Masked Bolus Gluten Challenge Low in FODMAPs Implicates Nausea and Vomiting as Key Symptoms Associated With Immune Activation in Treated Coeliac Disease

A. James M. Daveson; Jason A. Tye-Din; Gautam Goel; Kaela E. Goldstein; Holly L. Hand; Kristin M. Neff; Leslie J. Williams; Kenneth E. Truitt; Robert P. Anderson


Aliment Pharmacol Ther. 2020;51(2):244-252. 

In This Article

Abstract and Introduction


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.


Many patients with coeliac disease fail to achieve intestinal mucosal recovery despite reporting strict avoidance of dietary gluten.[1,2] This is clinically important as persistent intestinal mucosal injury carries increased risks of many complications such as osteoporosis, normally associated with untreated coeliac disease.[3,4] Persistent intestinal mucosal injury appears to be explained by recurrent, inadvertent gluten exposure.[5] Indeed, patients and clinicians may not be able to accurately recognise episodes of gluten ingestion if reported symptoms are attributed to irritable bowel syndrome (IBS).[6,7] The symptoms of IBS may be triggered by poorly absorbed, fermentable, short-chain carbohydrates (FODMAPs) present in many gluten-free foods as well as being enriched in wheat flour, the commonest source of gluten in Western diets.[8,9] Understanding the timing and nature of acute, immune-mediated symptoms caused by gluten in patients with coeliac disease following a gluten-free diet could allow patients and heath care professionals to better recognise when gluten has been ingested, and improve avoidance strategies. Additionally, regulatory authorities have emphasised the importance of patient-reported outcomes as efficacy endpoints when testing novel therapeutics for coeliac disease.[10]

Although the immune mechanisms are debated and supportive blood biomarkers are lacking, onset of digestive symptoms is about 2 hours after food exposure in non-IgE immune-mediated food hypersensitivities.[11] In contrast, clinical descriptions of coeliac disease, a T cell-mediated condition, emphasise chronic symptoms similar to IBS.[6,7] There are, however, reports of acute reactions to gluten in patients with coeliac disease on gluten-free diet,[6,7] but until recently there appeared to be no mechanistic explanation, and well-controlled gluten food challenge studies addressing this issue are absent.

Recently, we reported systemic cytokine release in conjunction with acute digestive symptoms in patients with coeliac disease 2 hours after injection of gluten peptides that directly activate gluten-specific CD4+ T cells.[12] Subsequently, we showed that patients with coeliac disease on gluten-free diets also experience a cytokine release phenomenon after consuming gluten.[12] Pronounced elevation of interleukin-2, a cytokine released by antigen-activated T cells, dominates the changes in serum cytokines after gluten ingestion.[13] Detailed time-course studies indicate peak serum levels of interleukin-2 occur four hours after gluten challenge,[12] and correlate with overall severity of digestive symptoms, and nausea in particular.[14]

Previously, at least three important factors have obscured understanding acute symptoms caused by gluten in coeliac disease: (1) there has been no biomarker to quantify acute gluten-mediated immune activation, (2) the potential for a nocebo effect, defined as participant anticipation of a harmful response[15] and (3) without matching the active and control food challenges for low FODMAPs content, there is the possibility that active and/or sham may cause IBS-like symptoms unrelated to immune-mediated effects of gluten.[16,17] To date, there have been no studies that have addressed each of these issues.

The aim of the present study was to establish acute gluten-specific symptoms linked to immune activation in coeliac disease.