From The Gut to The Brain: A New Clue to The Origin of Depression

Researchers have discovered that chronic stress weakens the gut, making it more permeable and promoting inflammation that can contribute to depression. A protein called reelin, found in the brain and gut, helps maintain this intestinal barrier strong and healthy. In experiments with rats, a dose of reelin was able to reverse the damage caused by stress, promoting the regeneration of intestinal cells and reducing inflammation. The discovery suggests that strengthening the gut may be a new way to protect the brain and mood as well.

Our gut is much more than an organ that digests food. It functions as an intelligent barrier, capable of controlling what enters and leaves the bloodstream. Under healthy conditions, only nutrients and safe substances cross this intestinal barrier. However, when we are subjected to chronic stress, especially that associated with mental disorders such as depression, this barrier can begin to fail.

The result is a phenomenon known as "leaky gut," in which the intestinal lining becomes porous and allows toxins and harmful microorganisms to pass into the bloodstream.

These changes are caused, in part, by stress hormones, such as cortisol, a type of glucocorticoid. In small amounts, cortisol has a protective function: it helps intestinal cells stay firmly together, preventing leakage of the intestinal barrier. However, when stress is constant and cortisol levels remain high for too long, the opposite effect occurs.

The intestinal barrier weakens, and the intestine begins to allow the entry of substances that should not circulate in the body. Furthermore, the immune system, which would normally respond in a balanced way, becomes resistant to the calming effect of cortisol, releasing even more inflammatory substances. This state of chronic inflammation can reach the brain and contribute to the emergence of depressive symptoms.

Recently, researchers discovered that a protein called reelin plays an important role in maintaining intestinal and brain health. Reelin is a molecule present in various parts of the body, such as the brain, liver, blood, and intestines, and is involved in essential processes of growth, regeneration, and cell communication.

In the brain, reelin helps in the organization of neurons and in plasticity, that is, the ability of brain cells to adapt and communicate. In people with major depressive disorder, scientists observed lower levels of reelin in the blood and in brain areas related to emotions, such as the hippocampus.

In experiments with rodents, chronic stress also reduced the amount of reelin in the brain and gut. To simulate the impact of prolonged stress, the animals received daily injections of corticosterone, a hormone similar to human cortisol.

After three weeks, the rats exhibited behaviors typical of depression and signs of intestinal damage, such as a weakened barrier and increased cell death in the villi, small projections that line the intestine and absorb nutrients.

Cells labeled with green antibody showing Reelin

The team of scientists then decided to test whether it would be possible to reverse this damage with the administration of reelin. In an experiment, mice received an intravenous injection of 3 micrograms of reelin.

The result was surprising: the protein was able to restore intestinal integrity, reducing the number of damaged cells by about 50% and re-establishing the natural process of intestinal cell renewal. This recovery occurred because reelin stimulates intestinal cells to multiply in the "crypts" (deep regions) and migrate to the "villi" (the absorption layer), replacing worn-out cells.

The scientists also observed that, although reelin acts on both the brain and the intestine, the beneficial effects in one organ do not necessarily depend on the other.

This indicates that reelin can act independently in different parts of the body, promoting specific repairs in each of them. Even without a direct correlation between protein levels in the brain and gut, gut improvement alone was sufficient to reduce physiological markers associated with stress and inflammation.

Communication pathways between the gut and the brain. The four main communication pathways between microbiota, gut, and brain. Damaged epithelium leads to increased translocation of gut bacteria into the circulation (A). Microbial metabolites, such as short-chain fatty acids (SCFAs), neurotransmitters, and cytokines, enter the circulation and affect central structures (B). The vagus nerve provides a bidirectional communication pathway to the gut and brain (C). Activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to cortisol production, which increases intestinal permeability and alters microbial composition (D). Source: Int. J. Mol. Sci. 2024, 25(2), 814; https://doi.org/10.3390/ijms25020814

These results open a new perspective on the connection between the gut and the brain. Gut integrity appears to directly influence emotional balance and mental health, and reelin may be a key player in this relationship.

Restoring levels of this protein may not only protect the gut against damage caused by chronic stress, but also prevent the development of depressive disorders.

The study reinforces a view increasingly accepted by science: mental health begins in the gut. By understanding how molecules like reelin help rebuild the body's natural defenses, we can move towards new therapies capable of treating not only the symptoms of depression, but also its biological origins.

READ MORE:

An Intravenous Injection of Reelin Rescues Endogenous Reelin Expression and Epithelial Cell Apoptosis in the Small Intestine Following Chronic Stress

Ciara S Halvorson, Carla Liria Sánchez-Lafuente, Brady S Reive, Lara S Solomons, Josh Allen, Lisa E Kalynchuk, and Hector J Caruncho 

Chronic Stress. Chronic Stress. 2025; 9

https://doi.org/10.1177/247054702513814

Abstract:

Chronic stress disrupts the integrity of the gut environment, including leaking of the intestinal epithelium. Reelin, an extracellular matrix protein, is released from cells of the lamina propria and promotes epithelial cell proliferation and migration up the crypt-villus axis to facilitate renewal of the gut lining. In the present study, we evaluated Reelin expression and apoptosis in the small intestine of Long Evan's rats treated with recombinant Reelin (3 µg) or vehicle following 3 weeks of daily corticosterone (40 mg/kg/day) or vehicle injections. We show that Reelin- and cleaved caspase-3- immunoreactive cells are diminished in the lamina propria or epithelial cells of the gut lining following chronic stress (∼ 50% and 55%, respectively), and that a single injection of 3 µg of Reelin delivered intravenously can reverse these parameters. We also found Reelin cell counts in the small intestine did not correlate to counts in the hippocampus regardless of exposure to chronic stress or Reelin treatment. Our results suggest that Reelin may serve a protective function over gut barrier integrity through the restoration of epithelial cell turnover, and that Reelin may have a role in reversing chronic stress-induced changes to the gut environment.