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

Disclosures

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

Abstract and Introduction

Abstract

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.

Introduction

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.

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Table 1. Baseline demographic and clinical characteristics
	Period 1 Gluten N = 17	Period 1 Placebo N = 16	Baseline total combined
Basic characteristics
Age, years^a	19.8 [18.9;20.8]	20.5 [20.1;20;9]	20.3 [19.2;20;9]
Sex, females (n%)^b	17 (100%)	16 (94%)	32 (97%)
Height, SD-score^c	−0.7 [−1.0;0.7]	−0.5 [−1.1;0.1]	−0.4 [−1.1;0.5]
Weight, SD-score^c	0.0 [−0.4;0.9]	−0.5 [−1.1;0.3]	−0.1 [−0.7;0.6]
Body-Mass-Index (BMI) kg/m^2,d	22.7 [21.0;24.4]	21.6 [20.6;24.4]	22.0 [20.6;24.4]
BMI, SD-score^c	0.4 [0.0;1.3]	0.1 [−0.7;1.1]	0.3 [−0.1;1.2]
Number of gastrointestinal symptoms (at least 4 out of 10)^e	5 [4;6]	5 [4;6]	5 [4;6]
IgE Wheat positive (n%)^f	0 (0%)	4 (25%)*	4 (12%)
On diet to obtain weight loss (n%)^g	5 (29%)	0 (0%)*	5 (15%)
Medication, fasting, or vomiting to obtain weight loss (n%)^h	2 (12%)	0 (0%)	2 (6%)
Wanting to be thin or afraid of weight gain (n%)ⁱ	12 (71%)	14 (88%)	26 (79%)
Exercising to obtain weight loss (n%)^j	11 (65%)	10 (63%)	21 (64%)
Autoimmune disease among first-degree relatives (n%)^j	0 (0%)	2 (13%)	2 (6%)
HLA status, positive HLA DQ2/DQ8 (n%)	11 (65%)	7 (47%)	18 (55%)
Primary outcome
VAS Symptom Score at baseline, 0–100 mm	19 [6–26]	21 [14–29]	21 [9–29]
VAS symptom Score at the beginning at Phase 1, 0–100 mm	55 [50–61]	54 [43–60]	55 [43–61]
Key secondary outcomes
SF-36 Mental Component Score, score: 0–100^k	48.1 (10.9)	45.9 (11.8)	47.0 (11.2)
SF-36 Physical Component Score, score: 0–100^k	53.3 (8.2)	51.5 (8.0)	52.4 (8.0)
WEMWBS: 14–70^k	52.1 (5.2)	50.1 (8.0)	51.1 (6.8)
Other secondary outcomes
VAS₁,/Abdominal pain, 0–100 mm	4 [0–38]	18 [3–23]	16.5 [0–28]
VAS₂,/Bloating, 0–100 mm	19 [9–29]	22 [10–35]	19 [10–31]
VAS₃/Flatulence, 0–100 mm	24 [16–17]	38 [24–44]	27 [19–44]
VAS₄,/Borborygmi, 0–100 mm	20 [11–49]	28 [15–75]	26 [11–57]
VAS₅,/Diarrhoea, 0–100 mm	0 [0–10]	10 [0–29]	2 [0–23]
VAS₆,/Constipation, 0–100 mm	11 [0–34]	18 [0–43]	17 [0–39]
VAS₇,/Incomplete evacuation after toilet visit, 0–100 mm	11 [0–33]	31 [17–56]	23 [0–42]
VAS₈,/Nausea, 0–100 mm	14 [0–28]	8 [0–14]	10 [0–26]
VAS₉,/Burping, 0–100 mm	1 [0–17]	4 [0–14]	0 [0–16]
VAS₁₀,/dyspepsia, 0–100 mm	0 [0–4]	2 [0–13]	0 [0–13]

Note: Values are means ± SDs, or median and interquartile range (depending on the empirical data distribution); unless otherwise stated. Significant differences (p < 0.05) are marked with an asterisk (*).
^aThe age was calculated as the age of the participants on September 1, 2020.
^bBased on the Danish personal identification number.
^cHeight, weight, and BMI were reported as SD scores to allow for age and sex using the Danish references for growth.⁴⁹ The values are obtained from the Glutenfunen cohort, including participants from 2018 to 2020.
^dBased on the questionnaire to the participants in the Glutenfunen cohort. The score reflects the number of gastrointestinal symptoms, with the maximum being 10. To be included in this study, a symptom score higher than 3 was necessary.
^eThe values are obtained from the Glutenfunen cohort, including participants from 2018 to 2020.
^fIgE wheat was measured at day 0. Higher than 0.35 kU/l was considered positive
^gWas considered positive if the participants answered "every day," "often," or "several times" and negative if participants answered "a couple of times," "never," or "do not know." The time scale was the last year.
^hWas considered positive if the participants answered "every day," "several times per week," "once a week," or "1-3 times per month," and negative if they answered "never," "do not know," or "less than once per month."
ⁱWas considered positive if the participants answered "every day," "often," or "sometimes," and it was considered negative if they answered, "rarely," "never," or "do not know."
^jBased on the questionnaire to the participants in the GlutenFunen cohort.
^kMeasured at day 0.

