What is “Leaky Gut” And What Does It Have to Do with Mental Health?

coyerly0
Mar 26
5 min read

By Calista Oyerly

When most people think about depression or anxiety, they think about the brain. However, many people do not realize the unique interconnectedness of our brain and gut.

Your digestive system and your brain are directly connected through nerves, hormones, and chemicals made by gut bacteria. The gut refers to the gastrointestinal (GI) tract, the long system of organs responsible for digesting food, absorbing nutrients, and eliminating waste. It includes organs such as the stomach and intestines, but it is also home to trillions of microorganisms and a large network of cells that help regulate digestion and communicate with the brain (Akram et al., 2023).

In fact, over 90% of serotonin, a neurotransmitter that helps regulate mood and behavior, is found in the gastrointestinal tract (Martin-Subero et al., 2015).

Fig. 1 Diagram of the gut-brain axis showing bidirectional signaling between the gut microbiota and

the brain through the neural (vagus nerve), immune, and endocrine pathways. Adapted from Wang et al.

This two-way communication system is called the gut-brain axis. As a result, when the gut is imbalanced, the brain is in turn affected as well.

An essential part of this connection involves the gut barrier, or the lining of the gastrointestinal system, which helps regulate what enters the bloodstream from the digestive system.

What is the Gut Lining?

Inside your intestines is a thin layer of cells that acts like a security system for the body. These cells are held together by proteins called tight junctions, including claudin, occludin, and zonulin (Petrut et al., 2025).

Fig. 2 Diagram comparing a healthy intestinal lining to increased intestinal permeability ("leaky gut"),

illustrating how damage to the gut barrier allows substances such as toxins and bacteria to pass into

the bloodstream. Adapted from Michigan Health and Wellness

Tight junctions can be thought of as the stitching between pieces of fabric. They keep the intestinal barrier sealed so that nutrients from food can pass through into the bloodstream, while harmful bacteria and toxins remain inside the digestive tract.

When helpful substances like nutrients pass through the gut lining and enter the bloodstream, they are then carried throughout the body, where they help support growth and overall health.

However, harmful substances such as bacteria and toxins are not meant to enter the bloodstream. If they do, they can travel to different parts of the body and trigger the immune system to respond. The immune system then must fight off these harmful substances, which contribute to increased inflammation and other health problems.

In a healthy system, the barrier is strong and highly selective.

However, when the gut microbiome becomes imbalanced, a condition known as dysbiosis occurs and these tight junctions can weaken. When this happens, the intestinal barrier becomes more porous.

This condition is commonly referred to as “leaky gut.” The scientific term for this process is increased intestinal permeability.

Fig. 3 Diagram illustrating intestinal permeability ("leaky gut"), where disruptions in the gut lining allow substances to pass

into the bloodstream, contributing to gastrointestinal and systemic symptoms. Adapted from Monash FODMAP.

What is “Leaky Gut”?

Leaky gut occurs when the gut barrier becomes too permeable, allowing substances that normally stay inside the gut to pass into the bloodstream.

When this happens, harmful substances can escape the digestive tract and trigger an immune response.

One important substance that can leak through is called lipopolysaccharide (LPS), a component of certain bacteria. While LPS is not harmful when it stays inside the gut, problems arise when it enters the bloodstream (Nikolova et al., 2021).

When LPS enters the blood, the immune system recognizes it as a threat and responds by releasing inflammatory chemicals. If the gut barrier remains weakened over time, this can lead to chronic, low-grade inflammation.

One factor that can contribute to this weakened barrier is a protein called zonulin. Zonulin helps regulate the tight junctions between cells in the gut lining. When zonulin levels are elevated, these junctions can loosen, allowing substances such as LPS to pass into the bloodstream.

Meta-analyses have found that patients with mental health conditions, including depression, often have significantly increased circulating levels of zonulin, suggesting increased intestinal permeability (Johns Hopkins Medicine, N.D.).

These findings suggest that gut barrier dysfunction plays a role in certain mental health conditions we see today.

Inflammation and Depression

Research published in journals such as Nature Communications has found that patients with major depressive disorder (MDD) showed significantly reduced expression of intestinal tight junction proteins in the gut lining. This suggests impaired gut barrier function, or increased intestinal permeability ("Gut Microbiome Alterations").

