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Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease. | LitMetric

AI Article Synopsis

  • Transglutaminase 2 (TG2) is crucial in the development of celiac disease by modifying gluten peptides, leading to a heightened immune response against gluten.
  • The study evaluates the effectiveness of the TG2 inhibitor ZED1227 in preventing gluten-induced damage in celiac patients on a gluten-free diet, revealing that it significantly safeguards intestinal health at the molecular level.
  • Findings indicate that ZED1227 treatment helps maintain healthy gene expression related to the gut's structure and function, and suggest a potential benefit in personalized treatment strategies based on specific genetic markers in celiac patients.

Article Abstract

Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11224021PMC
http://dx.doi.org/10.1038/s41590-024-01867-0DOI Listing

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Article Synopsis
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