Scientists Discover Protein That Could Treat Depression Through the Gut

New findings suggest that a protein known as Reelin could play a role in treating both “leaky gut” and severe depression.

Could an injectable protein someday help address both “leaky gut” and severe depression? A new study from the University of Victoria (UVic), published in Chronic Stress, points to a glycoprotein called Reelin as a possible future option.

Under normal conditions, the gastrointestinal system controls what passes from the stomach, colon, and intestines into the bloodstream. This system is often called the “gut.” But during chronic stress, or in stress-related conditions such as major depressive disorder (MDD), the gut’s protective barrier can weaken and become more permeable.

When this happens, sometimes described as “leaky gut,” bacteria and toxins can slip into circulation. That leakage may trigger immune activity and inflammation, which can in turn intensify depression symptoms. Because of this, therapies that strengthen and repair the gut barrier could be useful for helping prevent MDD.

Reelin as a Potential Therapeutic Target

One possible approach involves Reelin-based treatments, says Hector Caruncho, a professor of medical sciences at UVic and the study’s corresponding author. Reelin is found across the 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 many psychiatric 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.

Implications for Depression and Gut Health

“Taken together, these results may have important implications for the management of major depressive disorder,” says Ciara Halvorson, neuroscience PhD 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 against leaky gut by 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 Reelin as a promising new treatment for depression that targets processes in both the brain and the gut.

Reference: “An Intravenous Injection of Reelin Rescues Endogenous Reelin Expression and Epithelial Cell Apoptosis in the Small Intestine Following Chronic Stress” by Ciara S Halvorson, Carla Liria Sánchez-Lafuente, Brady S Reive, Lara S Solomons, Josh Allen, Lisa E Kalynchuk and Hector J Caruncho, 1 September 2025, Chronic Stress.
DOI: 10.1177/24705470251381456

This study was supported by funding from the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC).

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