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Plasma Proteomics Analysis of a Transglutaminase 2 inhibitor in Celiac Disease

ABSTRACT: Individuals with celiac disease (CeD) on a long-term gluten-free diet (GFD) underwent a 6-week gluten challenge combined with 100mg per day of the transglutaminase 2 enzyme -inhibitor, ZED1227 (PGCd, n = 28) or placebo (PGCp, n = 19). The 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 obtained from 47 CeD patients. Comparative analyses were performed between the groups, with adjustment for BMI, age, sex, and country of origin.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Celiac Disease

SUBMITTER: Robert Moulder

LAB HEAD: Professor Riitta Lahesmaa

PROVIDER: PXD069597 | Pride | 2026-06-15

REPOSITORIES: Pride

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			Action	DRS
	220118_Evo_HF_DIA33_Serum800ng_Pool2.raw	Raw
	220118_Evo_HF_DIA33_Serum800ng_TG2_A02.raw	Raw
	220118_Evo_HF_DIA33_Serum800ng_TG2_A05.raw	Raw
	220118_Evo_HF_DIA33_Serum800ng_TG2_A09.raw	Raw
	220118_Evo_HF_DIA33_Serum800ng_TG2_B02.raw	Raw

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Publications

Therapeutic TG2 inhibition reverses systemic multiomic dysregulation in celiac disease.

Dotsenko Valeriia V Le Hana Hien HH Rajić Sonja S Moulder Robert R Kettunen Jalmari J Hirvonen M Karoliina MK Dickens Alex M AM Hyötyläinen Tuulia T Tewes Bernhard B Zimmermann Timo T Mohrbacher Ralf R Suomi Tomi T Lehtimäki Terho T Lahesmaa Riitta R Orešič Matej M Elo Laura L LL Raitoharju Emma E Schuppan Detlef D Mäki Markku M Viiri Keijo K

BMC medicine 20260424 1

PMID: 42032651

Publication: 1/2

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Biopsy proteome score performs well as an effect measure in a gluten-challenge trial of coeliac disease

Project description:Objective Development of novel treatments for coeliac disease (CeD) is dependent on precise tools to monitor changes in gluten-induced mucosal damage. Current histology measures are subjective and difficult to standardise. Biopsy proteome scoring is an objective alternative to histology which is based on robust changes in biological pathways that directly reflect gluten-induced mucosal damage. In this study we aimed to evaluate biopsy proteome scoring as effect measure in a clinical trial setting by measuring intestinal remodeling in response to oral gluten challenge. Design We analyzed biopsies from a gluten challenge trial of treated CeD patients that consumed 3 g (n=6) or 10 g (n=7) gluten per day for 14 days. Sections from individually embedded biopsies collected before and after challenge were processed for proteome scoring (n = 109) and measurement of Vh:Cd ratio (n = 58). Proteome scores were compared to histology, intraepithelial lymphocyte (IEL) frequency and plasma interleukin-2 (IL-2). Results Change in proteome scores were significant for the group of patients who consumed 10 g gluten, but not for the group who consumed 3 g gluten. Altogether, 8 of 13 patients had changes in delta proteome scores above cut-off. Proteome scores correlated with Vh:Cd ratios both at run-in and at day 15. Proteome scores at day 15 correlated with IEL frequency and with serum IL-2 levels measured 4 hours post gluten intake. Conclusion Biopsy proteome scoring is a simple and reliable measure of gluten-induced mucosal remodeling in response to 14-day oral gluten challenge.

2025-04-08 | PXD050655 | Pride

Therapeutic TG2 Inhibition Reverses Systemic Multiomic Dysregulation in Celiac Disease

Project description: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 blood DNA methylomic changes in ZED1227-treated CeD patients undergoing a gluten challenge. Results: Drug treatment revealed consistent patterns suggesting normalization of the 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. Clinical trial: EudraCT 2017-002241-30

2026-06-18 | GSE319777 | GEO

Gene expression in the small intestine of mice colonized with Pseudomonas aeruginosa

Project description:Celiac disease (CeD) is a food sensitivity characterized by a breakdown of oral tolerance to gluten proteins in genetically predisposed individuals, although the underlying mechanisms are incompletely understood. To evaluate a functional role of bacterial proteases in CeD, we colonized germ-free or clean SPF mice with P.aeruginosa PA14 or P.aeruginosa PA14 disrupted in lasB gene (elastase). We show gluten-independent, PAR-2 mediated upregulation of inflammatory pathways by LasB in C57BL/6 mice without villus blunting. In mice expressing CeD risk genes, P. aeruginosa elastase synergized with gluten to induce more severe inflammation that was associated with moderate villus blunting.

