Double-Blind Randomized Clinical Trial: Gluten versus Placebo Rechallenge in Patients with Lymphocytic Enteritis and Suspected Celiac Disease

PLoS One. 2016 Jul 8;11(7):e0157879. doi: 10.1371/journal.pone.0157879. eCollection 2016.


Background: The role of gluten as a trigger of symptoms in non-coeliac gluten sensitivity has been questioned.

Aim: To demonstrate that gluten is the trigger of symptoms in a subgroup of patients fulfilling the diagnostic criteria for non-coeliac gluten sensitivity (NCGS), which presented with lymphocytic enteritis, positive celiac genetics and negative celiac serology.

Methods: Double-blind randomized clinical trial of gluten vs placebo rechallenge.

Inclusion criteria: >18 years of age, HLA-DQ2/8+, negative coeliac serology and gluten-dependent lymphocytic enteritis, and GI symptoms, with clinical and histological remission at inclusion. Eighteen patients were randomised: 11 gluten (20 g/day) and 7 placebo. Clinical symptoms, quality of life (GIQLI), and presence of gamma/delta+ cells and transglutaminase deposits were evaluated.

Results: 91% of patients had clinical relapse during gluten challenge versus 28.5% after placebo (p = 0.01). Clinical scores and GIQLI worsened after gluten but not after placebo (p<0.01). The presence of coeliac tissue markers at baseline biopsy on a gluten-free diet allowed classifying 9 out of the 18 (50%) patients as having probable 'coeliac lite' disease.

Conclusion: This proof-of-concept study indicates that gluten is the trigger of symptoms in a subgroup of patients fulfilling the diagnostic criteria for NCGS. They were characterized by positive celiac genetics, lymphocytic enteritis, and clinical and histological remission after a gluten-free diet.

Trial registration: NCT02472704.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Celiac Disease / diagnosis*
  • Diet, Gluten-Free*
  • Double-Blind Method
  • Enteritis / diagnosis*
  • Female
  • Glutens / chemistry*
  • Glutens / immunology*
  • Humans
  • Lymphocytes / cytology*
  • Male
  • Middle Aged
  • Quality of Life
  • Young Adult


  • Glutens

Associated data


Grants and funding

This study was funded by a grant from the 'Fundación Mutua Madrileña’ (Madrid, Spain). This sponsor had no role in the study design, acquisition, analysis or interpretation of the data, or the report writing.