Gut-Brain Connection: Stress and Mental Health

Published on January 2019.

Mental health continues to be a growing concern worldwide. Both Statistics Canada and The National Institute of Mental Health estimate that 1 in 5 Canadians and Americans live with a mental illness.1,2 The World Health Organization lists depression as the #1 cause of disability globally.3 Considering the rising rates and significant disease burden of mental illness, the increasing level of interest in novel clinical support options is no surprise.

One such option being explored is attempting to optimize the gastrointestinal (GI) environment to influence brain homeostasis and cognitive health.

Gut-Brain Connection

A connection between the GI environment and the central nervous system (CNS) has long been recognized,4 as have the positive impacts the microbiome has on various health markers. In fact, many psychological illnesses are frequently experienced alongside GI-related comorbidities, such as irritable bowel syndrome (IBS), leaky gut, and gastroesophageal reflux disease (GERD).5,6

The gut communicates with the brain through nerve connections, hormones, cytokines, neurotransmitters, and certain metabolites. Both directly and indirectly, the health of the GI tract plays an essential role in the health of the brain.

Research on causative factors of major depressive disorder (MDD) continue to evolve and suggest strong nutritional and lifestyle influences. Patients with MDD have been shown to have elevated levels of pro-inflammatory cytokines, increased oxidative stress, altered GI function, and lowered micronutrient and omega-3 fatty acid status.7

Significant differences have been identified between the gut microbiome of patients diagnosed with a depressive disorder compared to healthy controls,8 suggesting a balanced microbiome may play a role in the management of mental illness. Several of the factors associated with an increased susceptibility to mental illness are explored here.

Inflammation & Oxidative Stress

Research suggests that depression and inflammation fuel each other and hints to the fact that addressing depression thru an anti-inflammatory approach may enhance recovery and reduce the risk of recurrence.9

In the brain, pro-inflammatory cytokines can trigger neuroinflammation. Cytokines may also alter concentrations of various neurotransmitters in the brain related to mood regulation.10

Many studies show that a healthy microbiota helps reduce inflammatory burden in the body, not just benefiting gut-related disease, but the individual as a whole. In a recent study,11 researchers looked at inflammatory cytokines (CRP, TNF-a, IL-6) in patients with non-alcoholic fatty liver disease, measuring the markers before and after administration of a probiotic supplement. After taking the probiotics, inflammatory markers were substantially reduced.11

Oxidative stress, a contributing factor to mental illness, is often associated with high levels of tissue inflammation,12 and it has been suggested that people with depression are more likely to have increased oxidative stress.13 It is well documented that probiotics help improve antioxidant status and blunt oxidative damage.14,15

This research suggests that optimizing gut flora not only affects localized inflammation and oxidative stress in the digestive tract, but also outside the gut, and may be an effective strategy for addressing inflammation and oxidative stress associated with aggravation of depressive symptoms.

Hypothalamic Pituitary (HPA) Axis

Chronic stress leads to elevated hormones such as cortisol, the stress hormone, and may also cause lower levels of serotonin and other neurotransmitters in the brain, which have been linked to depression.16 In susceptible people, chronic stress may be a major contributing factor in the development of psychiatric diseases, such as anxiety and depression.

In a study using healthy volunteers, probiotic therapy was shown to reduce cortisol output and daily reported stress.17 It appears that a healthy microbiome may improve the stress response and reduce the likelihood of stress-induced depression and anxiety.

Metabolic Syndrome

Research shows a strong connection between metabolic syndrome and higher rates of depression.18 In fact, presence of diabetes doubles the risk of comorbid depression, making glycemic control a key potential target in the prevention and management of depression.19

Animal and human studies show an improvement in several metabolic markers with probiotic therapy. Supplementation with probiotics may ameliorate insulin resistance and reduce the expression of inflammatory adipocytokines.20

A 2010 human study determined that supplementation with L. acidophilus NCFM for 4 weeks preserved insulin sensitivity compared with placebo, suggesting an important role for probiotic therapy in the treatment of depression through glucose control.21

Several studies show positive influence on metabolic markers with probiotic therapy in women with PCOS, suggesting that the gut environment may offer a unique target as a therapeutic approach to metabolic dysfunction.22

Short-Chain Fatty Acids (SCFA)

A diet high in fiber has been shown to contribute to a healthy intestinal environment in several ways, one such way is by increasing SCFA production.

Fiber is fermented by bacteria to produce SCFA. High levels of SCFA have been shown to play an important role in reducing inflammatory markers22 and also exhibit antidepressant and anxiolytic effects,23 thereby contributing to a healthy brain.

The Blood-Brain Barrier (BBB)

The brain is sensitive to inflammation, cortisol, glucose, toxins, and other chemicals. Strict control of access to the brain tissue is required to maintain health.

The BBB is an important layer of cells surrounding the brain that acts to control what gets in to maintain homeostasis of the CNS. A healthy, balanced gut flora has been shown to decrease permeability of the BBB and increase tight junctions (i.e., making the BBB less leaky),23 yet another unique way that a healthy gut microbiome contributes to overall health and vitality.


Probiotic therapy is one method to promote a healthy, balanced gut environment. A diet rich in fiber is another. Stress, a significant factor in MDD, is known to negatively alter GI microflora, lowering levels of Lactobacilli and Bifidobacteria.7 Thus, stress management is also an important part of a healthy gut protocol.

Much of the research and mainstream marketing of probiotic products are attempting to use probiotic therapy in a “this-strain-for-that” approach, but the evidence suggests otherwise. Although individual strains may show promising benefits in certain areas, generally the research points to a more holistic approach – a healthy gut environment contributing to overall health and wellness. Ongoing research continues to elucidate what microbial mix in the gut is “healthy” and what factors contribute to that mix.

A balanced gut microbiome may help reduce the inflammatory response and oxidative stress, as well as increase the expression of adhesion proteins within the intestinal epithelium, reducing intestinal permeability.20 Such effects increase insulin sensitivity and reduce autoimmune response. Research suggests that a healthy microbiome can communicate with the CNS and may have the potential to lower systemic inflammatory cytokines, decrease oxidative stress, improve nutritional status, and correct conditions associated with dysbiosis.15 These effects are not only supportive in the prevention and management of mental illness, but in any number of chronic diseases.

At the end of his life, Louis Pasteur, the scientist who developed the germ theory, is quoted to have said: “the microbe is nothing; the milieu is everything.” The research seems to indicate he was on to something.


  1. Statistics Canada. Accessed January 16, 2019.
  2. Accessed January 14, 2019.
  3. Accessed January 14, 2019.
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  23. Ahmadi S et al. Probiotic supplementation and the effects on weight loss, glycaemia and lipid profiles in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Hum Fertil (Camb). 2017;20(4):254-261.
  24. Braniste V. The gut microbiota influences blood-brain-barrier permeability in mice. Sci Transl Med. 2014;6(263):263ra158.
    Gomes AC et al. Gut microbiota, probiotics and diabetes: a review. Nutr J. 2014;13:60.


Melissa Blake, BSc, ND

Dr. Melissa Blake is a clinical specialist on the Medical Information team at Metagenics. She completed her bachelor degree at Dalhousie University in Halifax, Nova Scotia and obtained her naturopathic medical training from the Canadian College of Naturopathic Medicine. Dr. Blake, ND has over 10 years of clinical experience, specializing in the integrative and functional management of chronic diseases.

Published by melissablake.nd

Naturopathic Doctor

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