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

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 (r_s =.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.