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      Combination enzyme therapy for gastric digestion of dietary gluten in patients with celiac sprue.

      Gastroenterology
      Animals, Celiac Disease, drug therapy, immunology, metabolism, physiopathology, Cell Line, Cell Proliferation, drug effects, Digestion, Dose-Response Relationship, Drug, Drug Combinations, Drug Synergism, Gastrointestinal Agents, isolation & purification, pharmacology, therapeutic use, Glutamine, Glutens, Hordeum, enzymology, Humans, Rats, Serine Endopeptidases, Sphingomonas, Substrate Specificity, T-Lymphocytes

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          Abstract

          Celiac sprue is a multifactorial disease characterized by an inflammatory response to ingested gluten in the small intestine. Proteolytically resistant, proline- and glutamine-rich gluten peptides from wheat, rye, and barley persist in the intestinal lumen and elicit an immune response in genetically susceptible persons. We investigated a new combination enzyme product, consisting of a glutamine-specific endoprotease (EP-B2 from barley) and a prolyl endopeptidase (SC PEP from Sphingomonas capsulata), for its ability to digest gluten under gastric conditions. The ability of this combination enzyme to digest and detoxify whole-wheat bread gluten was investigated. In vitro and in vivo (rat) experimental systems were developed to simulate human gastric digestion, and the resulting material was analyzed by high-performance liquid chromatography, enzyme-linked immunoabsorbent assay, and patient-derived T-cell proliferation assays. The analysis revealed that EP-B2 extensively proteolyzes complex gluten proteins in bread, whereas SC PEP rapidly detoxifies the residual oligopeptide products of EP-B2 digestion. In vitro dose variation data suggests that an approximate 1:1 weight ratio of the 2 enzymes should maximize their synergistic potential. The efficacy of this 2-enzyme glutenase was verified in a rat model of gastric gluten digestion. By combining 2 enzymes with gastric activity and complementary substrate specificity, it should be possible to increase the safe threshold of ingested gluten, thereby ameliorating the burden of a highly restricted diet for patients with celiac sprue.

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