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.

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

FINDINGS

Between Oct 19, 2018, and Feb 14, 2022, 165 people were screened and 84 were randomly assigned to E

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.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests MCGdG, CLL, FC, MAMH, and GvR report partial financing by a public–private partnership grant from Topsector Agri & Food Top Consortium for Knowledge and Innovation (TKI) for Well on Wheat? (TKI16060BMNU). AS reports consulting fees and financial support for conference attendance from Owlstone Medical (all outside submitted work). PLW reports part employment by the European Bakery Innovation Centre, Sonneveld Group, who provided the study breads; Sonneveld Group received payment from a public–private partnership grant of TKI Well on Wheat? (TKI16060BMNU) for providing the study bread. PRS reports a public–private partnership grant of TKI Well on Wheat? (TKI16060BMNU), Agriculture and Horticulture Development Board Studentship Project grant (061), FIBRAXFUN grant, the Biotechnology and Biological Sciences Research Council (BBSRC) grant (BB/S013954/1, BBSRC BB/S020101/1, BBSRC BB/T013923/1, and BBSRC BB/W01792X/1), and the Engineering and Physical Sciences Research Council grant (EP/S01679/1 GCRF Hub SANC South Asian Nitrogen Hub); an honorarium for membership of the Editorial Board of the Journal of Cereal Science (Elsevier); payment for conference flight, hotel, and registration costs by Gluten Workshop Madrid, Wheat Research Updates Norway, 8th International Conference on Dietary Fiber, From Seed to Pasta IV, and the British Society for Allergy and Clinical Immunology; being a member of the Irish Department of Agriculture, Food and the Marine grant board (paid to self); and employment at Rothamsted Research, which receive strategic funding from the BBSRC and whose work forms part of the Designing Future Wheat (BB/P016855/1) and Developing Sustainable Wheat (BB/X011003/1) strategic programmes. LAH reports acting as a consultant to GSK, Ironwood, and non-paid to Pfizer; receiving financial support to attend the Rome V foundation meeting in Chicago, IL, USA, in May, 2023; and being a member of the British Society of Gastroenterology Neurogastroenterology and Motility Committee and Food and Function Committee (all outside submitted work). DK reports receiving research funding from Grunenthal, Allergan, ZonMw, MLDS, the Rome Foundation, Horizon 2020, Horizon Europe, and United European Gastroenterology; receiving a speaker's fee (paid to host institution) from Dr Falk; participating on a data safety and monitoring and advisory board for the NUTRECOVER study (no financial reimbursement); and being a board member of the Dutch Society of Gastroenterology (no financial reimbursement; all outside submitted work). FJPHB reports receiving a public–private partnership grant of TKI Well on Wheat? (TKI16060BMNU); consulting fees from Lesaffre France; a personal speaker fee and travel cost reimbursement from Zeelandia Netherlands; and payment from Zeelandia and Lesaffre for travel or hotel costs (paid to institution) for invited scientific meetings. LD reports partial financing by a public–private partnership grant of TKI Well on Wheat? (TKI16060BMNU); being a past President of the International Life Sciences Institute Europe and current Co-Chair of the International Life Sciences Institute Global; receiving grant funding from Sanofi Consumer Healthcare; and sitting on the Hass Avocado Scientific Advisory Board. DMAEJ reports receiving a public–private partnership grant of TKI Well on Wheat? (TKI16060BMNU) and TKI grants from Agri & Food and Health Holland (AF18109, LWV20.187, LWV21.052, LSHM22057), the Carbokinetics programme as part of the Netherlands Organisation for Scientific Research–Carbohydrate Competence Center partnership, Organic A2BV/Mothersfinest, and Horizon 2020 (DISCOvERIE/848228). All other authors declare no competing interests.