title: Nutritional Wheat Amylase-Trypsin Inhibitors Promote Intestinal Inflammation via Activation of Myeloid Cells.
abstract: Wheat amylase-trypsin inhibitors (ATIs) are nutritional activators of innate immunity, via activation of the toll-like receptor 4 (TLR4) on myeloid cells. We aimed to characterize the biologic activity of ATIs in various foods and their effect on intestinal inflammation.
  
  
  
  We selected 38 different gluten-containing and gluten-free products, either unprocessed (such as wheat, rye, barley, quinoa, amaranth, soya, lentils, and rice) or processed (such as pizza, pasta, bread, and biscuits). ATIs were extracted and their biological activities determined in TLR4-responsive mouse and human cell lines. Effects of oral ATIs on intestinal inflammation were determined in healthy C57BL/6 mice on a gluten-free or ATI-free diet and in mice given low-level polyinosinic:polycytidylic acid or dextran sodium sulfate to induce colitis. Parameters of innate and adaptive immune activation were determined in duodenum, ileum, colon, and mesenteric lymph nodes.
  
  
  
  Modern gluten-containing staples had levels of TLR4-activating ATIs that were as much as 100-fold higher than in most gluten-free foods. Processed or baked foods retained ATI bioactivity. Most older wheat variants (such as Emmer or Einkorn) had lower bioactivity than modern (hexaploid) wheat. ATI species CM3 and 0.19 were the most prevalent activators of TLR4 in modern wheat and were highly resistant to intestinal proteolysis. Their ingestion induced modest intestinal myeloid cell infiltration and activation, and release of inflammatory mediators-mostly in the colon, then in the ileum, and then in the duodenum. Dendritic cells became prominently activated in mesenteric lymph nodes. Concentrations of ATIs found in a normal daily gluten-containing diet increased low-level intestinal inflammation.
  
  
  
  Gluten-containing cereals have by far the highest concentrations of ATIs that activate TLR4. Orally ingested ATIs are largely resistant to proteases and heat, and increase intestinal inflammation by activating gut and mesenteric lymph node myeloid cells.
authors.affiliation: Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Victor F
authors.initials: VF
authors.lastname: Zevallos
authors.affiliation: Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Department of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Raker
authors.affiliation: Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Institute of Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Tenzer
authors.affiliation: Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Carolina
authors.initials: C
authors.lastname: Jimenez-Calvente
authors.affiliation: Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashfaq-Khan
authors.affiliation: Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Rüssel
authors.affiliation: Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Geethanjali
authors.initials: G
authors.lastname: Pickert
authors.affiliation: Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Institute of Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.affiliation: Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Department of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Steinbrink
authors.affiliation: Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address: detlef.schuppan@unimedizin-mainz.de.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
mesh_terms: D056704:Adaptive Immunity; D000681:Amylases / Q000037:antagonists & inhibitors*; D000818:Animals; D002446:Celiac Disease / Q000276:immunology*; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D003106:Colon / Q000276:immunology; D016264:Dextran Sulfate / Q000633:toxicity; D055050:Diet, Gluten-Free; D004386:Duodenum / Q000276:immunology; D005983:Glutens / Q000276:immunology*; D006801:Humans; D007082:Ileum / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation; D007369:Interferon Inducers / Q000633:toxicity; D007422:Intestines / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D008643:Mesentery; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D010940:Plant Proteins / Q000276:immunology; D011070:Poly I-C / Q000633:toxicity; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D014908:Triticum / Q000276:immunology; D014361:Trypsin Inhibitors / Q000276:immunology*
chemical_list: D007369:Interferon Inducers; D010940:Plant Proteins; D051197:Toll-Like Receptor 4; D014361:Trypsin Inhibitors; D005983:Glutens; D016264:Dextran Sulfate; D000681:Amylases; D011070:Poly I-C
keywords: Celiac Disease; Digestion; Gluten; Wheat Sensitivity