The Effect of Gluten in Adolescents and Young Adults With Gastrointestinal Symptoms

A Blinded Randomised Cross-Over Trial

Caecilie Crawley; Nadia Savino; Cecilie Halby; Stine Dydensborg Sander; Anne-Marie Nybo Andersen; Manimozhiyan Arumugam; Joseph Murray; Robin Christensen; Steffen Husby


Aliment Pharmacol Ther. 2022;55(9):1116-1127. 

In This Article

Abstract and Introduction


Background: The popularity of the gluten-free diet and sales of gluten-free products have increased immensely.

Aims: To investigate whether gluten induces gastrointestinal symptoms, measured by self-reported questionnaires, as well as mental health symptoms in adolescents from a population-based cohort.

Methods: The eligible participants (n = 273) were recruited from a population-based cohort of 1266 adolescents and had at least four different gastrointestinal symptoms. Phase one (n = 54) was a run-in phase where the participants lived gluten-free for 2 weeks. If they improved they continued to phase 2 (n = 33), a blinded randomised cross-over trial. Participants were blindly randomised either to start with 7 days of gluten, eating two granola bars containing 10 g of gluten or to 7 days on placebo, eating two granola bars without gluten, followed by the reverse and separated by a 7-day washout period. The effects of the intervention on gastrointestinal symptoms and mental health symptoms were assessed.

Results: In total, 54/273 participants entered the run-in phase and 35 were eligible for randomization. A total of 33 were randomised and 32 completed the trial. The median age was 20.3 (IQR 19.2–20.9) and 32/33 participants were females. Compared with a placebo, gluten did not induce gastrointestinal symptoms. The difference in the average VAS was −0.01 (95% confidence interval −2.07 to 2.05). Nor did we find a difference in the outcomes measuring mental health.

Conclusion: Compared with placebo, adding gluten to the diet did not induce gastrointestinal symptoms or worsened mental health in adolescents recruited from a population-based cohort. The trial registration number is NCT04639921.


The gluten-free diet (GFD) has gained increasing popularity among healthy people without the coeliac disease (CeD) or wheat allergy. Survey-based studies show that those following a GFD are more likely to be female, well-educated, and younger (<50 years old).[1,2] The main reasons for following a GFD as explored in these surveys are weight control, the perception that a GFD is healthier, and the presence of symptoms after gluten ingestion.[3–5]

Concurrently, the global consumption of gluten-free products has increased and is expected to reach a value of 8.5 billion USD by 2025.[6] However, following a GFD is often expensive and inconvenient and carries an inherent risk of inducing macro- and micronutrient deficiencies.[7]

Non-coeliac gluten sensitivity (NCGS) is a newly described disease entity, where the individual shows signs of sensitivity to gluten, but with no evidence of IgE-mediated wheat allergy or coeliac disease (CeD).[8] The diagnosis is based on a food challenge, preferably blinded, with relief of symptoms on a GFD and a worsening of symptoms on a gluten-containing diet.[8] The clinical picture of NCGS is broad and can resemble the clinical presentation of CeD, with both gastrointestinal and extra-gastrointestinal symptoms, and irritable bowel syndrome (IBS) but without growth insufficiency and biochemical abnormalities as seen in CeD.[9,10] The reported prevalence of self-diagnosed NCGS shows wide variation, from 0.9% to 14% in survey-based studies,[5,11] possibly due to varying perceptions of symptoms in different populations. In general, the number is even higher for gluten-avoidance.[12]

Only a limited number of studies have explored the effect of gluten on gastrointestinal symptoms, and none in adolescents, and so far the results have been inconclusive.[13] This may be a result of heterogeneous study designs or the inclusion of highly selective participants with self-diagnosed NCGS, which carries the risk of a nocebo effect.[10,14–24]

The present study aimed to address the hypothesis that adding gluten to the diet results in a self-reported worsening of gastrointestinal symptoms (primary outcome) and mental health (key secondary outcomes) in a well-characterised group of adolescents.

To this end, we performed a randomised cross-over trial comparing the effects of a gluten-containing diet to an equivalent control diet (placebo) by having participants eat two granola bars with or without gluten per day for 1 week, separated by a 1-week washout period.