Schuppan et al., 2009). Like other diseases, there are multiple factors that may also trigger the onset of gluten intolerance, such as rotavirus and adenovirus exposures, and even the absence of breast feeding (Dubois et al., 2010). It appears that gluten protein fragments are similar in structure to adenovirus, rubella virus, and human herpes virus and thus cross-react with gluten proteins and activate the immune system to react (Plot & Amital, 2009; Sood, 2007).
Up to 97% of those with celiac disease express the HLA-DQ2 (human leukocyte antigen) or HLA-DQ8 genes, which ultimately contribute to an aberrant immune response to gluten, specifically gliadin fragments (Mowat, 2003; Trynka et al., 2011). However, some data indicate the majority (>80%) of those with celiac disease are clinically silent in that they do not present the classic chronic symptoms, such as diarrhea, gastrointestinal distress, headache, growth retardation, osteoporosis, and infertility. Genetic mapping suggests there may be an overlap of celiac disease with type 1 diabetes and rheumatoid arthritis (Smyth et al., 2008; Zhernakova et al., 2011).
Several recent assessments suggest that there has been about a fourfold increase in the prevalence of celiac disease since the late 1940s and early 1950s (Rubio-Tapia et al., 2009; Lohi et al., 2007; Cummins and Roberts-Thomson, 2009). This increase is associated with a significant healthcare economic burden, particularly among males (Long et al., 2010).
Wheat, of which the United States produces about 9.1% of the global supply of 24.5 billion bushels, represents about 100 years of hybridization (USDA, 2012). Breeders achieved the current diverse species through efforts to increase yield, improve adaptation to climate changes, develop disease resistance, and expand bread-making characteristics (Van de Wouw et al., 2010). Interestingly, the subsequent introduction of the D-genome from a wild-type species produced these more desirable qualities, and may have introduced more undigestible proline/glutamine-rich (prolamin) T-cell stimulatory epitopes, such as Glia-α9 and, to a lesser extent, Glia-α20. Epitopes are unique protein segments or antigenic determinants that may result in an adverse response by the immune system.
The current therapeutic approach to managing celiac disease is adherence to strict gluten-free dietary regimens. Compliance with these kinds of diets (plus nutritional challenges) is difficult to maintain. Thus, alternative interventions that are effective and economically reasonable are desired. One alternative is exploration of wheat variants and genetic modifications that produce cultivars with lower immunogenicity. Recent assessment of cereal grains to produce and store naturally occurring endopeptidases or endoproteases from food-approved bacteria or other grains suggest these enzymes may degrade immunogenic gluten peptides (Osorio et al., 2012).
Another consideration is the addition of proteolytic enzymes from some probiotic strains or fungi during dough fermentation, thereby decreasing immunotoxicity (Di Cagno et al., 2002; De Angelis et al., 2006; Rizzello et al., 2007). A recent, 60-day study among eight patients with celiac disease demonstrated 200 g sourdough bread treated with proteases from several strains of Lactobacillus and Aspergillus that yield <10 ppm gluten was well tolerated (Di Cagno et al., 2010).
An alternative is the oral administration of selected proteolytic enzymes that survive the hostile gastric environment and readily degrade proline residues unique to gliadin peptides that are resistant to human digestive proteases (Hausch et al., 2002). Attention to the physical properties and physiological functions of these enzymes in powders, tablets, or capsules is critical if the immunogenic peptides are to be adequately reduced or inactivated (Gass et al., 2007).
Celiac disease is a multi-factorial illness that represents another intersection of agriculture, food science, protein chemistry, genetics, immunology, pharmacology, and medicine. This intersection can address important issues of the management of celiac disease and provide novel avenues that produce foods that are less immunogenic. Success in this intersection requires greater understanding of the pathogenesis of celiac disease, particularly among those who are asymptomatic yet present related HLA genotypes, although only 20–30% of the population expresses HLA-DQ2 or HLA-DQ8.
References cited in this column are available from the authors.
Roger Clemens, Dr.P.H.,
Chief Scientific Officer, Horn Company, La Mirada, Calif.
Peter Pressman, M.D.,
CDR, Medical Corps, U.S. Navy, Director Expeditionary Medicine, Task Force for Business & Stability Operations