2019-02-01 | GSE125983 | GEO

A human autoimmune organoid model reveals IL-7 function in celiac disease

Project description:In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Celiac disease (CeD) is an autoimmune disease where dietary gluten-derived peptides bind the MHC- II molecules HLA-DQ2 or -DQ8 to initiate immune-mediated duodenal mucosal injury. Here, we generated air-liquid interface (ALI) duodenal organoids from endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The ALI organoid immune diversity spanned T, B, plasma, NK and myeloid cells with extensive T and B cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing CeD patient organoids, which was antagonized by MHC-II or NKG2C/D blockade. Gluten epitopes stimulated a CeD organoid network response in lymphoid and myeloid subsets alongside anti-TG2 autoantibody production. Functional studies in CeD organoids revealed IL-7 as a novel gluten-inducible pathogenic modulator which regulated CD8+ T cell-NKG2C/D expression and was necessary and sufficient for epithelial destruction. Further, endogenous IL-7 was markedly induced in patient biopsies from active CeD versus remission disease, predominantly in lamina propria mesenchyme. By preserving epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, facilitates mechanistic investigation, and establishes proof-of-principle for organoid modeling of autoimmunity.

2024-07-12 | GSE200075 | GEO

Identification of celiac-disease active peptides in gluten-free beers by nanoLC-MS/MS

Project description:Barley beers may be rendered gluten-free by specialized brewing processes. One controversial issue is whether these beers contain residual gluten peptides carrying at least one celiac disease (CeD)-active epitope, because routine methods to assess whether the beer is gluten-free like competitive enzyme-linked immunosorbent assays (ELISA) may fail to detect potentially harmful peptides. We used untargeted nano-liquid chromatography-tandem mass spectrometry (nanoLC MS/MS) to identify CeD-active peptides in 21 gluten-free barley beers and four regular or carbohydrate-reducedbeers. While the G12 ELISA confirmed gluten levels below 20 mg/kg in all gluten-free beers, the R5 ELISA detected gluten levels in four beers exceeding this threshold, highlighting method discrepancies. nanoLC-MS/MS identified 44 CeD active peptides in seven gluten-free and four non-gluten-free beers, of which 17 CeD-active peptides had no ELISA epitope and therefore escape detection. Accurate quantitation of thesepeptides combined with in vivo toxicity assessment will be needed to provide guidance on clinical relevance.

2026-04-01 | PXD059719 | Pride

Biopsy proteome scoring to determine mucosal remodeling in celiac disease

Project description:For celiac disease (CeD) the diagnosis and response to treatment is determined by histological evaluation of gut biopsies which depend on proper biopsy orientation and has poor inter-observer reproducibility. Biopsy proteome measurement that reports on the tissue state can be obtained by mass spectrometry (MS) analysis of formalin-fixed paraffin embedded (FFPE) tissue. Here we aimed to transform biopsy proteome data into numerical scores that would give observer-independent measures of mucosal remodeling in CeD. A pipeline was established that employs glass-mounted FFPE sections for MS-based proteome analysis. Proteome data was converted to a numerical score using two different approaches, by calculating a rank-based enrichment score and by training a machine-learning algorithm to calculate a disease-state prediction value. The scoring approaches were compared to each other and to histology using a validation cohort of 18 CeD patients comparing biopsies collected before and after treatment with gluten-free diet (GFD). Biopsies from non-CeD individuals (n = 18) served as controls.

2024-03-15 | PXD045913 | Pride

scRNAseq of human intestinal organoids infected with coxsackievirus B1

Project description:We applied 10X Genomic scRNAseq to profile cell population within human intestinal organoids infected with coxsackievirus B1. The intestinal epithelium represents the first line of defense in the gastrointestinal tract, forming an essential barrier that, when compromised, renders individuals with celiac disease (CeD) susceptible to mucosal damage. By connecting viral infections and gluten challenges, this study sheds light on a mechanistic bridge between viral infection and gluten peptide modification, a critical step in the onset of CeD.

2026-05-31 | GSE333246 | GEO

The long noncoding RNA lnc13 restrains inflammatory responses to maintain oral tolerance to gluten

Project description:Celiac disease (CeD) is an autoimmune disorder triggered by dietary gluten. While HLA-DQ2/8-mediated presentation of gliadin peptides is required for disease, the mechanisms that underlie the loss of oral tolerance to gluten remain incompletely understood. Long noncoding RNAs (lncRNAs) have been increasingly recognized as regulators of immune function, yet their role in oral tolerance has not been previously explored. Using a screen designed to identify lncRNAs responsive to T cell activation and enriched for CeD-associated GWAS variants, we identified lnc13 as a top candidate. In HLA-DQ8 transgenic mice lacking lnc13, unmanipulated gluten ingestion led to hallmark features of loss of oral tolerance to gluten: reduced regulatory T cells, and increased IFN-γ⁺ lymphocytes, IL-12⁺ myeloid cells, cytotoxic intraepithelial immune cells and crypt hyperplasia in the small intestine. Mechanistically, lnc13 binds specific DNA regulatory regions and limits inflammatory responses to pro-inflammatory signals. In particular, lnc13 restrains IL-15-driven differentiation of CD8⁺ NK-like lymphokine-activated killer cells—an IL-15–dependent pathway strongly implicated in CeD. These findings establish lnc13 as a critical noncoding modulator of oral gluten tolerance.

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2019-07-26 | GSE134900 | GEO

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