Can One Protein Injection Reset A Stressed Gut?

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VICTORIA, British Columbia — Chronic stress doesn’t just mess with your head. New research from the University of Victoria reveals that it systematically disrupts markers of intestinal health. Scientists have found that a single injection of a naturally occurring protein called Reelin can normalize these gut markers, while also reducing depression-like behaviors, at least in rats.

The study, published in the journal Chronic Stress, focuses on Reelin, a protein found throughout the body that seems to be important for both brain health and gut health. When researchers gave stressed rats just one small injection of Reelin through a tail vein, they saw signs that the gut lining was repairing itself. The same rats, in an earlier report, also showed fewer signs of depression-like behavior.

“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,” the researchers wrote.

Scientists have suspected for years that gut health and mental health are connected, but this study offers concrete evidence of how chronic stress affects the cells that line the intestines. When stress damages the gut lining and makes it “leaky,” harmful bacteria and toxins can slip into the bloodstream. This triggers inflammation that can make depression worse. Meanwhile, about 70% of people going through depression also struggle with digestive problems.

How Stress Damages The Gut Lining

The lining of the intestines completely replaces itself every three to five days, constantly swapping out old or damaged cells for new ones. Reelin appears to help with this replacement process. In this study, researchers looked at specific markers that show whether this renewal process is working properly.

The team gave male rats daily injections of corticosterone, a stress hormone, for three weeks. This mimics what happens in chronic stress and produces changes similar to depression. At the end of three weeks, some of the stressed rats got a single injection of Reelin while others got a placebo. Rats that weren’t stressed received either Reelin at a higher dose (to make sure it was safe) or a placebo.

Chronic stress cut the number of Reelin-producing cells in the small intestine by about half. The team also saw a similar drop in dying cells at the tips of the intestinal lining. That might sound like a good thing, but cell death at these tips is actually healthy. Old cells are supposed to die and get replaced by fresh ones moving up from below. When fewer cells are dying, it means the replacement process has slowed down and damaged cells are sticking around longer than they should.

When researchers gave Reelin to the stressed rats, both markers improved by about half. More Reelin-producing cells appeared, and more cells started dying at the tips where they’re supposed to, showing that the gut’s natural renewal process was starting to work again.

How One Injection Affected Both Brain and Gut

The same group of rats had been tested for depression-like behaviors before scientists examined their gut tissue. According to a 2022 paper from the same research team, the stressed rats showed more signs of giving up in a swimming test, which is a common way to measure despair-like behavior in rodents. One Reelin injection cut that giving-up behavior by more than half, similar to what happens with ketamine, a fast-acting antidepressant. Stressed rats also struggled with a memory test, and Reelin helped with that too.

Interestingly, the researchers found no correlation between Reelin levels in the gut and Reelin levels in the hippocampus, despite both being affected by chronic stress and responsive to Reelin treatment. This means that while stress simultaneously disrupts Reelin in multiple body systems, these systems may operate somewhat independently.

People diagnosed with major depression tend to have less Reelin in their brains, and their blood levels of Reelin are lower too. This study shows that stress also reduces Reelin in the gut, suggesting that depression affects the whole body, not just the brain.

Breaking the Inflammation Cycle

The researchers think that when chronic stress drains Reelin from the gut, it slows down the replacement of intestinal cells. Cells that hang around too long get beaten up by digestive enzymes, bacteria, and food particles. As the gut barrier gets weaker, bacterial fragments and other inflammatory triggers can leak into the bloodstream. This fires up the immune system and may contribute to the ongoing, low-grade inflammation often seen in depression.

Reelin might do more than just help cells turn over. The authors suggest that under chronic stress, certain amino acids can interfere with Reelin’s signals by overactivating a protein called mTOR. Restoring Reelin levels might help rebalance this system, though the study didn’t test this idea directly.

The study only looked at male rats, with eight in each group, so the results might not apply to females or larger populations. The researchers only examined one section of the small intestine, so they don’t know what happened in other parts of the digestive tract. More importantly, while they measured markers that suggest the gut barrier was improving, they didn’t directly test whether the gut was actually leakier or whether bacteria were getting into the bloodstream.

The research team plans to investigate whether repeated Reelin injections provide sustained benefits and whether the treatment works in female animals, which can show different responses to stress and antidepressants. They’re also interested in understanding exactly how intravenously delivered Reelin reaches the gut lining and whether it could be administered in other ways.

For now, the research adds weight to the idea that treating depression might mean taking care of gut health too. If Reelin helps restore the gut’s normal cell turnover, it could help break the cycle where stress, gut problems, and depression feed off each other.

Disclaimer: This article is general information about animal research. It is not medical advice and does not recommend any treatment. Findings in rats may not translate to people.