Scientists identify the exact location in the body where gluten causes an immune system response

A new study maps exactly where in the body gluten triggers the immune response that caused celiac disease. It matters because about one in 100 people live with the condition.

An international team centered at McMaster University built lab models and mouse systems to see which cells start the fight. Their results show how a specific layer in the gut sparks a targeted immune response to gluten.

The intestinal epithelium, the gut’s thin cell lining, turned out to be the spark plug. These cells do more than absorb nutrients and rebuild after injury.

The work was led by Elena F. Verdu, MD, PhD, at McMaster University. Her research focuses on celiac disease and how the gut lining and microbes shape immune responses.

Today the standard treatment is a strict gluten free diet, a position set out in a major guideline. Even so, avoiding all traces is hard in daily life.

Gluten, celiac, and genetics

Most people with celiac disease carry specific versions of HLA, immune system proteins that present antigens to T cells. These variants create a narrow path for gluten fragments to activate helper T cells in the small intestine.

Only a portion of people with these risk genes ever develop the condition. This difference points to how genes interact with diet, microbes, and the epithelial layer to start the early immune signal.

Researchers showed that epithelial cells display gluten fragments using major histocompatibility complex class II, proteins that show antigens to helper T cells. That finding shifts these cells from passive targets to active players.

The team used lab grown organoids, miniature tissue models, to watch the process up close. They also used mice that carry a human risk gene linked to celiac disease.

When antigens are presented, gluten specific CD4 T cells, immune cells that coordinate responses, switch on and multiply. Interferon gamma heightens the epithelial display, so the message to the immune system becomes louder.

Why microbes matter here

The study tested what happens when bacteria chop up gluten before it hits the lining. A bacterial enzyme called elastase, a protein cutter from microbes, boosted the activation signal.

This dovetails with reports that some pathobiont, a usually harmless microbe that can drive disease under stress, strains worsen gluten responses. It adds a microbial lever to a process once blamed only on genes.

That does not mean every infection will worsen symptoms. It suggests that certain enzymes and species can tip the balance during exposure.

Signals that spike fast in blood

One signal stands out in human challenge studies. Levels of IL-2, a T cell messenger, rise within about four hours after a single gluten dose.

That surge tracks with symptom intensity and offers a quick readout for future trials. It also reinforces the idea that the epithelial handshake with T cells starts the cascade.

Gluten-free diet and celiac disease

Current care asks people to remove gluten from every meal and snack. Many still report symptoms despite careful efforts, which is a real world problem.

“The only way we can treat celiac disease today is by fully eliminating gluten from the diet. This is difficult to do, and experts agree that a gluten-free diet is insufficient,” said Verdu. Her point highlights why targeting the lining could help.

If the lining itself presents gluten to T cells, therapies that act on those lining cells become plausible. That could include blocking antigen display, changing enzyme activity, or interrupting transport.

Human trials must still show that such strategies improve symptoms and heal tissue. Study models are strong tools, yet they are still models.

Lessons from celiac disease and gluten

Are mice and organoids enough to predict human benefit? The answer is no, but they reveal mechanisms that guide smarter trials.

Could genes alone explain the response? Not fully, because both the environment and the microbiome shape the trigger.

Will new drugs replace strict diets soon? Any timeline depends on safety, delivery to the small intestine, and clear relief.

Teams are exploring ways to blunt gluten processing in the gut and at the lining. Enzyme blockers and local inhibitors may lessen tissue injury during exposure.

Others are testing whether changing upper small intestine bacteria can dampen the activation signal. That approach leans on the idea that enzymes and species steer antigen formation.

More sensitive blood markers like IL-2 can speed early testing. Faster readouts reduce guesswork and lighten the burden on volunteers.

The study is published in Gastroenterology.

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