Summary: New research identifies the glycoprotein Reelin as a promising candidate to repair a weakened intestinal barrier (“leaky gut”) and to reduce symptoms of major depressive disorder by acting on the gut–brain axis. Chronic stress lowers Reelin levels in the gut, which weakens the intestinal lining and allows bacterial products and toxins to enter circulation, provoking inflammation that can worsen depression. Restoring Reelin levels strengthens gut integrity and produced antidepressant-like effects in preclinical models.
Researchers report that a single intravenous dose of Reelin restored normal Reelin expression in the small intestine, reduced cell death in the gut lining, and reversed stress-induced changes. These findings point to a novel therapeutic direction that targets both gut health and brain chemistry to treat depression and associated gastrointestinal problems.
Key Facts:
- Dual action: Reelin supports neuronal function and helps maintain the intestinal barrier, influencing both mood and gut health.
- Stress impact: Chronic stress reduces Reelin expression in the gut, increasing intestinal permeability and immune activation linked to depressive symptoms.
- Therapeutic potential: In preclinical studies, a single intravenous injection of Reelin normalized gut levels and produced antidepressant-like outcomes while restoring epithelial renewal.
Source: University of Victoria
Could a protein injection mend both leaky gut and severe depression?
A new study from the University of Victoria, published in Chronic Stress, explores how Reelin—a large extracellular matrix glycoprotein present in the brain, blood, liver and intestines—may help protect and restore the gut lining while influencing mood. The research focuses on how chronic stress alters Reelin expression in the gut and how restoring that expression affects intestinal health and behavior in laboratory models.
Under normal conditions, the gastrointestinal tract controls which nutrients and substances cross into the bloodstream. The epithelial layer that lines the gut renews itself every four to five days to replace cells damaged by the gut environment. When chronic stress or stress-related disorders like major depressive disorder (MDD) are present, this renewal process and barrier function can be disrupted, increasing permeability. The resulting “leaky gut” can permit microbes and toxins to activate the immune system and trigger inflammation—a process that can feed back to worsen depressive symptoms.
According to Hector Caruncho, professor of medical sciences at the University of Victoria and corresponding author of the study, Reelin appears to play an important role in maintaining gut barrier integrity by promoting epithelial cell proliferation and migration along the crypt–villus axis. The study showed that chronic stress reduced Reelin and markers of epithelial cell turnover in the small intestine of experimental animals; a single intravenous injection of 3 µg of recombinant Reelin restored those measures toward normal.
Previous research has reported reduced Reelin in the brains of people with depression and in animal models exposed to chronic stress; those studies also found that a single intravenous dose of Reelin produced antidepressant-like effects in rodents. The current study extends these findings to the gut, supporting the idea that Reelin supports the renewal of the intestinal lining and may protect against inflammation-driven worsening of depression.
Ciara Halvorson, the study’s first author and a neuroscience PhD student at UVic, notes that these results are especially relevant for people living with both depression and gastrointestinal disorders. If Reelin can protect or restore the gut lining, it may reduce the inflammatory responses triggered by leaked gut material and thereby help prevent the exacerbation of depressive symptoms.
While translation to clinical treatments requires further study, these results position Reelin as a compelling target for therapies that act on both brain and gut processes to treat depression and related gastrointestinal dysfunction.
Funding: This research was supported by the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC).
Key Questions Answered:
A: Reelin is an extracellular matrix glycoprotein that supports neuronal organization and function, helps regulate the gut barrier, and promotes renewal of epithelial tissues.
A: Chronic stress can increase intestinal permeability, allowing bacteria and toxins to enter circulation and activate immune responses. This inflammation is associated with worsening depressive symptoms, linking gut health and mood.
A: By restoring gut barrier integrity and modulating brain-relevant pathways, Reelin-based treatments could act on both the gut and the brain, offering a dual-target approach for depression and comorbid gastrointestinal conditions.
About this depression and microbiome research news
Author: Heather Walmsley
Source: University of Victoria
Contact: Heather Walmsley – University of Victoria
Image: The image is credited to Neuroscience News
Original Research: Open access.
“An Intravenous Injection of Reelin Rescues Endogenous Reelin Expression and Epithelial Cell Apoptosis in the Small Intestine Following Chronic Stress” by Ciara Halvorson et al., Chronic Stress.
Abstract
An Intravenous Injection of Reelin Rescues Endogenous Reelin Expression and Epithelial Cell Apoptosis in the Small Intestine Following Chronic Stress
Chronic stress disrupts the gut environment, including increased permeability of the intestinal epithelium. Reelin, an extracellular matrix protein released by cells in the lamina propria, promotes epithelial proliferation and migration along the crypt–villus axis, supporting renewal of the gut lining.
This study evaluated Reelin expression and apoptosis in the small intestine of Long Evans rats exposed to three weeks of daily corticosterone injections. Animals received either recombinant Reelin (3 µg) or vehicle. Chronic stress reduced Reelin-immunoreactive and cleaved caspase-3–positive cells in the lamina propria and epithelial layer by about half. A single intravenous dose of 3 µg Reelin reversed these reductions.
Reelin cell counts in the small intestine did not correlate with counts in the hippocampus, regardless of stress exposure or Reelin treatment. The findings suggest Reelin supports gut barrier integrity by restoring epithelial turnover and may counteract chronic stress–induced changes in the intestinal environment.