Author Identifier (ORCID)
Utpal Bose: https://orcid.org/0000-0003-1156-6504
Michelle J. Colgrave: https://orcid.org/0000-0001-8463-805X
Abstract
Background & Aims: Celiac disease is an immune-mediated enteropathy triggered by gluten ingestion. The effect of very small gluten exposures remains uncertain, contributing to international variations in food-labeling standards. Interleukin 2 (IL2) rises rapidly after gluten ingestion, serving as a biomarker of immune activation. We aimed to identify the lowest gluten dose that elicits a measurable IL2 response and accompanying symptoms in treated celiac disease. Methods: We conducted a randomized double-blind, placebo-controlled adaptive dose–response trial in adults with biopsy-proven celiac disease on a gluten-free diet for >2 years. Participants (n = 51; median age, 52 years; 69% were female) underwent 3 oral gluten (1–1000 mg) or placebo challenges at 4-week intervals at a tertiary clinical trials center in Brisbane, Australia. The primary outcome was a ≥2-fold rise in serum IL2 within 6 hours. Secondary outcomes were patient-reported symptoms. Eliciting dose (EDp, ie, the dose at which p% of people respond) was estimated by interval-censored survival analysis. Results: Fifty-one participants completed 153 challenges. Gluten induced dose-dependent IL2 elevations, with ≥2-fold increases in 83% at 1000 mg, 83% at 610 mg, 36% at 90 mg, 17% at 13 mg, 27% at 8 mg, and 17% at 3 mg; none responded to 5 mg, 2 mg, 1 mg, or placebo. Estimated ED50 was 111 mg (95% CI, 0–244 mg), ED10 was 2.4 mg (95% CI, 0–5.3 mg), ED05 was 0.8 mg (95% CI, 0–1.8 mg), and ED01 was 0.1 mg (95% CI, 0.0–0.3 mg). Symptom scores increased after challenges but not beyond placebo. Conclusions: Acute IL2 release occurs at gluten doses below current food-labeling thresholds. Symptoms are unreliable at exposures <1000 mg. These findings provide a framework for defining exposure limits based on immune activation. (Australian and New Zealand Clinical Trials Registry, Number: 12621000781842).
Keywords
celiac disease, eliciting dose, interleukin 2
Document Type
Journal Article
Date of Publication
1-1-2026
PubMed ID
41903816
Publication Title
Gastroenterology
Publisher
Elsevier
School
Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science / School of Science
Funding Information
The study was funded by Wesley Research Institute and Coeliac Australia.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Comments
Daveson, A. J. M., Craig, E., Vitak, A., Ware, R. S., Schafer, J., Sehgal, A., Bose, U., Colgrave, M. J., Hardy, M. Y., Tye-Din, J. A., & Anderson, R. P. (2026). A randomized double-blind, placebo-controlled dose–response study to assess the gluten threshold dose in celiac disease. Gastroenterology. Advance online publication. https://doi.org/10.1053/j.gastro.2026.03.011