Mouse Model Realistically Replicates Human Celiac Disease

Humanized Model Could Significantly Improve Preclinical Research on Drugs for Celiac Disease

08/12/2026

Researchers at Mainz University Medical Center have optimized and validated a humanized mouse model for celiac disease that could enable more targeted investigation of the efficacy and mechanism of action of new drugs for this autoimmune disease. In a new study, the model exhibited the same intestinal changes that are typical in people with celiac disease. In addition, the model was used to realistically demonstrate the effect of an active drug for celiac disease that has already undergone successful clinical trials. In the future, this could, for the first time, allow to specifically test new drugs for celiac disease even before they are evaluated in complex clinical trials in humans. The results were published in the journal Gastroenterology.

Celiac disease is an autoimmune disorder in which the immune system reacts to gluten. More than one percent of the population in Germany is affected by it. In these individuals, gluten proteins found in wheat, rye, and barley trigger inflammation in the small intestine, which can damage the intestinal villi, and even promote disease outside of the intestinal tract. Despite following a gluten-free diet, up to 30 percent 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 a supportive drug therapy for celiac disease. However, developing such drugs has been challenging so far. While various drugs are currently being tested in clinical trials on humans, preclinical testing methods – especially a suitable animal model – had not been defined.

For this reason, a research team led by Prof. Dr. Dr. Detlef Schuppan, Director of the Institute for Translational Immunology (TIM), specifically refined an existing mouse model in the study “A Humanized Celiac Disease Mouse Model Reflects Histologic and Immune Effects of Transglutaminase Inhibition in Patients”: The human antigen-presenting molecule HLA-DQ8 found on immune cells, which is 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,” says study leader Prof. Schuppan.

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 were already able to demonstrate 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,” explain Prof. Schuppan and first author Aline Pesi. “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 to make the transition from laboratory research to clinical application significantly more efficient.

Original publication:

Aline Pesi, Manuel A. Encalada-Ventura, Hicham El Mard, Victor F. Zevallos, Elena F. Verdu, Detlef Schuppan, ZED1227 Celiac Disease Study Group.
A Humanized Celiac Disease Mouse Model Reflects Histologic and Immune Effects of Transglutaminase Inhibition in Patients, Gastroenterology (2026).

DOI: https://doi.org/10.1053/j.gastro.2026.07.026

Further information:
Phase 2a trial of the first celiac disease drug | UM press release dated 13/07/2021

Contact:
Univ.-Prof. Dr. Dr. Detlef Schuppan
Director of the Institute of Translational Immunology
University Medical Center Mainz
phone +49 (0)6131 17-7356
email

Press contact:
Nadine Berger M. Sc.
Corporate Communications
University Medical Center Mainz
phone +49 (0)6131 17-8434
email