Cytokine release after gluten ingestion differentiates coeliac disease from self‐reported gluten sensitivity

Background Diagnosing coeliac disease (CD) in patients on a gluten‐free diet (GFD) is difficult. Ingesting gluten elevates circulating interleukin (IL)‐2, IL‐8 and IL‐10 in CD patients on a GFD. Objective We tested whether cytokine release after gluten ingestion differentiates patients with CD from those with self‐reported gluten sensitivity (SR‐GS). Methods Australian patients with CD (n = 26) and SR‐GS (n = 18) on a GFD consumed bread (estimated gluten 6 g). Serum at baseline and at 3 and 4 h was tested for IL‐2, IL‐8 and IL‐10. Separately, Norwegian SR‐GS patients (n = 49) had plasma cytokine assessment at baseline and at 2, 4 and 6 h after food bars containing gluten (5.7 g), fructan or placebo in a previous double‐blind crossover study. Results Gluten significantly elevated serum IL‐2, IL‐8 and IL‐10 at 3 and 4 h in patients with CD but not SR‐GS. The highest median fold‐change from baseline at 4 h was for IL‐2 (8.06, IQR: 1.52–24.0; P < 0.0001, Wilcoxon test). The two SR‐GS cohorts included only one (1.5%) confirmed IL‐2 responder, and cytokine responses to fructan and placebo were no different to gluten. Overall, cytokine release after gluten was present in 22 (85%) CD participants, but 2 of the 4 non‐responders remained clinically well after 1 y on an unrestricted diet. Hence, cytokine release occurred in 22 (92%) of 24 ‘verified’ CD participants. Conclusions Gluten challenge with high‐sensitivity cytokine assessment differentiates CD from SR‐GS in patients on a GFD and identifies patients likely to tolerate gluten reintroduction. Systemic cytokine release indicating early immune activation by gluten in CD individuals cannot be detected in SR‐GS individuals.