Suspected Nonceliac Gluten Sensitivity Confirmed in Few Patients After Gluten Challenge in Double-Blind, Placebo-Controlled Trials  
Molina-Infante J & Carroccio A (2017) Suspected Nonceliac Gluten Sensitivity Confirmed in Few Patients After Gluten Challenge in Double-Blind, Placebo-Controlled Trials. Clin Gastroenterol Hepatol. 15(3):339-348.

In recent years a considerable number of people who have not been diagnosed with coeliac disease, are adopting a gluten-free diet. Gluten has been blamed as a trigger of symptoms by 20-45% of adults who self-report food sensitivity.

Non-coeliac gluten sensitivity (NCGS) is a term that is used to describe individuals who are not affected by coeliac disease or wheat allergy yet who have gastrointestinal and/or non-gastrointestinal symptoms related to gluten ingestion, with improvement in symptoms upon gluten withdrawal. It is suggested that NCGS is a complex heterogeneous condition, with different subgroups potentially characterised by different pathogenesis, clinical history, and clinical course. There also appears to be an overlap between NCGS and irritable bowel syndrome (IBS).

The prevalence of NCGS remains unclear. To date there is still a lack of a clinical diagnostic biomarker, so the randomised double-blind placebo-controlled (DBPC) food challenge is considered the gold standard for diagnosis. However, there are limitations when looking at the reported outcomes of such challenges because of differences in, for example, patient selection, challenge methods and doses and duration of gluten and placebo used. Of note are studies using FODMAP containing placebos. FODMAPs are short chain carbohydrates poorly absorbed in the small intestine that are thought to trigger certain gastrointestinal symptoms in IBS patients.

So how reliable is the diagnosis of NCGS derived from these controlled food challenges?

Study objective
The authors of the study aimed to review studies that have evaluated NCGS through DBPC trials in either self-reported NCGS or IBS patients to understand whether these are effective in confirming NCGS.

Study design
A literature search was conducted through PubMed, up to 31 March 2016, to find all published randomised DBPC trials evaluating gluten challenge in either NCGS or IBS patients. Patients with coeliac disease or other gluten-related disorders (gluten ataxia, autism, neurologic symptoms) were excluded.

Main findings
Ten DBPC trials with gluten/wheat challenge with a total of 1312 adult patients with suspected NCGS were included. Six studies had a cross-over DBPC design. The studies included self-diagnosed NCGS patients with IBS-like symptoms showing improvement on a gluten-free diet.

Main outcomes

  • When overall symptoms were reported quantitatively (sum of symptom scores in all patients), gluten or wheat was shown to significantly trigger more symptoms compared with placebo in 7 studies.
  • However only 4 studies (n=231) also reported the challenge outcome qualitatively, looking at patients with specific-gluten symptoms or patients with similar or more symptoms on placebo than with gluten (nocebo effect).
    - Only 38 of the 231 (16%) NCGS patients showed gluten-specific symptoms.
    - A nocebo response was observed in 94 of 231 (40%) patients.
  • When the study using a FODMAP-containing placebo was excluded (n=35), the nocebo effect remained unaltered (77 of 196; 39%).

Author conclusions
More than 80% of patients with suspected NCGS cannot be formally diagnosed after a DBPC cross-over gluten challenge.
The authors argue that gluten may not be responsible for the symptoms in many self-reported NGCS patients. The authors point to a number of issues with a diagnosis of NCGS in patients in studies that report improved symptoms on a gluten exclusion diet including:

  • Inclusion of different cohorts of patients with symptoms to non-gluten wheat proteins or other cereal related triggers (e.g. amylase trypsin inhibitors and wheat-germ agglutinin), or those reacting to FODMAPs rather than gluten
  • Inclusion of coeliac patients that have been misdiagnosed (studies have reported relabelling of patients ruled out as coeliac after more advanced diagnostic tests)
  • Inclusion of patients with non-IgE food allergies (sometimes known as  delayed non‐IgE mediated allergy) or other food hypersensitivities  

Self-reporting NCGS patients typically have a strong expectation that their symptoms can be controlled through dietary modification. This expectation may promote a nocebo effect, which is a negative effect from an inert treatment.

This review revealed heterogeneity and potential methodology flaws (e.g. doses and duration for gluten and placebo challenges) among the included studies in this review of gluten challenges. The researchers conclude this casts doubts on gluten as the culprit food component in many patients with presumed NCGD and highlights the importance of considering the nocebo effect in studies on food hypersensitivity.

There has been an increase in the use of a gluten-free diet outside a diagnosis of coeliac disease or IgE-mediated wheat allergy, yet prevelance of food hypersensitivity with regards gluten is unclear. NCGS is used as an umbrella term for patients with IBS-like symptoms yet it is not without its uncertainties, in particular pertaining to whether it is the gluten or non-gluten components of the grain evoking symptoms; evidence suggests that fermentable carbohydrates, amylase trypsin inhibitors and wheat-germ agglutinin can also be responsible culprits.

One of the interesting findings in this study is a nocebo effect. Patients who expect unfavourable side effects are more likely to develop them than those who do not. This is not uncommon in studies of food intolerances. For example the nocebo effect was implicated as the likely reason as to why patients with a negative hydrogen breath test (the standard test for lactose intolerance) reported symptoms to lactose ingestion.

The study suggest that optimisation of double blind placebo controlled studies are important in order for more robust results and a better understanding of this complex  condition.


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