It’s not all in your head

The connection between the gut, brain and mood

by Dr. Sarah Nyrose BSc ND

For decades the leading scientific theory proposed that low mood and depression were the result of low serotonin levels in the brain. Today, we know that multiple factors contribute to mood: one of these being the connection to the gut and gut bacteria.

“Feeling blue”, low mood, depression. These are all terms we’re familiar with, and depression alone affects more than 300 million people worldwide. It’s a condition that negatively affects how you think, how you act, and elicits feelings of sadness and disinterest. Often under-diagnosed and untreated, depression is commonly termed a “silent illness”, despite affecting a staggering one in six people at some point in their lives.1

Given the high prevalence of depression, it’s surprising that we don’t fully understand the mechanism or cause of this illness. In the 1980’s, scientists and medical doctors were excited about the invention of a little white and green pill containing fluoxetine hydrochloride – commonly known as Prozac. This antidepressant was heralded as a wonder drug for those with depression. Prozac is a selective serotonin reuptake inhibitor (SSRI) and it increases serotonin levels between nerve cells. For decades, the central theory in psychiatry was that depression was caused by low serotonin levels. Serotonin is a neurotransmitter that facilitates communication between nerve cells. The signals between nerve cells are increased when serotonin levels are high. This was proposed to improve mood and outlook.

However, this theory is now widely criticized. While numerous people benefit from the use of antidepressants, not everyone’s symptoms of depression resolve with the use of these drugs. Furthermore, scientific studies have shown conflicting results and have seriously challenged the theory that low serotonin levels are the single cause of depression. 

The latest research has shown that while serotonin is central in regulating mood, its role is complex, and furthermore, there are multiple factors that play into mood and emotions.

One of the recently discovered factors is the gut.

We’ve known for a long time that there’s a link between the gut and the brain. Expressions such as “a gut feeling” or “butterflies in your stomach” highlight this understood connection. However, for centuries our scientific understanding supported the belief that the brain controlled the digestive system and largely viewed the gut and its microbial community as independent from emotional regulation. 

That is, until recently.

Research in the early 2000’s started to challenge our understanding of the gut-brain axis. In particular, the idea that mood was solely controlled by the brain was turned on its head. 

A new paradigm for this axis highlights that the gut and brain are intricately connected through neurotransmitters, hormones, the nervous system and immune system. The relationship is bidirectional and the gut may have more of an influence on mood and mental health than we ever imagined.

Microbiota and Serotonin

For decades, our focus for treating depression has been on increasing serotonin between nerve cells. This was achieved by using antidepressant medications (i.e. Prozac) that blocked the reabsorption of serotonin, causing it to accumulate between the space in-between nerve cells (neural synapses). 

But where is serotonin produced in the first place? Surprisingly, in the gut. 

Approximately 95% of our serotonin is produced in the gut. There are three types of cells that produce serotonin: immune cells, nerve cells and predominantly, enterochromaffin (EC) cells. EC cells live in the lining of our gastrointestinal system and they are responsible for intestinal motility, secretion, and the production of serotonin. In one study, researchers found that production of serotonin by the EC cells in germ free (mice without normal gut bacteria) mice was 60% less than the mice with normal gut bacteria.2 They further discovered that the EC cells utilize metabolic by-products from the gut bacteria in order to synthesize serotonin. Together, EC cells and bacteria work synergistically together to produce this crucial and mood-altering neurotransmitter. 

Vagus nerve

The neural connections between our brain and gut are complex and interconnected. The brain and digestive system interact predominantly via the enteric nervous system (ENS) and the central nervous system (CNS). The ENS contains 200–600 million neurons; picture it as a spider web like network lining your entire digestive system. It has been referred to as the “second brain”, based on its size, complexity and that it can operate independently of the brain and spinal cord.3 The ENS is responsible for maintaining equilibrium and directing digestion. 

The CNS on the other hand, is largely represented by the vagus nerve. The vagus nerve has central control over gastrointestinal functioning so it can respond to stressful events. These two neural pathways influence each other, slowing down or initiating digestion, in response to the environment and digestive needs.

It was thought that this crosstalk between the brain and gut predominantly influenced gastrointestinal function. It wasn’t until the last 10 years, that researchers began to scientifically understand that this continual conversation also affected mood, cognitive function and motivation. Furthermore, it wasn’t just the gut talking, but also the billions of bacteria that make up our gastrointestinal microbiota. 

In 2012, a group of researchers studied the involvement of bacteria in the gut-brain axis. Using germ-free mice , the study observed changes in the brain related to emotion and cognition, and a reduction in stress and depression-like behaviours when they introduced specific gut bacteria called Bifidobacerium sp. The results of this study reconfirmed that our microbiota can influence the communication between the gut and brain, and the biochemistry of the brain. 4 

What perplexed researcher’s was: how were the bacteria inducing changes in the brain? The answer is: the vagus nerve. While the mechanism is not fully understood, when researchers tried to replicate the study in mice without a vagus nerve, they observed no change with the introduction of Bifidobacerium sp. This suggested that the vagus nerve is a crucial route of communication for our microbiota and brain. 

