Abstract
BackgroundPatients with coeliac disease (CD) commonly report a variety of adverse symptoms to gluten, but descriptions of the symptomatic response in the literature may have been confounded by the presence of food components such as fermentable carbohydrates (FODMAPs) causing symptoms of irritable bowel syndrome independent of gluten. In recent unmasked and masked low FODMAP gluten challenge studies in small groups of treated CD patients, nausea and vomiting were shown to be the key symptoms associated with serum interleukin (IL)-2 release. Our objective was to utilise a large and diverse cohort of people with CD undertaking a standardised gluten food challenge to characterise the demographic, genetic and clinical factors influencing the severity and timing of acute gluten reactions and IL-2 production.MethodsA total of 295 adults treated for CD were observed for 6 h after an unmasked food challenge consisting of 10 g vital wheat gluten (low in FODMAPs) in 100 ml water. Assessments included patient-reported outcomes, serum IL-2 and adverse events. Responses were analysed according to patient characteristics, HLA-DQ genotype, duodenal histology and response to a second gluten challenge.ResultsPeak symptom severity was at 3 h (median severity 5/10). Peak IL-2 was at 4 h (median 4 pg/ml, range undetectable to 1028 pg/ml). Older age, older age at diagnosis, HLA-DQ2.5 positivity and homozygosity for HLA-DQB1*02 were each significantly associated with IL-2 elevations after gluten. Patients positive for HLA-DQ2.5, DQ8, DQ2.2 or DQ7 showed elevated IL-2 after gluten. Patient factors were not significantly associated with severity of digestive symptoms, but symptoms were correlated to one another and serum IL-2. Gluten challenge after 5 months caused more vomiting and higher IL-2 levels, but responses correlated with the first.ConclusionsGluten-induced symptoms and cytokine release is common in adults with treated CD. Age, genetics and previous response to gluten predict these acute reactions to gluten challenge. Structured symptom assessment and serum IL-2 after standardised gluten challenge may inform on patient diagnosis, the role of gluten in symptomatology and the need for adjunctive treatment.Trial registrationClinicalTrials.gov, NCT03644069 Registered 21 May 2018.
Highlights
Patients with coeliac disease (CD) commonly report a variety of adverse symptoms to gluten, but descriptions of the symptomatic response in the literature may have been confounded by the presence of food components such as fermentable carbohydrates (FODMAPs) causing symptoms of irritable bowel syndrome independent of gluten
Patients with CD commonly report adverse symptoms associated with gluten ingestion [3], but there are few studies that rigorously control for confounding effects to enable accurate gluten-related symptomatology to be recorded
An almost identical set of digestive symptoms and systemic cytokine release occurs after patients with treated CD receive an intradermal injection of gluten peptides corresponding to immuno-dominant HLA-DQ2.5-restricted epitopes for gluten-specific CD4+ T cells [8, 11]
Summary
Patients with coeliac disease (CD) commonly report a variety of adverse symptoms to gluten, but descriptions of the symptomatic response in the literature may have been confounded by the presence of food components such as fermentable carbohydrates (FODMAPs) causing symptoms of irritable bowel syndrome independent of gluten. In several recent gluten food challenge studies in small groups of patients with treated CD, unmasked and double-blind, sham-controlled gluten challenges designed to be low in FODMAPs cause significant worsening of nausea, sometimes with vomiting, within 2-h and peak at 3 to 4 h, but rarely caused diarrhoea [6, 7] This acute symptomatic reaction to gluten in patients with treated CD is linked to significant concomitant elevations in serum cytokines, which are not observed in individuals without CD or those with self-reported nonCD gluten sensitivity [7,8,9]. More detailed understanding requires studies in substantially larger cohorts that are not focused on patients positive for HLA-DQ2.5 alone
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