The Gut-Brain Connection and Mental Health

by Melissa Blake, BSc, ND

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 leverage gut microbiota to influence brain homeostasis and cognitive health. 

The gut-brain connection

A connection between the gastrointestinal (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.⁷ Both directly and indirectly, the health of the GI tract plays an essential role in the health of the brain.

Mental health disorders can affect people of any age, race, gender, religion, or socioeconomic status and includes any conditions that disrupt a person’s thoughts, feelings, mood, ability to relate to others, and daily functioning.⁸ Major depressive disorder (MDD) is one of the most common mental health disorders in the US and globally.⁸ Stress management is important in mitigating MDD, and stress is known to negatively alter GI microbiota, specifically lowering levels of Lactobacilli and Bifidobacteria.⁹

Research on causative factors of major depressive disorder (MDD) continues to evolve, but suggests significant dietary and lifestyle influences. Various strategies, modifying lifestyle factors such as exercise and nutritional supplementation, have been investigated as beneficial behaviors to help reduce the symptoms of depression.

For example, vitamin D supplementation may benefit patients with MDD,¹⁰ and moderate exercise has been shown to help in combination with pharmacotherapy for treatment-resistant MDD.¹¹ Various probiotics have been tested in patients with MDD, demonstrating possible benefits in multiple studies which require further validation, especially to identify key strains that may be of benefit.^9,12

Multiple studies have identified differences between the gut microbiome of patients diagnosed with a depressive disorder compared to healthy controls, yet there remains more research to be done to identify which types of bacteria relate most to depression.¹³ A recent review of multiple studies¹⁴ suggests that probiotic supplementation may play a role in the management of mental illness.

Several of the factors associated with an increased susceptibility to mental illness and their connection to the gut microbiome and probiotic therapy are explored here.

Inflammation and oxidative stress

Research suggests that depression and inflammation fuel each other and hints to the fact that addressing depression through an anti-inflammatory approach may enhance recovery and reduce the risk of recurrence.¹⁵ In the brain, proinflammatory cytokines can trigger neuroinflammation. Cytokines may also alter concentrations of various neurotransmitters in the brain related to mood regulation.¹⁶

A meta-analysis recently summarized that probiotic supplementation may reduce inflammatory burden in the body, not just benefiting gut-related disease, but the individual as a whole.¹⁷ This study documented decreases in major inflammatory markers such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-a), and interleukins IL-6, IL-12, and IL-4.¹⁷ In a recent study involving administration of a particular probiotic supplement,¹⁸ researchers found that several inflammatory cytokines (CRP, TNF-α, IL-6) were substantially reduced in patients with non-alcoholic fatty liver disease (NAFLD).¹⁸

Oxidative stress, a contributing factor to mental illness, has been associated with high levels of tissue inflammation in MDD.^15,19 And it has been suggested that people with depression are more likely to have increased oxidative stress.²⁰ Probiotic therapy has the opportunity to help improve antioxidant status and reduce inflammatory markers.^21-24

In a trial of women with PCOS and depression, significant improvements in depression, anxiety, and stress scale scores were observed following the co-administration of vitamin D and probiotic supplementation over a 12-week period. This intervention also netted reductions in high-sensitivity C-reactive protein (hs-CRP) levels and an increase in total antioxidant capacity (TAC).²¹

In patients with diabetic neuropathy, supplementation with probiotics was associated with a significant reduction in hs-CRP and elevation in plasma total glutathione.²² Similar improvements in biomarkers of inflammation and oxidative stress have been observed in patients with gestational diabetes receiving probiotic therapy.^23,24

This research suggests that using probiotic supplementation 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-adrenal (HPA) axis  

Chronic stress leads to elevated hormones such as cortisol, the stress hormone, and in susceptible people, may be a major contributing factor in the development of psychiatric diseases, such as anxiety and depression. In fact, HPA dysregulation has been seen in approximately 70% of patients with depression.²⁵

In a study using healthy volunteers, probiotic therapy was shown to reduce cortisol output and daily reported stress.²⁶ It appears that this type of probiotic supplementation 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.²⁷ 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.²⁸

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.²⁹

A 2010 human study determined that supplementation with L. acidophilus NCFM for 4 weeks preserved insulin sensitivity compared with placebo,³⁰ suggesting an important role for probiotic therapy in the treatment of depression through glucose control.

Research also indicates a positive influence on metabolic markers, such as lipid profiles and glycemic control, with probiotic therapy in women with PCOS,³¹ suggesting that the gut microbiota may offer a unique target in a therapeutic approach to address metabolic dysfunction.

Short-chain fatty acids (SCFA)

A diet high in fiber has been shown to contribute to a healthy intestine and feed many types of gut microbiota. Typically, fiber consumption results in increasing SCFA production, with fibers fermented by bacteria to produce SCFAs.

In vitro studies have shown anti-inflammatory properties of SCFAs,³² and animal studies are investigating connections between SCFA levels and autism spectrum disorder (ASD)-linked neurochemical changes and behaviors.³³ In one human study, low levels of SCFAs were associated with depressive symptoms in women,³⁴ so SCFAs may contribute to depression phenotype. Additional clinical research is needed to further elucidate the possible antidepressant or anxiolytic effects of fiber and SCFAs.

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 reaches the brain to maintain homeostasis of the CNS.

Preclinical research (in mice) reveals that treatment with bacterial strains that produced SCFAs decreases BBB permeability and increases tight junctions³⁵ (i.e., making the BBB less leaky), yet another unique way that microbial metabolites likely contribute to overall health and vitality.

Summary

There are multiple players in the gut-brain-microbiome connection, with research revealing more insights all the time. A diet rich in prebiotic fibers is an important dietary tool to promote a healthy intestine and healthy brain. Probiotic therapy via targeted supplementation can also support the health of the gastrointestinal environment, as well as have positive, mitigating effects on inflammatory responses and oxidative stress; other systemic benefits of probiotics include increased insulin sensitivity and improved stress response. Taken together, these effects are not only supportive in the prevention and management of mental illness, but in any number of chronic diseases.

Citations

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