Table 2. Summary results for each study group and period
	Period 1		Period 2	Period 3		Statistical tests: Fixed effects
	Gluten	Control	Washout	Gluten	Control	Period*group	Period	Group
Primary outcome						p-values	p-values	p-values
Average VAS, 0–100 mm	24.4 (2.2)	21.8 (2.2)	17.5 (1.9)	19.6 (2.2)	22.1 (2.2)	0.15	0.03	0.99
Key secondary outcomes
SF-36 Mental Component Score, score: 0–100	48.3 (1.7)	48.7 (1.6)	48.5 (1.3)	51.4 (1.6)	49.5 (1.8)	0.52	0.10	0.54
SF-36 Physical Component Score, score: 0–100^g	51.0 (0.8)	51.5 (0.8)	51.8 (0.6)	50.7 (0.8)	52.2 (0.8)	0.59	0.73	0.69
WEMWBS: 14–70	50.4 (1.3)	51.9 (1.1)	51.9 (0.8)	51.9 (1.1)	52.3 (1.2)	0.67	0.28	0.28
Other secondary outcomes
VAS₁/Abdominal pain, 0–100 mm	29.1 (3.5)	18.4 (3.3)	17.7 (2.9)	19.0 (3.4)	28.0 (3.5)	0.00	0.90	0.65
VAS₂/Bloating, 0–100 mm	37.4 (4.1)	30.7 (4.0)	25.8 (3.6)	29.2 (4.0)	34.5 (4.1)	0.07	0.27	0.73
VAS₃/Flatulence, 0–100 mm	34.9 (3.8)	32.6 (3.7)	26.3 (3.3)	30.6 (3.7)	32.7 (3.9)	0.51	0.31	0.97
VAS₄/Borborygmi 0–100 mm	23.2 (3.4)	27.1 (3.4)	18.6 (3.0)	23.7 (3.4)	19.5 (3.4)	0.15	0.04	0.92
VAS₅/Diarrhoea 0–100 mm	15.9 (2.9)	13.5 (2.9)	11.9 (2.5)	14.6 (3.0)	15.8 (3.1)	0.53	0.77	0.72
VAS₆/Constipation 0–100 mm	20.6 (3.2)	20.0 (3.1)	14.8 (2.7)	13.8 (3.2)	16.1 (3.2)	0.62	0.00	0.64
VAS₇/Incomplete evacuation after toilet visit, 0–100 mm	29.4 (3.9)	28.0 (3.8)	26.2 (3.3)	28.7 (3.8)	38.3 (3.9)	0.09	0.02	0.04
VAS₈/Nausea, 0–100 mm	29.0 (3.7)	20.5 (3.6)	16.2 (3.1)	17.9 (3.6)	22.5 (3.7)	0.05	0.02	0.34
VAS₉/Burping, 0–100 mm	12.8 (2.5)	18.4 (2.5)	10.9 (2.2)	12.0 (2.5)	6.3 (2.6)	0.01	<0.00	0.97
VAS₁₀/dyspepsia, 0–100 mm	11.0 (2.1)	12.2 (2.0)	6.8 (1.7)	8.3 (2.0)	6.7 (2.1)	0.47	0.00	0.87

Notes: Values are Least-Squares Means (SE) unless otherwise stated.
Statistical tests are based on a repeated-measures linear mixed-effects model (participants modelled as a random effects variable).

Table 3. Summary of results for each intervention group derived from the cross-over design (i.e. all periods included)
	Gluten (active)	Control (placebo)	Difference between groups (95% confidence interval)	p-value
Primary outcome
Average VAS, 0–100 mm	22.0 (2.2)	22.0 (2.2)	−0.01 [−2.1 to 2.1]	0.99
Key secondary outcomes
SF-36 Mental Component Score, score: 0–100	49.8 (1.7)	49.1 (1.7)	−0.7 [−3.1 to 1.6]	0.54
SF-36 Physical Component Score, score: 0–100	50.8 (0.8)	51.9 (0.8)	1.0 [−0.2 to 2.2]	0.10
WEMWBS: 14–70	51.1 (1.1)	52.1 (1.1)	1.0 [−0.8 to 2.7]	0.28
Other secondary outcomes
VAS₁,/abdominal pain, 0–100 mm	24.0 (3.4)	23.2 (3.4)	−0.9 [−4.6 to 2.9]
VAS₂/Bloating, 0–100 mm	33.3 (4.1)	32.6 (4.1)	−0.7 [−4.6 to 3.2]	0.72
VAS₃/Flatulence, 0–100 mm	32.7 (3.8)	32.7 (3.8)	−0.1 [−4.1 to 4.0]	0.97
VAS₄,/Borborygmi, 0–100 mm	23.5 (3.4)	23.3 (3.4)	−0.2 [−3.5 to 3.1]	0.92
VAS₅,/Diarrhoea, 0–100 mm	15.3 (3.0)	14.6 (3.0)	−0.6 [−4.2 to 2.9]	0.72
VAS₆,/Constipation, 0–100 mm	17.2 (3.2)	18.0 (3.2)	0.9 [−2.8 to 4.5]	0.64
VAS_7,/Incomplete evacuation after toilet visit, 0–100 mm	29.1 (3.8)	33.2 (3.8)	4.1 [0.2 to 8.0]	0.04*
VAS₈/Nausea, 0–100 mm	23.4 (3.6)	21.5 (3.6)	−1.9 [−5.9 to 2.1]	0.34
VAS₉/Burping, 0–100 mm	12.4 (2.5)	12.3 (2.5)	−0.1 [−2.8 to 2.7]	0.97
VAS₁₀/dyspepsia, 0–100 mm	9.7 (2.0)	9.5 (2.0)	−0.2 [−2.6 to 2.2]	0.87

Notes: Values are Least Squares Means (SE) unless otherwise stated. Statistical tests are based on Repeated-Measures Linear Mixed-Effects Model (participants modelled as a random effects variable). Significant differences (p < 0.05) are marked with an asterisk (*).

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

A Blinded Randomised Cross-Over Trial

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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