Post Summary: The Stress-Gut-Depression Cycle — And a Promising New Discovery
This article explores the cyclical relationship between chronic stress, gut microbiome dysbiosis, leaky gut, and depression, drawing on Nicole Apelian’s personal experience managing multiple sclerosis through gut health. Key topics include how chronic stress reduces short-chain fatty acid-producing gut bacteria, increases intestinal permeability, and triggers inflammation linked to depressive symptoms; the role of lipopolysaccharide (LPS) and pro-inflammatory cytokines (IL-6, IL-1 beta, TNF-alpha) in activating the HPA axis and elevating cortisol; small intestinal bacterial overgrowth (SIBO) as a complicating factor; and new research on the glycoprotein Reelin, which shows promise for reducing depressive symptoms and restoring gut lining integrity. For natural support addressing the stress-gut-brain axis, Nicole Apelian, PhD recommends her Anxiety & Stress Blend and Balanced Gut Blend, available at nicolesapothecary.com.
The Foundation of Health
I have written extensively on the impact of leaky gut on autoimmune conditions, menopause, mood disorders, immunity, and more. A compromised gut lays the foundation for a range of health issues that erode quality of life, promote fatigue, and increase the risk of chronic pain. From my personal experience with multiple sclerosis (MS), I knew that unless I addressed my gut issues, the disease would be difficult to manage. This is why a recent study that linked chronic stress, leaky gut, and a novel protein caught my eye.
A Challenging Cycle of Stress, Microbiome Dysbiosis, and Leaky Gut
As I wrote in “How Stress Changes Your Microbiome for the Worse“, chronic stress disrupts the gut microbiome, which then leads to leaky gut. This in turn increases systemic inflammation that can cause the development and worsening of disease.
How so?
The process works on multiple levels. When we are under chronic stress, it negatively impacts a class of gut bacteria that produce short-chain fatty acids (SCFAs) when they digest fiber. This causes an increase in intestinal inflammation, which promotes leaky gut. Since inflammation also plays a role in depression, the two conditions often go hand in hand.
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Processed foods and refined sugar, excessive alcohol consumption, medications such as NSAIDs and antibiotics, and food sensitivities can also exacerbate leaky gut. Adding to the complexity, a compromised gut also allows for small intestinal bacterial overgrowth (SIBO), especially E. Coli, Serratia, and Proteus bacterial strains that produce their own stress hormones, further contributing to this challenging cycle of poor gut health.
“When the gut lining becomes permeable, “increased levels of microbial breakdown products such as lipopolysaccharide (LPS) more readily enter into the bloodstream. Increased LPS causes greater release of stress hormones and increased release of mediators of inflammation such as IL-6, IL-1 beta, and TNF-alpha,” says William Davis, MD, a gut specialist and author of Wheat Belly.This triggers the hypothalamic-pituitary-adrenal (HPA) axis to go into overdrive and release high levels of cortisol. When we struggle with elevated levels of this stress hormone, we gain weight, promote insulin resistance and high blood sugar levels, and, you guessed it, create further microbiome dysbiosis.”1
Now, a team of researchers have identified a specific, injectable protein that may break this cycle, lower stress, heal leaky gut, and calm depression.
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The Research
A new study published in the journal Chronic Stress established that a glycoprotein by the name of Reelin could play a significant role in restoring gut health and reducing symptoms of major depression.2 This important protein is found throughout the body — including in the liver, blood, intestines, and brain. In preclinical models, researchers have discovered that chronic stress lowers Reelin levels in the gut, while earlier studies have found that those with major depressive disorder have lower levels of it in their brains. Interestingly, previous research has shown that a single injection of Reelin (3 µg) produces significant antidepressant effects and also helps to renew the gut lining to normal levels.
