Esophagus to Small Intestine

Lancet Gastroenterol Hepatol. 2024;9(2):110–23

de Graaf MCG, Lawton CL, Croden F, Smolinska A, Winkens B, Hesselink MAM, van Rooy G, Weegels PL, Shewry PR, Mooney PD, Houghton LA, Witteman BJM, Keszthelyi D, Brouns FJPH, Dye L, Jonkers DMAE

The effect of expectancy versus actual gluten intake on gastrointestinal and extra-intestinal symptoms in non-celiac gluten sensitivity: A randomized, double-blind, placebo-controlled, international, multicenter study

Background: Many individuals without celiac disease or wheat allergy reduce their gluten intake because they believe that gluten causes their gastrointestinal symptoms. Symptoms could be affected by negative expectancy. Therefore, the authors aimed to investigate the effects of expectancy versus actual gluten intake on symptoms in people with non-celiac gluten sensitivity (NCGS).
Methods: This randomized, double-blind, placebo-controlled, international, multicenter study was done at the University of Leeds (UK), Maastricht University (The Netherlands), and Wageningen University and Research (The Netherlands). People aged 18-70 years with self-reported NCGS (i.e., gastrointestinal symptoms within 8 hours of gluten consumption) without celiac disease and wheat allergy were recruited. Participants had to follow a gluten-free or gluten-restricted diet for at least 1 week before (and throughout) study participation and had to be asymptomatic or mildly symptomatic (overall gastrointestinal symptom score ≤ 30 mm on the Visual Analogue Scale [VAS]) while on the diet. Participants were randomly assigned (1:1:1:1; blocks of 8; stratified by site and gender) to 1 of 4 groups based on the expectation to consume gluten-containing (E+) or gluten-free (E-) oat bread for breakfast and lunch (2 slices each) and actual intake of gluten-containing (G+) or gluten-free (G-) oat bread. Participants, investigators, and those assessing outcomes were masked to the actual gluten assignment, and participants were also masked to the expectancy part of the study. The primary outcome was overall gastrointestinal symptom score on the VAS, which was measured at and corrected for baseline (before breakfast) and hourly for 8 hours, with lunch served after 4 hours, and analyzed per-protocol. Safety analysis included all participants incorporated in the per-protocol analysis.
Findings: Between October 19, 2018, and February 14, 2022, 165 people were screened and 84 were randomly assigned to E+G+ (n = 21), E+G- (n = 21), E-G+ (n = 20), or E-G- (n = 22). One person in the E+G+ group was excluded due to not following test day instructions, leaving 83 participants in the per-protocol analysis. Median age was 27.0 years (interquartile range, 21.0–45.0), 71 of 83 people (86%) were women, and 12 (14%) were men. Mean overall gastrointestinal symptom score was significantly higher for E+G+ (16.6 mm [95% confidence interval {CI}: 13.1–20.0]) than for E-G+ (6.9 mm [95% CI: 3.5–10.4]; difference 9.6 mm [95% CI: 3.0–16.2], p = 0.0010) and E-G- (7.4 mm [95% CI: 4.2–10.7]; difference 9.1 mm [95% CI: 2.7–15.6], p = 0.0016), but not for E+G- (11.7 mm [95% CI: 8.3–15.1]; difference 4.9 mm [95% CI: -1.7–11.5], p = 0.28). There was no difference between E+G- and E-G+ (difference 4.7 mm [95% CI: -1.8–11.3], p = 0.33), E+G- and E-G- (difference 4.2 mm [95% CI: -2.2–10.7], p = 0.47), and E-G+ and E-G- (difference -0.5 mm [95% CI: -7.0–5.9], p = 1.0). Adverse events were reported by 2 participants in the E+G- group (itching jaw [n = 1]; feeling lightheaded and stomach rumbling [n = 1]) and 1 participant in the E-G+ group (vomiting).

Interpretation: The combination of expectancy and actual gluten intake had the largest effect on gastrointestinal symptoms, reflecting a nocebo effect, although an additional effect of gluten cannot be ruled out. These results necessitate further research into the possible involvement of the gut-brain interaction in non-celiac gluten sensitivity.

Prof. Dr. D.M.A.E. Jonkers, Department of Gastroenterology-Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands, E-Mail:

DOI: 10.1016/s2468-1253(23)00317-5

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