How a Gluten-Free Diet Affects Immune Cells in Diabetes-Prone Mice

Celiac.com 06/02/2025 - Researchers have known for years that a gluten-free diet can delay or even reduce the risk of type 1 diabetes in a special kind of lab mouse known as the nonobese diabetic mouse. However, the exact reasons why removing gluten helps have remained unclear. Scientists wondered whether gluten might directly change important immune cells that are involved in the development of autoimmune diseases like diabetes. In this study, they decided to carefully examine the immune system of these mice — particularly different types of T cells — to see exactly how a gluten-free diet influences them.

What the Researchers Did

The researchers compared two groups of nonobese diabetic mice. One group ate a standard diet containing gluten, while the other group followed a gluten-free diet. They looked closely at immune cells from two important locations in the body: the spleen and the pancreatic lymph nodes. These areas are critical because they help regulate how the immune system responds to threats — or in the case of autoimmune disease, how it mistakenly attacks the body’s own tissues.

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Using advanced techniques that allow scientists to study individual cells and their gene activity, the team analyzed T cells and other immune cells to find any differences between the two groups.

Key Findings

No Major Overhaul of the Immune System

One of the first things the researchers noticed was that the gluten-free diet did not cause dramatic changes to the types or numbers of immune cells. There was no major expansion or disappearance of any one cell type that would explain why a gluten-free diet protects against diabetes. Instead, the changes were much smaller and more spread out across different groups of T cells.

Subtle but Important Shifts

Even though the changes were minor, the gluten-free diet appeared to encourage certain beneficial immune cells. Some of these cells are known to help regulate the immune system and prevent it from attacking healthy tissue. These included:

• Regulatory T cells (Tregs): These cells help keep the immune system from becoming overactive. While the total number of Tregs did not dramatically rise, a special type of Treg with potentially strong protective abilities was slightly more common in mice on a gluten-free diet.
• Gamma delta T cells (γδT cells): This unique type of T cell was found in a form that is believed to be more calming to the immune system in the gluten-free mice. These cells are thought to produce helpful substances that prevent inflammation.
• Natural Killer T cells (NKT cells): In the gluten-free group, these cells shifted toward types that may help regulate the immune system better and suppress autoimmunity, whereas the mice on a standard diet had more aggressive types of NKT cells that might contribute to disease.

Different Gene Activity Patterns

The researchers also found differences in the way genes were switched on or off in the immune cells. In mice on the gluten-free diet, genes involved in promoting healthy immune activation and communication between cells were more active. On the other hand, the mice eating a standard diet showed signs of a more stressed immune system, with higher activity of genes linked to inflammatory responses.

Interestingly, the gluten-free diet seemed to stimulate signals involving key immune growth factors like interleukin 2, interleukin 7, and interleukin 15, all of which play roles in developing a balanced immune system. Meanwhile, the standard diet triggered genes that respond to type I interferons, molecules often associated with the early stages of autoimmune diseases.

What This Means for Diabetes Development

Instead of stopping diabetes by making one big change to the immune system, the gluten-free diet seems to work by gently nudging many small parts of the immune system toward a healthier balance. This "many small changes" approach might be enough to prevent the chain reaction that normally leads to autoimmune diabetes in these mice.

One particularly interesting finding is that a standard diet — not the gluten-free one — was linked to a more immature and inactive immune system. This fits with the "hygiene hypothesis," which suggests that not exposing the immune system to enough challenges early in life could actually make it more prone to developing autoimmune diseases later.

Additionally, the gluten-free diet’s effect on critical immune cells like regulatory T cells, gamma delta T cells, and natural killer T cells highlights the importance of subtle immune system tuning in preventing autoimmune attacks on the body’s own tissues.

Why This Study Matters for People with Celiac Disease

Although this study was done in mice and focused on diabetes, it has meaningful insights for people with celiac disease and other autoimmune conditions. Celiac disease is itself an autoimmune disorder where the immune system attacks the small intestine in response to gluten. This research shows that removing gluten from the diet can cause small but important shifts across many parts of the immune system, leading to a more controlled and less aggressive immune response.

For people with celiac disease, this suggests that strict adherence to a gluten-free diet might not only protect the gut but could also help restore better overall immune balance. Additionally, since autoimmune diseases often cluster together (people with celiac disease are at higher risk for diseases like type 1 diabetes and thyroid disease), this study supports the idea that a gluten-free diet could have broader health benefits beyond managing intestinal symptoms.

In conclusion, even small, subtle shifts in the immune system caused by a gluten-free diet might have powerful long-term effects, reducing the risk of autoimmune attacks and promoting healthier immune function. This research offers hope that dietary changes can meaningfully influence autoimmune diseases — not just treating symptoms, but potentially reshaping the immune system itself toward a more balanced state.

Read more at: onlinelibrary.wiley.com