“Taken together, these results may have important implications for the management of major depressive disorder,” says Ciara Halvorson, a neuroscience PhD student at UVic and the study’s lead author. “This is especially true for people who live with both depression and gastrointestinal conditions.3
While additional research is needed before a Reelin-based treatment will be available in clinical settings, the findings show exceptional promise in mitigating both leaky gut and depression.
The Takeaway
This fascinating research reinforces what I’ve seen time and again: the state of the gut and mental health are deeply intertwined — and breaking the cycle of chronic stress is essential for lasting physical and mental wellbeing. As we wait for Reelin-based treatments to become available, medicinal herbs are an excellent option to soothe the stress response, ease depression, and heal leaky gut. Nicole’s Apothecary Anxiety & Stress Blend and Balanced Gut Blend are here to help. Visit nicolesapothecary.com to get started today.
Nicole Apelian
Actions Steps & FAQs
Action Steps
- Reduce chronic stress. Incorporate daily stress-reduction practices such as deep breathing, time in nature, or prayer and reflection to help protect your gut microbiome.
- Limit gut-disrupting foods. Reduce processed foods, added sugar, and alcohol, which can worsen intestinal permeability and microbiome imbalance.
- Review medication use. Talk to your healthcare provider about NSAIDs and antibiotics if used frequently, as these can contribute to leaky gut over time.
- Support your nervous system naturally. Explore Nicole’s Apothecary Anxiety & Stress Blend to help calm the stress response and ease inflammation linked to depressive symptoms.
- Heal and restore the gut lining. Use Nicole’s Apothecary Balanced Gut Blend to repair gut permeability and support a healthy gut-brain axis.
- Stay informed on emerging research. Follow developments on Reelin-based treatments, which show early promise for addressing both leaky gut and depression at the root.
FAQ: Leaky Gut, Depression, and Reelin Protein
What is leaky gut and how does it relate to stress? Leaky gut refers to increased intestinal permeability, where the gut lining becomes more porous than it should be, allowing larger particles to pass into the bloodstream that trigger inflammation. Chronic stress disrupts beneficial gut bacteria that produce short-chain fatty acids, which contributes directly to the development of leaky gut.
Can leaky gut contribute to depression? Yes. Increased intestinal permeability allows compounds like lipopolysaccharide (LPS) to enter the bloodstream, raising inflammatory markers such as IL-6, IL-1 beta, and TNF-alpha. Since inflammation plays a role in depression, leaky gut and depressive symptoms often occur together.
What is Reelin and how does it relate to gut health and depression? Reelin is a glycoprotein found throughout the body, including the gut and brain. Research shows that chronic stress lowers Reelin levels in the gut, and people with major depressive disorder tend to have lower Reelin levels in the brain. Research has shown a single injection of Reelin produced antidepressant effects and helped restore the gut lining.
What natural remedies support gut health and stress reduction? Nicole Apelian, PhD formulated an Anxiety & Stress Blend to calm the nervous system, ease inflammation, and clear brain fog, along with a Balanced Gut Blend to repair the gut lining and restore microbiome balance. Both are available at nicolesapothecary.com.
What other factors contribute to leaky gut? Processed foods, excessive sugar and alcohol, certain medications like NSAIDs and antibiotics, food sensitivities, and small intestinal bacterial overgrowth (SIBO) can all worsen intestinal permeability.
Nicole’s Apothecary Products in this Post
Anxiety & Stress Tincture
Balanced Gut Blend Tincture
References
- “How Stress Changes Your Microbiome for the Worse” by Nicole Apelian, PhD, November 29, 2022.
- Halvorson, Ciara S et al. “An Intravenous Injection of Reelin Rescues Endogenous Reelin Expression and Epithelial Cell Apoptosis in the Small Intestine Following Chronic Stress.” Chronic stress (Thousand Oaks, Calif.) vol. 9 24705470251381456. 29 Sep. 2025, doi:10.1177/24705470251381456
- University of Victoria. “Scientists discover protein that could heal leaky gut and ease depression.” ScienceDaily. ScienceDaily, 2 February 2026.
