Humanized mouse model could significantly improve preclinical research on drugs for celiac disease

by Nadine Berger, Johannes Gutenberg University Mainz

edited by Lisa Lock, reviewed by Alexander Pol

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Celiac disease is an autoimmune disorder in which the immune system reacts to gluten. More than 1% of the population in Germany is affected. In these individuals, gluten proteins found in wheat, rye and barley trigger inflammation in the small intestine, which can damage the intestinal villi and promote disease outside the intestinal tract. Despite following a gluten-free diet, up to 30% of patients with celiac disease still experience symptoms. This is usually due to unavoidable gluten contamination in their daily diet.

Consequently, there is a high need for supportive drug therapy for celiac disease. However, developing such drugs has been challenging. While various drugs are currently being tested in clinical trials in humans, preclinical testing methods—especially a suitable animal model—had not been established.

For this reason, a research team led by Dr. Detlef Schuppan, director of the Institute for Translational Immunology (TIM), refined an existing mouse model in the study "A humanized celiac disease mouse model reflects histologic and immune effects of transglutaminase inhibition in patients," published in the journal Gastroenterology.

The human antigen-presenting molecule HLA-DQ8, found on immune cells and responsible for the development and progression of celiac disease in humans, was introduced into the mouse genome using genetic engineering. Only people who carry this or the related genetic marker HLA-DQ2 can develop celiac disease. "Our mice with this transgene developed the typical characteristics of human celiac disease, including changes in the small intestinal mucosa and a pronounced immune response," Schuppan said.

The research team validated the mouse model using the highly specific drug candidate ZED1227. In a phase 2a clinical trial involving 160 patients, the researchers demonstrated in 2021 that this drug can prevent gluten-induced damage to the small intestinal mucosa by inhibiting a specific enzyme, transglutaminase 2. This enzyme plays a key role in the development of celiac disease.

In the mouse model, the compound demonstrated the same protective effects as in the human study: The intestinal villi were largely preserved, the inflammatory response was reduced, and the molecular changes in the immune response corresponded to the results of the clinical trial.

"Our optimized mouse model has particular translational significance," Schuppan and first author Aline Pesi said. "For the first time, it gives us the opportunity to investigate new active compounds in a mouse model and directly compare the results with data from clinical trials. In addition, the molecular mechanisms of promising active compounds could be better investigated even before clinical trials."

The new mouse model could also be suitable for testing additional classes of drugs that specifically target the disease-causing immune mechanisms. It thus has the potential to accelerate the development of new drugs for celiac disease and make the transition from laboratory research to clinical application significantly more efficient.

Publication details

Aline Pesi et al, A humanized celiac disease mouse model reflects histologic and immune effects of transglutaminase inhibition in patients, Gastroenterology (2026). DOI: 10.1053/j.gastro.2026.07.026

Journal information: Gastroenterology

Key medical concepts

Celiac DiseaseTissue transglutaminase

Clinical categories

GastroenterologyAllergy and immunologyClinical pharmacologyCommon illnesses & Prevention Provided by Johannes Gutenberg University Mainz Who's behind this story?

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