Researchers refer to a subtype of depression known as inflammatory depression, which is associated with elevated levels of inflammation and may sometimes be more resistant to traditional treatments (Collins, 2019).

Studies have also found that individuals with inflammatory depression tend to have higher levels of pro-inflammatory bacteria, such as Bacteroides, and lower levels of beneficial bacteria like Clostridium, which help regulate inflammation.

In simple terms, a weakened gut barrier can allow bacterial products to enter circulation. This can activate the immune system and increase inflammation throughout the body, including in the brain, which has been shown to influence mood.

The Microbiome’s Role

Your gut contains trillions of bacteria, collectively known as the gut microbiome. Some of these bacteria are beneficial, while others can contribute to inflammation when they become too abundant.

Beneficial bacteria often produce compounds called short-chain fatty acids (SCFAs). These compounds help strengthen the gut lining, reduce inflammation, and support brain health.

When levels of these beneficial bacteria decrease, the gut barrier can become more vulnerable, increasing the risk of gut permeability, which in turn has direct effects on the brain via the gut-brain axis.

Why Digestive Disorders and Depression Often Occur Together

Digestive disorders such as inflammatory bowel disease (IBD) and depression frequently occur together.

Both conditions are associated with increased intestinal permeability, immune activation, and elevated inflammatory markers. Because of this overlap, researchers believe the gut barrier represents a shared pathway linking digestive and mental health symptoms.

What Does This Actually Mean?

Leaky gut does not explain all forms of depression. Mental health is complex and influenced by many factors, including genetics, life experiences, stress, sleep, hormones, and environment.

However, research suggests that in some individuals, particularly those with chronic inflammation, digestive symptoms, autoimmune conditions, and treatment-resistant depression, the gut barrier plays an important role.

It is important to remember that the gut is much more than a digestive organ. It acts as a barrier, an immune regulator, a communication center, and a chemical factory that all directly impact the brain.

When that barrier weakens, the effects extend beyond the digestive tract, influencing both mood and mental health.

Mental health and physical health are deeply connected, which is why supporting gut health supports brain health.

Sources

Akram, N., et al. “Exploring the Serotonin–Probiotics–Gut Health Axis.” Biotechnology and Applied Biochemistry, 2023, https://pmc.ncbi.nlm.nih.gov/articles/PMC10867509/.
Martin-Subero, M., et al. “The Gut–Brain Axis: Interactions between Enteric Microbiota, Central and Enteric Nervous Systems.” Annals of Gastroenterology, vol. 28, no. 2, 2015, pp. 203–209, https://pubmed.ncbi.nlm.nih.gov/26307347/.
Petrut, S.M., et al. “Gut Microbiota and the Gut–Brain Axis: Neurotransmitter Production and Mental Health Implications.” Frontiers in Microbiology, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11901622/
Nikolova, V.L. et al. “Association of Intestinal Permeability Biomarkers with Major Depressive Disorder.” JAMA Psychiatry, 2021, https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2784328.
“The Brain–Gut Connection.” Johns Hopkins Medicine, n.d., https://www.hopkinsmedicine.org/health/wellness-and-prevention/the-brain-gut-connection.
Liu, P., et al. “Gut Microbiome Alterations and Depression-Related Inflammation.” Nature Communications, 2024, https://www.nature.com/articles/s41467-024-47273-w.
Collins, L., et al. “The Gut Permeability & IBS: Do I Really Have a ‘Leaky’ Gut?” Monash FODMAP, 2019, https://www.monashfodmap.com/blog/gut-permeability-ibs-do-i-really-have-leaky-gut/.
“Navigating Leaky Gut Naturally.” Michigan Health and Wellness, 16 Feb. 2024,
https://michiganhealthandwellness.com/navigating-leaky-gut-naturally/.
Safadi, J.M., et al. “Microbiome and Inflammatory Depression.” Molecular Psychiatry, 2021, https://www.nature.com/articles/s41380-021-01032-1.
Wang, Xiaoqi, et al. “The Bidirectional Signal Communication of Microbiota–Gut–Brain Axis in Hypertension.” International Journal of Hypertension, 2021,https://www.researchgate.net/publication/357227644.

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