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Given that celiac disease is wholly dependent on the ingestion of glutens, alternative strategies implementing genetically modified grains, and externally applied (in food processing) or orally delivered enzymes of microbial origin are being earnestly pursued.
October 31, 2006
Mix the wrong hand in the game of genetic poker with a dietary ingredient — say, gluten, a storage protein present in wheat and comprising a family of proteins called gliadins — perhaps especially in the first few months of life, and coeliac disease (CD) may manifest. This intestine-centric inflammatory condition can persist lifelong among those afflicted — five to 10 people out of every thousand in the populations evaluated. Far more sinister is the fact that many CD individuals are overtly asymptomatic, lacking gut-specific symptoms yet presenting with short stature, bone loss and iron-deficiency anaemia. The only evidence-based therapy for CD is stringent dietary exclusion of gluten and related proteins present in rye and barley.
However, given that CD is wholly dependent on the ingestion of glutens, alternative strategies implementing genetically modified grains, and externally applied (in food processing) or orally delivered enzymes of microbial origin are being earnestly pursued. Both of these strategies effectively lessen or remove the dietary gluten/gliadin payload, with the latter appearing to provide the greatest promise.1
One of the most antigenic gliadin peptide fragments to immune cells (CD4+ T cells) from CD patients is a peptide composed of 33 amino acids (33g).2 This peptide was found in wheat, rye and barley (foods notorious for being toxic to CD patients) yet absent in otherwise innocuous foods. Protein-digesting enzymes (proteases) produced and liberated by the stomach, intestinal cells and pancreas are unable to completely digest dietary gliadins, including 33g. As with many gliadin peptides, 33g is rich in proline and glutamine, with the proline residues in these peptides often being enzymatically 'elusive.'
Coperfusion of 33g into the intestine (jejunum) of rats, along with a bacterial origin (Flavobacterium meningosepticum) enzyme specific for digestively targeting proline as it exists in the interior of peptides (prolyl endopeptidase; PEP) resulted in nearly complete digestion of 33g.2,3 The activity of PEP was synergistic with the native proteases that are present in the intestinal cells.
Harnessing biofermentation techniques to overexpress a PEP in appropriate micro-organisms may offer a commercial viability advantage over using F. meningosepticum. The same group that first undertook the in vitro/in vivo PEP experiments described above have recently shown that a PEP derived from barley, and expressed in a recombinant strain of E. coli, displays robust and rapid glutenase activity both in vitro and upon oral administration to rats, acting on the glutamine residues in gluten.4,5 Notably, this PEP is active in acidic conditions, not unlike those seen in the stomach, and again works synergistically with native gastric and pancreatic enzymes. Glutenase enzyme cocktails with the F. meningosepticum-derived PEP, which is most active in the less-acidic compartment of the small intestine, plus the barley PEP, have shown essential elimination of gluten-derived antigens.6
These very promising data have fostered clinical trials assessing the safety and efficacy of oral glutenase therapy in CD patients, likely to be a pharmaceutical pursuit. They also suggest that glutenase pretreatment of gluten-containing foodstuffs may offer an on-the-shelf liberating solution for CD persons, who must adhere to a very rigorous diet.
The $21 million equity financing of Alvine Pharmaceuticals, which has a license for international patent applications centering upon PEP, with investment by Cargill Ventures,7 suggests that both of these bioactive approaches will be assessed rapidly. The existence of unique, sourdough-derived Lactobacillus sanfrancisco and L. plantarum strains that also display potent glutenase activity in vitro also hints that 'designer bakery items' for CD patients may be attainable.
1. Fasano A and Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology 2001;120:636-51.
2. Shan L, et al. Structural basis for gluten intolerance in celiac sprue. Science 2002;297:2275-8.
3. Hausch F, et al. Intestinal digestive resistance of immunodominant gliadin peptides. Am J Physiol Gastrointest Liver Physiol 2002;283:G996-G1003.
4. Bethune MT, et al. Heterologous expression, purification, refolding, and structural-functional characterization of EP-B2, a self-activating barley cysteine endoprotease. Chem Biol 2006;13:637-47.
5. Gass J, et al. Effect of barley endoprotease EP-B2 on gluten digestion in the intact rat. JPET 2006;318:1178-86.
6. Siegel M, et al. Rational design of combination enzyme therapy for celiac sprue. Chem Biol 2006;13:649-58.
Anthony Almada, MSc, is president and CSO of IMAGINutrition. Respond: [email protected]
CEO, Vitargo Global Sciences
Anthony L. Almada, MSc, FISSN, has collaborated on more than 50 university-based human studies assessing sports nutrition products. He was the co-founder of EAS (which introduced creatine to North America in 1993) and is the CEO of Vitargo Global Sciences Inc.
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