Masked bolus gluten challenge low in FODMAPs implicates nausea and vomiting as key symptoms associated with immune activation in treated coeliac disease

Abstract

Summary Background In patients with coeliac disease, FODMAPs in gluten‐containing foods, and participant anticipation of a harmful (‘nocebo’) effect, may contribute to acute symptoms after gluten challenge. Aim To establish acute gluten‐specific symptoms linked to immune activation in coeliac disease Methods We included 36 coeliac disease patients on a gluten‐free diet receiving placebo in the RESET CeD trial. Double‐blind, bolus vital wheat gluten (~6‐g gluten protein) and sham challenges low in FODMAPs were consumed 2 weeks apart. Assessments included daily Coeliac Disease Patient Reported Outcome (CeD PRO) symptom scores (0‐10), adverse events and serum interleukin‐2 (baseline and 4 hours). Results Median CeD PRO score for nausea increased most (sham: 0 vs gluten: 5.5; P < .001). Apart from tiredness (1 vs 4, P = .005) and headache (0 vs 2, P = .002), changes in other symptoms were small or absent. Only nausea increased significantly in occurrence with gluten (11% vs 69%, P < .001). Without nausea, only tiredness and flatulence were common after gluten. Nausea (6% vs 61%, P < .001; median onset: 1:34 hours) and vomiting (0% vs 44%, P < .001; 1:51 hours) were the only adverse events more common with gluten than sham. Interleukin‐2 was always below the level of quantitation (0.5 pg/mL) at baseline, and after sham. Interleukin‐2 was elevated after gluten in 97% of patients (median fold‐change: 20), and correlated with severity of nausea (rs = .49, P = .0025) and occurrence of vomiting (P = .0005). Conclusions Nausea and vomiting are relatively specific indicators of acute gluten ingestion, and correlate with immune activation. IBS‐like symptoms without nausea are unlikely to indicate recent gluten exposure.

Baseline quantitative histology in therapeutics trials reveals villus atrophy in most patients with coeliac disease who appear well controlled on gluten‐free diet

“…In the three phase 1 studies, which have been reported in detail elsewhere, patients with coeliac disease were maintaining their usual gluten‐free diet had no study interventions before their pre‐treatment biopsy. In the phase 2 (‘RESET CeD’) trial, which has also been described elsewhere, patients with coeliac disease were maintaining their usual gluten‐free diet, but had a single bolus gluten challenge (6 g of gluten protein taken as 10 g vital wheat gluten flour in water) 3 weeks before biopsy collection according to the protocol described by Tye‐Din et al…”

“…All patients gave written, informed consent prior to undergoing any trial‐related procedures. Eligibility criteria for each clinical trial have been reported fully elsewhere . In brief, for all four studies, patients who had biopsies collected had met initial screening criteria, which included being aged between 18 and 70 years, having documented duodenal villus atrophy while consuming gluten, being positive for HLA‐DQA1*05 and DQB1*02 (‘HLA DQ2.5’), and having maintained a gluten‐free diet for at least 1 year.…”

“…Quantitative histology in baseline duodenal biopsies collected in phase 1 and 2 clinical trials assessing an investigational immunotherapy, Nexvax2®, for coeliac disease provided the opportunity to assess duodenal injury in patients with ‘well controlled’ coeliac disease on gluten‐free diet . The primary objective of this study was to use quantitative histology to assess duodenal mucosal injury in treated coeliac disease, and in particular those patients who are well established on gluten‐free diet, and in serological remission.…”

Patient factors influencing acute gluten reactions and cytokine release in treated coeliac disease

“…These include nocebo effects, where patient's negative expectations to potential gluten exposure influence their symptoms and the presence of non-gluten dietary components such as fermentable carbohydrates (FODMAPs) that can cause symptoms of irritable bowel syndrome (IBS) independent of gluten [4,5]. In several recent gluten food challenge studies in small groups of patients with treated CD, unmasked and also 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 non-CD gluten sensitivity [7][8][9].…”

Randomized, Placebo Controlled Trial of Experimental Hookworm Infection for Improving Gluten Tolerance in Celiac Disease

“…The condition is becoming increasingly diagnosed and is estimated to affect 2% of many ethnically diverse populations ( 5 , 6 ). Strict compliance with a gluten-free diet is the only effective treatment, but the diet is inconvenient and expensive, and inadvertent gluten exposures are common ( 7 ), which can cause debilitating symptoms such as vomiting, diarrhea, and diminished well-being ( 8 ).…”