byUniversity of Victoria

Experimental timeline and immunostaining. Rats were injected (s.c.) daily for 21 days with vehicle (0.9% NaCl with 2% polysorbate-80) or CORT (40 mg/kg, suspended in vehicle). On the last day of injections, rats were administered vehicle (0.1 M PBS) or 3 µg of recombinant reelin at a volume of 0.5 mL via the lateral tail vein. Rats underwent behavioral tests and were perfused 4 days post-reelin Injection. A middle segment of the small intestine was cryosectioned at 30 µm, and cross sections were stained for reelin or cleaved caspase-3. Reelin and Cleaved caspase-3 density were determined and compared between treatment groups. Credit:Chronic Stress(2025). DOI: 10.1177/24705470251381

What if a protein could be injected to help heal both "leaky gut" and severe depression? New research from the University of Victoria (UVic),publishedinChronic Stress, shows that a glycoprotein called reelin may one day be able to do just that.

In a healthy body, the gastrointestinal system—which includes the stomach, colon, and intestines, and is often referred to as the "gut"—controls which nutrients enter the bloodstream. When a person experienceschronic stress, or a stress-related condition such as major depressive disorder (MDD), the gut barrier can become more permeable.

This "leaky gut" can then allow harmful bacteria and toxins to enter circulation, which can lead to an immune system reaction and inflammation. This can further exacerbate symptoms of depression. Treatments that restore the integrity of the gut barrier may therefore be helpful in preventing MDD.

Reelin-based therapeutics could potentially offer such treatment, according to Hector Caruncho, professor of medical sciences at UVic and corresponding author on the study. Reelin is a protein that is found throughout the human body, including in the brain, blood, liver and intestines.

"This study aimed to understand the role of reelin in the gut, especially under conditions of chronic stress," says Caruncho. "The gut-brain axis is becoming essential to understanding manypsychiatric disorders, including depression."

The study found that chronic stress decreased Reelin in the intestines of preclinical models, and that a single injection of 3 µg of reelin normalized levels.

Previous studies have shown that individuals diagnosed with major depressive disorder have less reelin in their brains, as do rodents exposed to chronic stress, and that a single intravenous injection of 3 µg of reelin can produce antidepressant-like effects in these rodents. They have also shown reelin to be necessary for proper gut lining renewal.

"Taken together, these results may have important implications for the management ofmajor depressive disorder," says Ciara Halvorson, neuroscience Ph.D. student at UVic, and first author on the paper. "This is especially true for people who live with both depression and gastrointestinal conditions.

"Under healthy conditions, the gut lining is renewed every four to five days. This is important as the cells in the gut lining are constantly exposed to damaging factors in the gut. If reelin protects againstleaky gutby supporting the renewal of the gut lining, reelin may thereby protect against the worsening of depression symptoms triggered by inflammatory immune responses to leaked gut material."

While more research is needed before reelin will be available in the clinic, these findings position it as a promising new treatment for depression that targets processes in both the brain and the gut.

More information: Ciara S Halvorson et al, An Intravenous Injection of Reelin Rescues Endogenous Reelin Expression and Epithelial Cell Apoptosis in the Small Intestine Following Chronic Stress, Chronic Stress (2025). DOI: 10.1177/24705470251381456

Provided by University of Victoria