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

Gastroenterology. 2007 Aug;133(2):472-80. doi: 10.1053/j.gastro.2007.05.028. Epub 2007 May 21.


Background and aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


  • Drug Combinations
  • Gastrointestinal Agents
  • Glutamine
  • Glutens
  • Serine Endopeptidases
  • PREPL protein, human
  • Prolyl Oligopeptidases