New insight into how and where the response to gluten in celiac disease begins

Study points to the single layer of cells that line the intestine as the instigator of the process

By Amy Ratner, director of scientific affairs

The answers to how and where the response to gluten in celiac disease begins have been found in the single layer of cells that line the small intestine, according to new research from an international team of investigators. Scientists have long been trying to better understand exactly where this process begins and how it unfolds.

Research has previously focused on immune cells deeper inside the intestine as the instigator of this process with gluten getting through the intestinal wall and in contact with the immune cells. But the role of the epithelial cells lining the intestine has been overlooked, according to the study published in the journal, Gastroenterology. A team of medical and bioengineering researchers based at McMaster University in Canada spent six years working on the study.

The lining of the intestine has cells that don’t belong to the immune system, but the study found that they play an active role by touching off the damaging reaction to gluten in celiac disease.

Cells at center stage

The study put the epithelial cells “center stage” because it demonstrated that these cells stimulate an immune response, according to Elana Verdu, PhD, a study author and director of McMaster’s Farncombe Family Digestive Health Research Institute.

Using biopsy tissue from patients with active celiac disease, researchers measured where in the lining of the gut the cells that bind to gluten and make it more visible to the immune cells were found.  Next, they set out to determine if the epithelial cells activate the immune system.

A model of the intestine

In collaboration with bioengineers, researchers  built a functioning model of the intestine called an organoid. The organoid was composed only of epithelial cells that have the molecule that “sees” gluten and then makes it more visible to CD-4 T-lymphocytes, the immune cells involved in the immune response in celiac disease.  

Researchers added T-lymphocytes to the organoid and then gluten was introduced. The researchers were able to observe how the molecules alert immune cells to the presence of gluten and to conclude definitively that the epithelium plays a crucial role in activating the immune system in celiac disease. These observations would be difficult to study in the complex gut inside the human body. An organoid outside the body, for example in a petri dish or test tube, makes the research possible.

Study findings could potentially lead to a new approach for drugs being developed to treat celiac disease, according to the authors. The research results could be used to understand the precise mechanism of action in celiac disease.

Role of pathogens

Additionally, the study found that after detecting gluten the epithelial cells send stronger signals to immune cells if pathogens are also present. Many tiny organisms live in the gut and when they cause disease, for example bacteria, fungi and viruses, they are called pathogens.

In the future it may be possible to detect the pathogens in a person at risk of developing the disease and stop the interactions with gluten and the epithelium to prevent the disease, according to Sara Rahmani, lead study author and a researcher at McMaster.

Parts of the puzzle

Arnold Han, MD, a gastroenterologist at Columbia University, who was not involved in the study said it provides evidence that the expression by intestinal epithelial cells of the molecules that play a role immune response is important in driving celiac disease. Additionally, the study provides important clues about the role these cells and intestinal microbes, such as bacteria, play in the activation of the CD4 T-cells responsible for celiac disease, he said.

Han, recipient of a Beyond Celiac/Society for the Study of Celiac Disease Early Career Investigator grant, is currently investigating the precise way that gluten sets off damage to the intestine in those who have celiac disease.  His study, while not directly related to the McMaster research, addresses different parts of the same puzzle, he said.

You can read more about the McMaster study here.