There is accumulating evidence that our gut bacteria play a crucial role in regulating stress and altering the expression of neurotransmitter receptors in the brain. In one study, treatment with probiotics in rats significantly reduced their stress hormone (cortisol) and reduced their response to chronic stressors. 5

Immune system and Inflammation

The gut is often an understated key player in its role with the immune system. After all, the gut is home to the largest immune organ, the gut-associated lymphoid tissue, which accounts for more than 70% of our total immune system. Together, with a team of bacteria lining the small and large intestine, the gut plays an important role in mediating inflammation. 

But there are a lot of drivers of gastrointestinal inflammation, such as a diet full of processed foods, inflammatory foods, pathological bacteria, and exposure to environmental toxins. 

Gastrointestinal inflammation causes our body to release cytokines – immune signalling proteins. These cytokines place stress on the microbiome and contribute to interstitial permeability, commonly known as “leaky gut syndrome”. Interstitial permeability occurs when the cells in our gut lining pull apart, allowing molecules and bacteria to leak through the lining and into the systemic circulation. When bacteria and their endotoxins circulate through the body, this elicits an immune response and chronic inflammation. 

New studies have emerged linking inflammation and an increase in cytokine production to mood disorders, particularly depression.6 It has become apparent that we can’t ignore gut inflammation in the context of mood and mental health. When treating depression, particular attention needs to be directed towards reducing inflammation and improving digestion. This includes supporting a healthy microbiome. 

Research has shown that a healthy microbiota reduces interstitial permeability and gut inflammation. In studies with mice, dosing them with a probiotic containing Bifidobacterium longum, reduced their anxiety-like symptoms and inflammation.7 A recent study on humans demonstrated that the use of a multistrain probiotic reduced the negative thoughts in non-depressed patients.8

Healthy Gut + Healthy Mind

Given the complex relationship between the brain, gut and microbiome, it’s not surprising that rates of depression are three times higher among individuals with inflammatory bowel disease.9 The link between gut health, inflammation and mental health is indisputable. We’ve come one step closer to understanding the contributing factors for the development of depression and other mental health illnesses. 

Yet, there is still a lot we don’t know. Current research is focusing on numerous unanswered questions, such as which specific probiotics could benefit people with depression and anxiety, or how gut signaling affects early brain development. We also need to translate what we’ve seen in animal studies, to human clinical trials. 

However, given what we know, focusing on supporting digestion and reducing inflammation are two key first steps at improving mental health, and as adjunctive treatment for low mood and depression. Eliminating foods that are inflammatory, supporting your microbiome and ensuring you’re eating a nutrient-dense diet is a great first start. Incorporating in anti-inflammatory herbs such as curcumin, the active ingredient in turmeric, is a simple addition to your diet. Finally, focusing on stress reduction and connecting with community all help to improve mood and support digestive health.

1. Parekh, R. (2017, January). What Is Depression? Retrieved July, 2019, from https://www.psychiatry.org/patients-families/depression/what-is-depression
2. Yano, J. M., Yu, K., Donaldson, G. P., Shastri, G. G., Ann, P., Ma, L., … & Hsiao, E. Y. (2015). Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 161(2), 264-276
3. Mayer, E. A. (2011). Gut feelings: the emerging biology of gut–brain communication. Nature Reviews Neuroscience, 12(8), 453.
4. Bercik, P., Park, A. J., Sinclair, D., Khoshdel, A., Lu, J., Huang, X., … & Berger, B. (2011). The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut–brain communication. Neurogastroenterology & Motility, 23(12), 1132-1139.
5. Foster, J. A., Rinaman, L., & Cryan, J. F. (2017). Stress & the gut-brain axis: regulation by the microbiome. Neurobiology of stress.
6. Miller, A. H., Maletic, V., & Raison, C. L. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biological psychiatry, 65(9), 732-741.
7. Bercik, P., Verdu, E. F., Foster, J. A., Macri, J., Potter, M., Huang, X., … & Lu, J. (2010). Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology, 139(6), 2102-2112.
8. Steenbergen, L., Sellaro, R., van Hemert, S., Bosch, J. A., & Colzato, L. S. (2015). A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain, behavior, and immunity, 48, 258-264
9. Byrne, G., Rosenfeld, G., Leung, Y., Qian, H., Raudzus, J., Nunez, C., & Bressler, B. (2017). Prevalence of anxiety and depression in patients with inflammatory bowel disease. Canadian Journal of Gastroenterology and Hepatology, 2017.

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