New Mouse Model Mimics Celiac Disease in People
Researchers have developed a new mouse model that mimics the immune system features and gluten-dependent intestinal damage seen in people with celiac disease, providing a new research tool for discovering and testing therapies. Celiac disease is an autoimmune reaction in the gut that is triggered by consuming gluten, a protein found mainly in foods containing wheat, barley, and rye. This autoimmune reaction—where the body targets its own cells—damages the small intestine, interfering with the intestine’s ability to absorb nutrients from foods. This can result in chronic diarrhea, bloating, anemia, and, in children, slower growth and short stature. The only treatment for celiac disease is a strict gluten-free diet, which is difficult for many people. Scientists are trying to identify non-dietary treatments for celiac disease, but research has been hampered by the lack of animal models that accurately mimic the human form of the disease.
In new research, scientists used their understanding of human celiac disease to genetically engineer a new model of the disease in female and male mice. In people, the presence of certain genetic variants in the human leukocyte antigen (HLA) region of the genome—which is responsible for regulating the immune system—increases the likelihood of developing celiac disease. Additionally, people with the disease have high levels of an immune system-produced protein called interleukin-15 (IL-15) in their small intestines. The researchers engineered a mouse model with similar characteristics. Just like in people, the mice developed damage to their small intestines after eating gluten for 30 days, and the damage was reversed when the animals were no longer fed gluten. The animals’ immune systems also produced some of the same types of antibodies that are commonly used to diagnose celiac disease in people, and the mice had similar gene activity in the presence and absence of gluten as observed in people with the disease, suggesting that the mouse model could be useful for testing therapies before they are tried in humans. Further experiments suggested that the model could be useful for drug discovery. For example, the model gave insights into the critical role for IL-15 in the disease. The researchers also found that they could prevent small intestine damage by treating gluten-fed mice with a drug that inhibits a protein known to be involved in the underlying cause of celiac disease. Thus, this new animal model that replicates features of human celiac disease upon introduction of gluten could be a useful research tool not only for increasing understanding of the underlying biology of celiac disease, but also for identifying new therapeutic targets and testing novel prevention and treatment strategies before they are tested in people.
Abadie V, Kim SM, Lejeune T,…Jabri B. IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature 578: 600-604, 2020.