Animal models have enabled us to learn an incredible amount of new information about human biology, health, and disease. But these animals can't always serve as a reliable example of the human body. As such, researchers turned to models called organoids. By genetically reprogramming cells, scientists have been able to develop miniature, simplified versions of human organs for use in the lab.
In a new study, scientists collected intestinal tissue from celiac disease patients to make intestinal organoids that modeled celiac, These models are slightly more complex than previous intestinal organoid models, and included more cell types. When these organoids were exposed to gluten, the researchers were able to determine how gluten causes damage to the intestine in celiac patients. The investigators found that a molecule called IL-7, which has previously been linked to autoimmune disease, is a major influence on celiac disease and could be a target for treatment. The findings have been reported in Nature.
"These organoids provide an accurate reproduction of what happens in people with celiac disease," said senior study author Calvin Kuo, MD, PhD, professor of medicine at Stanford University.
"This is really a game changer for the study of celiac disease," noted first study author and postdoctoral scholar António Santos, PhD. "It is a human organoid that contains all of the cells of the small intestine and thrives in a laboratory dish."
It's estimated that about one percent of the world's population has celiac disease. In this disorder, a molecule known as gluten that is found in wheat, rye, barley and other grains triggers an autoimmune attack in the intestine. This leads to damage to the intestinal mucosa, and symptoms like bloating, nausea, constipation, and diarrhea, Intestinal symptoms do not always occur, however, and diagnosis may be challenging. Right now, the only treatment for patients is to totally avoid eating foods that contain gluten.
The researchers were able to obtain intestinal biopsy samples from 81 people with celiac, 59 of whom actively had symptoms whiel the remainder folloed a gluten-free diet and id dnot have symptoms. Biopsies from another 54 people without the disease were also included in the study. The organoids were created from these samples, and then exposed to gluten. The investigators found that the production of a molecule called IL-15 was activated in gut epithelial cells. Next, immune cells that identify gluten started to proliferate, while other cells produced antibodies to a protein known as type 2 transglutaminase (TG2). Although TG2 is not usually associated with immune reactions, the autoantibodies to that protein are a hallmark of celiac disease. Immune cells called CD8 T cells were then activated to destroy epithelial cells, probably promoted by CD4 T cells, the researchers suggested. None of that happened in organoids made from unaffected people.
"The organoids from people with celiac disease were clearly responding in ways that organoids from healthy people were not," Santos said. "We were able to see many of the key features of the disease, from epithelial cell kill to immune activation and depletion of other cells that make up the villi, or protrusions of the intestinal lining."
Previous work has indicated that immune signaling molecules called IL-2 and IL-15 aid in CD4 and CD8 T cell communication in celiac disease patients. However, blocking their activity does not relieve celiac disease.
In this study, the researchers focused on a different immune signal known as IL-7. When IL-7 activity was blocked in celiac-affected organoids, the epithelial cells were no longer destroyed during gluten exposure. The expression of IL-7 increased in response to gluten, and was higher in those with active celiac disease. Celiac patients on a gluten-free diet had lower levels of IL-7.
When IL-7 was induced in those organoids, epithelial cell death ramped up, even when no gluten was present. Healthy organoids were not affected.
"These results show that IL-7 is a previously unrecognized modulator of celiac disease," Kuo said. "Although more research needs to be done, we believe that the organoids faithfully reflect what is happening in people with celiac disease and that there may be therapeutic opportunities for blocking IL-7 activity."
Sources: Stanford University, Nature