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Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease
  1. Melanie Uhde1,
  2. Mary Ajamian1,
  3. Giacomo Caio2,
  4. Roberto De Giorgio2,
  5. Alyssa Indart1,
  6. Peter H Green1,3,
  7. Elizabeth C Verna1,
  8. Umberto Volta2,
  9. Armin Alaedini1,3,4
  1. 1Department of Medicine, Columbia University Medical Center, New York, New York, USA
  2. 2Departments 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
  3. 3Celiac Disease Center, Columbia University Medical Center, New York, New York, USA
  4. 4Institute of Human Nutrition, Columbia University Medical Center, New York, New York, USA
  1. Correspondence to Dr Armin Alaedini, Department of Medicine, Columbia University Medical Center, 1130 Saint Nicholas Ave., Room 937; New York, NY 10032, USA; aa819{at}


Objective 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.

Design 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.

Results 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.

Conclusions 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.


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  • Contributors AA had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. AA: study concept and design. MU, MA, GC, RDG, AI, ECV, PHG, UV and AA: contribution to study design. MU, MA, GC, RDG, AI and UV: acquisition of data. MU, MA, GC, RDG, AI, ECV, PHG, UV and AA: analysis and interpretation of data. MU and AA: drafting of the manuscript. MU, MA, GC, RDG, PHG, ECV, UV and AA: critical revision of the manuscript for important intellectual content. MU and AA: statistical analysis. GC, RDG, ECV, PHG, UV and AA: administrative, technical or material support. AA: obtained funding. AA: study supervision.

  • Funding This study was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR000040 (to AA) and The Stanley Medical Research Institute through grant number 08R-2061 (to AA). Additional support was provided by the Italian Ministry of University, Research and Education through grant number 2009MFSXNZ_002 (to RDG), the Italian Ministry of Public Health through Ricerca Finalizzata Regione Emilia Romagna-2009 (to RDG), and funds from the University of Bologna. The funding agencies had no role in the design and conduct of the study; in the collection, analysis and interpretation of the data; or in the preparation, review or approval of the manuscript.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Institutional Review Board of Columbia University Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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