Scientists Reveal How Gluten Reactions in The Gut Lining Lead to Celiac Damage

Celiac disease is a serious lifelong condition, where the immune system attacks the small intestine whenever the gluten protein is digested. For people with the condition, wheat, barley, and rye are all off the menu.

We know that genetics play a part in triggering celiac disease, and that certain gene variations make people more vulnerable to developing it. What’s less clear is exactly how the loud alarm that sounds in the immune system leads to tissue damage.

In a comprehensive review published in Frontiers in Immunology, researchers from the University of Rome Tor Vergata pulled together findings from more than 100 previous studies to get a wider picture of the celiac disease chain reaction – getting us closer to figuring out how it works, and how it might be better treated.

“We here review the available evidence supporting the role of immune cells in celiac disease-associated tissue damage and discuss the basic mechanisms by which this destructive immune response is amplified,” write the researchers in their published paper.

That emphasis on amplification is key to the review. Only some people with a genetic predisposition to celiac disease go on to develop it, so there must be other contributing factors (amplifiers) at play.

What’s well established is that one factor in developing celiac disease comes from a disruption to the delicate balance of bacteria in the gut. The immune system needs to keep out dangerous threats, without going on the offensive to the extent that healthy tissue gets affected.

When it comes to gluten, an enzyme called tissue transglutaminase 2 (TG2) helps to break it down – but in those with certain gene variants, this makes gluten’s by-products look like foreign invaders to the immune system, which dispatches an army of soldier T-cells to attack.

“Under normal conditions, TG2 is mostly inactive in the intestine,” write the researchers in their published paper.

“Nevertheless, inflammatory stimuli or cellular stress can increase the production and enzymatic activity of TG2, thus escalating immune responses to gluten.”

However, T cells and the inflammatory signals they produce aren’t the whole story. Those signals and other accompanying chemical messages kick immune cells called intraepithelial lymphocytes into action, which actually kill off the cells in the gut lining.

There’s then more amplification: The review points to more recent research suggesting that structural cells in the gut called stromal cells communicate with the immune system to perpetuate the damage.

Other reviewed studies provide evidence that the gut bacteria mix has an influence on the whole process, as do other wheat proteins and antiviral-type signals called type I interferons, all contributing to the stress that the gut lining is put under.

And with so many variables contributing to gut bacteria, it follows that these variables may be related to celiac disease too.

“Some microbial communities may affect not only gluten deamidation but also activation of TG2, hence suggesting that celiac disease pathogenesis requires the interplay of genetic, environmental, and immunological factors,” write the researchers.

This review adds to the findings of a 2024 study published in Gastroenterology, which found that the gut lining can be an active participant in celiac disease, not just a victim under attack from T cells.

That’s backed up by the other research linked to from this review, providing the most comprehensive look yet at how the starting gun for the condition has a series of knock-on effects that all contribute to the related symptoms.

Without careful monitoring of their diet, those with celiac disease – around 1 in a 100 people – can experience bloating, pain, diarrhea, constipation, or vomiting simply by eating the wrong foodstuff.

Thankfully, better understanding the mechanisms behind the condition could eventually led to new treatments beyond going gluten-free.

Related: Evidence Emerges That Celiac Disease Could Be Triggered by a Seemingly Harmless Virus

“It will be necessary to further improve celiac disease-like models to unravel the order of pathogenic events and to carry out preclinical testing of novel therapeutic strategies,” write the researchers.

The research has been published in Frontiers in Immunology.

This article was fact-checked and edited by Michael Irving. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.