Therapeutic Restoration of Systemic Multiomic Responses by Transglutaminase 2 inhibitor in Celiac Disease: A Gluten Challenge Approach

ABSTRACT Background and Aims 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 100mg 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, along with genome-wide DNA methylation analysis, were applied to plasma samples matched with duodenal histology. 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 correlated with kidney function which decreased significantly in PGCp. Glomerular filtration rate and plasma creatinine were restored with ZED1227. 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 the plasma.