Shocking: Scientists Identify Source of Gluten Reactions

The Inflammatory Response: A Key Player in the Pathology

Celiac disease is a lifelong autoimmune disorder triggered by the presence of gluten in the intestines. Eating virtually anything made with wheat, barley, or rye puts people with the condition at risk of transient symptoms like bloating, pain, diarrhea, constipation, and sometimes reflux and vomiting. Currently, the only way to avoid the symptoms is to avoid the foods that trigger them.

Over the longer term, immune attacks triggered by gluten can damage the small intestine’s villi. These tiny structures increase the internal surface area of the intestinal walls, which aids absorption of nutrients from food. People with celiac disease – particularly if it’s untreated – face serious health risks, such as being more likely to develop colorectal cancer and cardiovascular disease.

The disease is associated with a myriad of conditions, with just some examples including anemia, osteoporosis, growth delays, reproductive issues, and neurological disorders. “The only way we can treat celiac disease today is by fully eliminating gluten from the diet,” says McMasters gastroenterologist Elena Verdu. “This is difficult to do, and experts agree that a gluten-free diet is insufficient.”

The Breakthrough Discovery

Using Transgenic Mice to Identify the Crucial Role of Gut Cells

Around 90 percent of people diagnosed with the condition carry a pair of genes that encode for a protein called HLA-DQ2.5. Of the remaining 10 percent, most have a similar protein called HLA-DQ8. Like other kinds of ‘HLA’ (or human leukocyte antigen) proteins, the proteins hold pieces of fallen invaders aloft like macabre trophies on a class of immune cells, warning other defensive tissues to be on the lookout.

In the specific case of HLA-DQ2.5 and HLA-DQ8, the proteins are shaped to hold chunks of gluten peptide that are resistant to digestion, instructing murderous T cells to go on the hunt. Unfortunately, these instructions aren’t the clearest at distinguishing between a threat and similar-looking materials in our body, meaning those with the genes are at risk of a variety of autoimmune conditions.

Creating Functional Living Models of the Gut: Organoids

Not everybody who expresses either HLA-DQ2.5 or HLA-DQ8 will develop an immune disorder like celiac disease, however. For that to happen, those torn-up pieces of gluten first need to be carried across the gut wall by a transporting enzyme that binds with the peptide and alters it in ways to make it even more recognizable. Cells in the intestinal wall are responsible for releasing this transporting enzyme into the gut, so they clearly have a critical role in the early stages of the disease.

They are also known to express the family of proteins to which HLA-DQ2.5 and HLA-DQ8 belong, which are typically regulated by inflammatory responses in the gut. What hasn’t been clear is how this staging ground for people with celiac disease actually functions within the pathology itself.

Pinpointing the Specific Cause and Effect of Gluten Reactions

To focus on this important link in the chain, the research team double-checked the expression of the major immune complex in the cells lining the intestines of people with treated and untreated celiac disease, and in mice with the human genes for HLA-DQ2.5. They then created functional living models of the gut, called an organoid, using the mouse intestinal cells in order to study the expression of their immune proteins up close, subjecting them to inflammatory triggers as well as predigested and intact gluten.

“This allowed us to narrow down the specific cause and effect and prove exactly whether and how the reaction takes place,” says McMasters biomedical engineer Tohid Didar. From this, it became evident the cells lining the gut weren’t just passive bystanders suffering collateral damage in a misguided effort to rid the body of gluten – they were key agents, presenting a mash-up of gluten fragments broken down by gut bacteria and transporting enzymes to gluten-specific immune cells firsthand.

Implications and Future Directions

A New Era of Therapies: Targeting Gut Cells and Inflammatory Responses

Knowing the types of tissue involved and their enhancement by the presence of inflammatory responses, researchers can now focus on developing targeted therapies that address the root cause of gluten reactions. This breakthrough discovery has the potential to revolutionize the treatment of celiac disease, moving beyond the current limited options of a gluten-free diet.

The Potential for Personalized Treatment Approaches

The identification of the crucial role played by gut cells in gluten reactions also opens up possibilities for personalized treatment approaches. By understanding the specific genetic and environmental factors that contribute to an individual’s risk of developing celiac disease, researchers can develop tailored therapies that address their unique needs.

The Importance of Further Research: Unraveling the Complexity of Gluten Reactions

While this breakthrough discovery is a significant step forward, it is essential to continue researching the complex mechanisms underlying gluten reactions. Further studies will be necessary to fully understand the interplay between genetic and environmental factors, as well as the role of gut cells in the development of celiac disease.