The effect of expectancy versus actual gluten intake on gastrointestinal and extra-intestinal symptoms in non-coeliac gluten sensitivity: a randomised, double-blind, placebo-controlled, international, multicentre study.

Marlijne C G de Graaf, Clare L Lawton, Fiona Croden, Agnieszka Smolinska, Bjorn Winkens, Martine A M Hesselink, Gonny van Rooy, Peter L Weegels, Peter R Shewry, Lesley A Houghton, Ben J M Witteman, Daniel Keszthelyi, Fred J P H Brouns, Louise Dye, Daisy M A E Jonkers

Journal: The lancet. Gastroenterology & hepatology 2024;9(2):110-123

PMID: 38040019

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Plain Language Summary

Even though consumption of whole grain cereal foods has been associated with several beneficial health effects, wheat products can also elicit adverse (immune-mediated) effects, such as coeliac disease (CD) and wheat allergy (WA). In addition, a substantial proportion of the general population is avoiding or reducing their consumption of wheat products due to self-reported symptoms following wheat intake, without having CD or WA. This study’s main aim was to investigate the effects of gluten intake expectancy versus actual gluten intake on GI and extra-intestinal symptoms in individuals with self-reported non-coeliac gluten sensitivity (NCGS). This study was a randomised, double blind, placebo-controlled, international multicentre study. It enrolled participants aged 18–70 years with self-reported NCGS (gastrointestinal [GI] symptoms within 8 hours of gluten consumption) without coeliac disease or wheat allergy. Participants were randomly assigned to either consume gluten-containing or gluten-free bread. Results showed that the combined effect of expectancy and actual gluten intake had the largest effect on overall GI symptoms. Repeated exposure compounded this effect, evidenced by the more pronounced effect in the afternoon (after lunch) compared to the morning (after breakfast). Similar patterns were found for predominant GI symptoms, abdominal discomfort and bloating. Furthermore, expectancy had a significant effect on the extra-intestinal symptoms (confusion/foggy mind and headache). Most differences between intervention groups persisted throughout follow-up. Authors concluded that expectancy plays a significant role in symptom perception among individuals with NCGS, emphasising the importance of psychological factors in gluten-related symptoms.

Abstract

BACKGROUND

Many individuals without coeliac 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, we aimed to investigate the effects of expectancy versus actual gluten intake on symptoms in people with non-coeliac gluten sensitivity (NCGS).

METHODS

This randomised, double-blind, placebo-controlled, international, multicentre study was done at the University of Leeds (Leeds, UK), Maastricht University (Maastricht, the Netherlands), and Wageningen University and Research (Wageningen, the Netherlands). People aged 18-70 years with self-reported NCGS (ie, gastrointestinal symptoms within 8 h of gluten consumption) without coeliac 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 eight; stratified by site and gender) to one of four groups based on the expectation to consume gluten-containing (E) or gluten-free (E) oat bread for breakfast and lunch (two 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 h, with lunch served after 4 h, and analysed per-protocol. Safety analysis included all participants incorporated in the per-protocol analysis. The study is registered at ClinicalTrials.gov, NCT05779358, and has ended.

FINDINGS

Between Oct 19, 2018, and Feb 14, 2022, 165 people were screened and 84 were randomly assigned to EG (n=21), EG (n=21), EG (n=20), or EG (n=22). One person in the EG group was excluded due to not following test day instructions, leaving 83 participants in the per-protocol analysis. Median age was 27·0 years (IQR 21·0-45·0), 71 (86%) of 83 people were women, and 12 (14%) were men. Mean overall gastrointestinal symptom score was significantly higher for EG (16·6 mm [95% CI 13·1 to 20·0]) than for EG (6·9 mm [3·5 to 10·4]; difference 9·6 mm [95% CI 3·0 to 16·2], p=0·0010) and EG (7·4 mm [4·2 to 10·7]; difference 9·1 mm [2·7 to 15·6], p=0·0016), but not for EG (11·7 mm [8·3 to 15·1]; difference 4·9 mm [-1·7 to 11·5], p=0·28). There was no difference between EG and EG (difference 4·7 mm [-1·8 to 11·3], p=0·33), EG and EG (difference 4·2 mm [-2·2 to 10·7], p=0·47), and EG and EG (difference -0·5 mm [-7·0 to 5·9], p=1·0). Adverse events were reported by two participants in the EG group (itching jaw [n=1]; feeling lightheaded and stomach rumbling [n=1]) and one participant in the EG 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. Our results necessitate further research into the possible involvement of the gut-brain interaction in NCGS.

FUNDING

Government of the Netherlands Topsector Agri & Food Top Consortium for Knowledge and Innovation, AB Mauri Global Bakery Ingredients, Baking Industry Research Trust, Borgesius-Albert Heijn, CSM Innovation Centre, the International Maize and Wheat Improvement Center (CIMMYT), DSM Food Specialties, Fazer, Healthgrain Forum, the International Association for Cereal Science and Technology, the International Wheat Gluten Association, Lantmännen, Mondelez International, Nederlands Bakkerij Centrum, Nutrition & Santé, Puratos, Rademaker, Sonneveld Group, and Zeelandia HJ Doeleman.

Address: Department of Gastroenterology-Hepatology, Maastricht University Medical Center+, Maastricht, Netherlands; NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands.; School of Psychology, University of Leeds, Leeds, UK.; NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands; Department of Pharmacology and Toxicology, Maastricht University, Maastricht, Netherlands.; Department of Methodology and Statistics, Care and Public Health Research Institute, Maastricht University, Maastricht, Netherlands.; Laboratory of Food Chemistry, Wageningen University and Research, Wageningen, Netherlands; European Bakery Innovation Centre, Sonneveld Group, Papendrecht, Netherlands.; Rothamsted Research, Harpenden, UK.; Division of Gastroenterology and Surgical Sciences, Leeds Institute of Medical Research, University of Leeds, Leeds, UK; Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA.; Division of Human Nutrition, Wageningen University and Research, Wageningen, Netherlands; Division of Gastroenterology-Hepatology, Gelderse Vallei Hospital, Ede, Netherlands.; NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands; Department of Human Biology, Maastricht University, Maastricht, Netherlands.; School of Psychology, University of Leeds, Leeds, UK; School of Food Science and Nutrition, University of Leeds, Leeds, UK.; Department of Gastroenterology-Hepatology, Maastricht University Medical Center+, Maastricht, Netherlands; NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands. Electronic address: [email protected].

DOI: 10.1016/S2468-1253(23)00317-5