Therapeutic TG2 inhibition reverses systemic multiomic dysregulation in celiac disease.

BACKGROUND: Celiac disease (CeD) is an autoimmune disease triggered by dietary gluten in genetically predisposed individuals. Deamidation of gluten peptides by the CeD autoantigen and enzyme transglutaminase 2 (TG2) is central to the pathogenesis of CeD. Inhibition of TG2 with the specific inhibitor ZED1227 effectively prevents gluten-induced histological damage in CeD patients. Here we aimed to explore the systemic plasma lipidomic, proteomic and DNA methylomic changes in ZED1227-treated CeD patients undergoing a gluten challenge. METHODS: Individuals with CeD on a long-term gluten-free diet (GFD) underwent a 6-week gluten challenge combined with daily 100 mg ZED1227 drug (PGCd, n = 28) or placebo (PGCp, n = 19). Samples were collected at baseline (GFD) and post-gluten challenge (PGC). Mass spectrometry-based lipidomic and proteomics profiling were applied to plasma samples matched with duodenal histology. Whole blood samples (drug, n = 20; placebo, n = 16) were subjected to DNA methylation analysis. Comparative analyses were performed between the groups, with adjustment for BMI, age, sex, and country of origin. RESULTS: Significantly different gluten-induced plasma lipidomic changes were detected between GFD vs. PGCp and between GFD vs. PGCd, with 46 lipids differentially expressed in the placebo group and 6 in the drug group suggesting that the ZED1227 normalized gluten-induced lipidomic changes in plasma. Changes in medium-chain fatty acylcarnitines (CARs), particularly CAR 10:1 and CAR 9:0, were correlated with transient, non–clinically significant changes in renal biomarkers, with kidney function remaining within the normal range in the PGCp group. Glomerular filtration rate and plasma creatinine were restored with ZED1227. Integrated multi-omics analysis revealed a coordinated immune–epigenetic–lipid module centered on Ficolin-2, PUFA-enriched triglycerides, and a tightly co-regulated CpG cluster in the PER3 circadian regulator gene, highlighting selective immunometabolic coupling independent of clinical stratification. Drug treatment revealed consistent patterns suggesting normalization of the proteome and DNA methylome indicating that ZED1227 attenuated the systemic responses to gluten challenge. CONCLUSIONS: These findings provide evidence that ZED1227 can significantly prevent the gluten-induced CeD-associated systemic changes in plasma/blood. CLINICAL TRIAL: EudraCT 2017-002241-30.