For roughly 1 in 100 people, even foods containing tiny amounts of gluten can cause significant gastrointestinal harm.
Although the domino effect of the immune response can be traced back to genetic causes, numerous factors also play a role, making it difficult to pinpoint the exact chain of events that leads to the development of gluten intolerance.
An international team led by scientists at McMaster University in Canada has used genetically modified mice to identify a key role played by cells that make up the intestinal lining, representing a major stepping stone that could lead to new treatments.
Celiac disease is essentially an autoimmune disorder caused by the presence of a group of structural proteins called gluten in the intestine.
Eating almost any food made with wheat, barley or rye – including most baked goods, breads and pastas – puts people with the disease at risk for bloating, pain, diarrhea, constipation, and sometimes reflux and vomiting.
Currently, the only way to avoid symptoms is to avoid the foods that cause them.
“Currently, the only way to treat celiac disease is to completely eliminate gluten from the diet,” says gastroenterologist Elena Verdu of McMaster University. “This is difficult, and experts agree that a gluten-free diet alone is not enough.”
About 90% of people diagnosed with the disease have a pair of genes that code for a protein called HLA-DQ2.5. Most of the remaining 10% have a similar protein called HLA-DQ8.
Like other types of “HLA” (human leukocyte antigen) proteins, these proteins float pieces of fallen invaders on immune cells like macabre trophies, warning other defenses to be on their guard.
In the specific case of HLA-DQ2.5 and HLA-DQ8, the protein is shaped to hold onto chunks of indigestible gluten peptides, instructing killer T cells to go on the hunt.
Unfortunately, these instructions are not very clear at distinguishing between threats and similar substances in the body, meaning that people who carry the gene are at risk for a variety of autoimmune diseases.
However, not everyone who expresses either HLA-DQ2.5 or HLA-DQ8 will develop an immune disorder like celiac disease. For this to happen, pieces of torn gluten must first be transported across the intestinal wall by transport enzymes, where they bind to peptides and modify them to make them more easily recognizable.
The cells of the intestinal wall are responsible for releasing this transport enzyme into the intestine and therefore clearly play an important role in the early stages of the disease. They are also known to express a family of proteins, including HLA-DQ2.5 and HLA-DQ8, which are normally regulated by the inflammatory response in the intestine.
What’s unclear is how this preparatory step for celiac disease patients actually works within the condition itself.
To zero in on this important link in the chain, the team reexamined the expression of key immune complexes in the intestinal lining cells of treated and untreated celiac disease patients, and in mice carrying the human gene for HLA-DQ2.5.
The researchers then used mouse intestinal cells to create functional living models of the gut, called organoids, and exposed them to pro-inflammatory substances and digested and undigested gluten to closely study the expression of immune proteins.
“This allowed us to narrow down a specific cause and effect and prove exactly whether and how a reaction would occur,” says Tohid Didar, a biomedical engineer at McMasters.
This makes it clear that, rather than being passive bystanders suffering collateral damage in a misguided effort to rid the body of gluten, the cells lining the intestine are key agents in presenting the mixture of gluten fragments broken down by gut bacteria and transporting enzymes directly to gluten-specific immune cells.
Knowing which types of tissues are involved and how the presence of inflammatory microbes strengthens them could give researchers a list of new targets for future treatments, potentially allowing millions of people around the world to enjoy a gluten-containing pastry or two without the risk of discomfort.
The study was published in the journal Gastroenterology.
