Your trusted health, nutrition, and personalized lifestyle medicine resource

The Gut-Brain Connection and Mental Health

Supporting intestinal health to influence brain homeostasis

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.


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.


  1. Statistics Canada. Accessed January 16, 2019.
  2. Accessed January 14, 2019.
  3. Accessed January 14, 2019.
  4. Dinan TG et al. Psychobiotics: a novel class of psychotropic. Biol Psychiatry. 2013;74(10):720-726.
  5. Saulnier DM et al. The intestinal microbiome, probiotics and prebiotics in neurogastroenterology. Gut Microbes. 2013;4(1):17-27.
  6. Quirk SE et al. Physical health comorbidities in women with personality disorder: data from the Geelong Osteoporosis Study. Eur Psychiatry. 2016;34:29-35.
  7. Sampson TR et al. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe. 2015;17(5):565-576.
  8. Mental health and chronic diseases. Accessed April 3, 2019.
  9. Logan C et al. Major depressive disorder: probiotics may be an adjuvant therapy. Med Hypotheses. 2005;64(3):533-538.
  10. Sepehrmanesh Z et al. Vitamin D supplementation affects the Beck Depression Inventory, insulin resistance, and biomarkers of oxidative stress in patients with major depressive disorder: a randomized, controlled clinical trial. J Nutr. 2016;146(2):243-248.
  11. Mota-Pereira J et al. Moderate exercise improves depression parameters in treatment-resistant patients with major depressive disorder. J Pyschiatr Res. 2011;45(8):1005-1011.
  12. Wallace CJK et al. The effects of probiotics on depressive symptoms in humans: a systematic review. Ann Gen Psychiatry. 2017;16:14.
  13. Cheung SG et al. Systematic review of gut microbiota and major depression. Front Psychiatry. 2019;10:34.
  14. Scriven M et al. Neuropsychiatric disorders: influence of gut microbe to brain signaling. Diseases. 2018;6(3):E78.
  15. Kiecolt-Glaser JK et al. Inflammation: depression fans the flames and feasts on the heat. Am J Psychiatry. 2015;172(11):1075-1091.
  16. Kim N et al. Mind-altering with the gut: modulation of the gut-brain axis with probiotics. J Microbiol. 2018;56(3):172-182.
  17. Milajerdi A et al. The effect of probiotics on inflammatory biomarkers: a meta-analysis of randomized clinical trials. Eur J Nutr. 2019;March 11 [Epub ahead of print].
  18. Javadi L et al. Pro- and prebiotic effects on oxidative stress and inflammatory markers in non-alcoholic fatty liver disease. Asia Pac J Clin Nutr. 2018;27(5):1031-1039.
  19. Lindqvist D. Oxidative stress, inflammation and treatment response in major depression. Psychoneuroendocrinology. 2017;76:197-205.
  20. Black CN et al. Is depression associated with increased oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology. 2015;51:164-175.
  21. Ostadmohammadi V et al. Vitamin D and probiotic co-supplementation affects mental health, hormonal, inflammatory and oxidative stress parameters in women with polycystic ovary syndrome. J Ovarian Res. 2019;12(1):5.
  22. Mafi A et al. Metabolic and genetic response to probiotics supplementation in patients with diabetic nephropathy: a randomized, double-blind, placebo-controlled trial. Food Funct. 2018;9(9):4763-4770.
  23. Badehnoosh B et al. The effects of probiotic supplementation on biomarkers of inflammation, oxidative stress and pregnancy outcomes in gestational diabetes. J Matern Fetal Neonatal Med. 2018;31(9):1128-1136.
  24. Babadi M. The effects of probiotic supplementation on genetic and metabolic profiles in patients with gestational diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Probiotics Antimicrob Proteins. 2018;Dec 8 [Epub ahead of print].
  25. Holsboer F et al. The corticosteroid receptor hypothesis of depression. 2000;23(5):477–501.
  26. Allen AP et al. Bifidobacterium longum 1714 as a translation psychobiotic: modulation of stress, electrophysiology, and neurocognition in healthy volunteers. Transl Psychiatry. 2016;6(11):e939.
  27. Dunbar JA et al. Depression: an important comorbidity with metabolic syndrome in a general population. Diabetes Care. 2008;31(12):2368–2373.
  28. Lustman PJ et al. Depression in diabetic patients: the relationship between mood and glycemic control. J Diabetes Complications. 2005;19(2):113-122.
  29. Le TK et al. Oral administration of Bifidobacterium spp. improves insulin resistance, induces adiponectin, and prevents inflammatory adipokine expressions. Biomed Res. 2014;35(5):303-310.
  30. Andreasen AS et al. Effects of Lactobacillus acidophilus NCFM on insulin sensitivity and the systemic inflammatory response in human subjects. Br J Nutr. 2010;104(12):1831-1838.
  31. 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 017;20(4):254-261.
  32. van der Beek CM et al. Role of short-chain fatty acid in colonic inflammation, carcinogenesis, and mucosal protection and healing. Nutr Rev. 2017;75(4):286-305.
  33. Macfabe D et al. Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb Ecol Health Dis. 2012;24:23.
  34. Skonieczna-Żydecka K et al. Faecal short chain fatty acids profile is changed in Polish depressive women. Nutrients. 2018;10(12):E1939.
  35. Braniste V. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014;6(263):263ra158.


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.


Leave a Reply

Metagenics Institute is a trusted, peer-to-peer, evidence-based educational resource for nutrition and personalized medicine.
At Metagenics Institute, we translate credible research with scientific integrity into innovative and actionable clinical
decision-making. Metagenics Institute supports a diverse practitioner base to optimize patient outcomes by shifting existing paradigms in healthcare. Our mission is to transform healthcare by inspiring and educating practitioners, and their patients, about personalized lifestyle medicine.

Sponsored by
© 2024 Metagenics Institute. All Rights Reserved