Therapeutic TG2 inhibition reverses systemic multiomic dysregulation in celiac disease - UTU Research Portal

A1 Refereed original research article in a scientific journal

Therapeutic TG2 inhibition reverses systemic multiomic dysregulation in celiac disease;

Authors: Dotsenko, Valeriia; Le Hana, Hien; Rajić, Sonja; Moulder, Robert; Kettunen, Jalmari; Hirvonen, M. Karoliina; Dickens, Alex M; Hyötyläinen, Tuulia; Tewes, Bernhard; Zimmermann, Timo; Mohrbacher, Ralf; Suomi, Tomi; Lehtimäki, Terho; Lahesmaa, Riitta; Orešič, Matej; Elo, Laura L.; Raitoharju, Emma; Schuppan, Detlef; Mäki, Markku; Viiri, Keijo; on behalf of the CEC-3 Investigators

Publisher: Springer Science and Business Media LLC

Publication year: 2026

Journal: BMC Medicine

Article number: 350

Volume: 24

Issue: 1

eISSN: 1741-7015

DOI: https://doi.org/10.1186/s12916-026-04892-y

Publication's open availability at the time of reporting: Open Access

Publication channel's open availability : Open Access publication channel

Web address : https://doi.org/10.1186/s12916-026-04892-y

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/523328941

Self-archived copy's licence: CC BY

Self-archived copy's version: Publisher`s PDF

Abstract

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.

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Funding information in the publication:
Open access funding provided by Tampere University (including Tampere University Hospital). This work was supported by the Research Council of Finland (Grant no. 370828), University of Oulu and Research Council of Finland Profi8 (Grant no. 365202), the Finnish Cultural Foundation, Dr. Falk. Pharma GmbH, Mary och Georg C. Ehrnrooths Stiftelse, and the State funding for university-level health research, Tampere University Hospital, Wellbeing services county of Pirkanmaa / Project No. T63474 and T66984. SR acknowledges support from Yrjö Jahnsson foundation and Päivikki and Sakari Sohlberg foundation. TL acknowledges Research Council of Finland (Grant no. 356405), Finnish Foundation for Cardiovascular Research and Juho Vainio Foundation. RL acknowledges support from the Research Council of Finland (Grant no. 331793 and 329277), RL, LLE and MO acknowledge the support for InFLAMES Flagship Programme from Research Council of Finland (Grant no. 337530). LLE acknowledges support from the Research Council of Finland (Grant no. 341342, 364700). ER acknowledges support from the Research Council of Finland (Grant no. 338395). DS acknowledges CeD-related research support from Collaborative Research Centre grant TRR 355/1 (490846870) project B08, and EU-BMBF project ImmunoSafe-CeD (01EA2205B). Research is also supported by Biocenter Finland. The funding sources played no role in the design or execution of this study or in the analysis and interpretation of the data.