title: Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease.
abstract: Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy.
  
  
  
  Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components.
  
  
  
  Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals.
  
  
  
  These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease.
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Uhde
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Ajamian
authors.affiliation: Departments of Medical and Surgical Sciences and Digestive System, Centro di Ricerca Biomedica Applicata (C.R.B.A.), University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Caio
authors.affiliation: Departments of Medical and Surgical Sciences and Digestive System, Centro di Ricerca Biomedica Applicata (C.R.B.A.), University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: De Giorgio
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Indart
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York, USA.|Celiac Disease Center, Columbia University Medical Center, New York, New York, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Green
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Verna
authors.affiliation: Departments of Medical and Surgical Sciences and Digestive System, Centro di Ricerca Biomedica Applicata (C.R.B.A.), University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Volta
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York, USA.|Celiac Disease Center, Columbia University Medical Center, New York, New York, USA.|Institute of Human Nutrition, Columbia University Medical Center, New York, New York, USA.
authors.forename: Armin
authors.initials: A
authors.lastname: Alaedini
mesh_terms: D000209:Acute-Phase Proteins; D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000097:blood*; D016022:Case-Control Studies; D002446:Celiac Disease / Q000097:blood / Q000175:diagnosis* / Q000276:immunology*; D050556:Fatty Acid-Binding Proteins / Q000097:blood*; D005260:Female; D005408:Flagellin / Q000097:blood*; D005983:Glutens / Q000009:adverse effects*; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology*; D018950:Lipopolysaccharide Receptors / Q000097:blood*; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood*; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D011795:Surveys and Questionnaires; D021182:Wheat Hypersensitivity / Q000097:blood / Q000175:diagnosis*; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D001323:Autoantibodies; D015415:Biomarkers; D002352:Carrier Proteins; D050556:Fatty Acid-Binding Proteins; D005408:Flagellin; D005983:Glutens; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein
keywords: CELIAC DISEASE; GUT INFLAMMATION; INTESTINAL BARRIER FUNCTION; INTESTINAL EPITHELIUM