Low-Dose Gluten Exposure Triggers Immune Activation in Treated Celiac Disease Despite Minimal Symptoms
Very small amounts of gluten triggered measurable immune activation in adults with treated celiac disease, even when symptoms were absent, according to a randomized, placebo-controlled dose-response trial. The findings suggest that immune responses may occur below current food-labeling thresholds and could inform future standards for gluten exposure.
Investigators enrolled 51 adults with biopsy-confirmed celiac disease who had followed a gluten-free diet for more than two years. Participants underwent three randomized oral gluten challenges ranging from 1 mg to 1000 mg or placebo at four-week intervals. The primary endpoint was a twofold or greater increase in serum interleukin 2 (IL2) within six hours of gluten ingestion, while secondary endpoints included patient-reported symptoms.
Across 153 completed challenges, gluten produced dose-dependent increases in IL2. A twofold or greater IL2 increase occurred in 83% of participants after both 1000 mg and 610 mg gluten doses, 36% after 90 mg, 17% after 13 mg, 27% after 8 mg, and 17% after 3 mg. No participants demonstrated an IL2 response following 5 mg, 2 mg, 1 mg, or placebo.
Dose-response modeling estimated an ED50 of 111 mg (95% CI, 0-244 mg), an ED10 of 2.4 mg (95% CI, 0-5.3 mg), an ED05 of 0.8 mg (95% CI, 0-1.8 mg), and an ED01 of 0.1 mg (95% CI, 0.0-0.3 mg).
Although symptom scores increased following gluten challenges, symptom severity did not exceed that observed with placebo, indicating that clinical symptoms were a poor indicator of low-dose gluten exposure.
The authors concluded that “acute IL2 release occurs at gluten doses below current food-labeling thresholds.” They also noted that “symptoms are unreliable at exposures <1000 mg,” suggesting that immune activation may occur without clinically apparent reactions.
Reference
Daveson AJM, Craig E, Vitak A, et al. A randomized double-blind, placebo-controlled dose-response study to assess the gluten threshold dose in celiac disease. Gastroenterology. 2026;171(2):285-297. doi:10.1053/j.gastro.2026.03.011
