with Sabrina Mörkl, MD, PhD, and Kara Landau, RD

Major depressive disorder is a constant and growing concern for the general population. As clinical understanding advances, there is a growing interest in novel interventions to treat both the physiological and psychological aspects of depression. The microbiota–gut–brain axis is thought to modulate mood via the production of microbial metabolites and immune mediators, which trigger changes in neurotransmission and neuroinflammation. As clinical treatment merges across disciplines, with a focus on the interconnection between mind and body, perhaps there is no greater neurological and biological crosstalk than the gut-brain axis, a regulatory system that ongoing research links to major depressive disorder (MDD).1

Despite variable success rates and a litany of side effects, pharmaceuticals are the most frequently prescribed form of intervention for MDD.2 Indeed, clinical trials estimate that only 50% of patients will have a clinical response to medications meant to decrease depression.3 One reason the clinical community is largely still guided by medication may be its reliance on a measurable dose-response result and/or the ease of administration.

On the other hand, lifestyle interventions (such as exercise prescription) have received positive reports for their ability to decrease symptoms of depression. In fact, some have postulated that exercise and dietary interventions may have biological effects similar to those of SSRIs.4 The challenge is that patient adherence to behavioral changes can be more challenging – there is a low likelihood of a depressed individual going for a morning jog. Gut health (while similarly variable), however, may offer a clearer path to improved mood and a reduced state of depression – particularly in those with MDD and even treatment-resistant depression.5

The Gut-Brain Axis, a Physiological Pathway to Depression

The gut microbiome is in continuous conversation with our mood, health, and thoughts. It’s been roughly a decade since researchers first began to understand the importance of the microbiome-gut-brain axis, creating an emerging area of research from the once wild idea that micro-organisms could influence our brains and our mental health.

“Between the gut and the brain, there is a bidirectional communication system, termed the gut-brain-axis. Its main player is the vagal nerve, connecting the internal organs to the brain,” explains Sabrina Mörkl, MD, PhD, who is based at the Medical University of Graz in Austria – she specializes in the gut microbiome.

In 2018, Dr. Mörkl and her colleague, Jolana Wagner-Skacel, MD, founded the first European university course on nutrition-based prevention and treatment approaches in psychiatric care, highlighting the growing importance and recognition of nutritional psychiatry.

Kara Landau, RD, a pre-biotic dietician and founder of Uplift Food, has seen its relevance in action with her clients. “We now know that depression can be influenced by inflammation in the body, and that poor gut health can lead to inflammation, so there are dual compounding mechanisms going on,” she shares. “There is crosstalk between our gut and our brain, with stress leading to gut dysbiosis (a negative imbalance of bacteria) whereas when we have good gut health, it can play a supportive roll in mental health.”

How can our guts influence our mood? Dr. Mörkl explains that, “The map of psychobiotic-gut-brain-communication is complex and involves metabolic, neural, endocrine and immunological pathways.” Among others, gut health influences the following pathways relevant to mood disorders:

  • modification of the hypothalamic-pituitary-adrenal-axis (HPA-axis)
  • production of neurotransmitters (such as serotonin and dopamine)
  • modulation of brain-derived neurotrophic factor (BDNF) and oxytocin
  • adjustment of vagal tone
  • production of short-chain fatty acids
  • modification of the immune system

All of these factors have been implemented in major depressive disorder. MDD is understood to affect monoamine neurotransmitters such as serotonin (5-HT), norepinephrine, and dopamine.6 The glutamatergic and acetylcholine systems are thought to be hyperactive, while the GABA system is inhibited.7 Additionally, there is often impaired functioning of the hippocampus and prefrontal cortex, with increased activity in the amygdala.8 Negative feedback of the HPA-axis is also disturbed, resulting in chronic increases in circulating glucocorticoid (GC) and adrenocorticotrophic hormone (ACTH), further inhibiting 5-HT synthesis.9 A subpopulation of patients diagnosed with depression present with immune dysfunction and chronic inflammation, additional factors in disturbed feedback of the HPA axis and reduced synthesis of 5-HT.10

There is no single pharmacologic option that addresses the multitude of biological changes implicated in MDD. The potential to treat symptoms of MDD via the gut, by correcting many of the physiological imbalances associated with depression, has led researchers to consider dietary intervention, along with pre- and probiotics as an adjunct treatment and as a preventive measure in persons at an increased risk for developing depression.

Recent Research on the Relationship Between Gut Health and Mental Health

A growing collection of research has linked gut dysbiosis to an increased incidence of depression.1,12 In one study, published in Nature Microbiology, researchers sought to better understand how exactly microbiota can influence mood.13 They used DNA sequencing to analyze microbiota in the feces of more than 1,000 people enrolled in the Flemish Gut Flora Project. Next, the team correlated different microbial taxa with the participants’ quality of life and incidence of depression, using self-reported and physician-supplied diagnoses.

The researchers validated their findings using a cohort of 1,063 individuals in The Netherlands’ LifeLines DEEP project and then mined the data to generate a catalogue describing the microbiota’s capacity to produce or degrade molecules that can interact with the human nervous system.

Their findings:

“Butyrate-producing Faecalibacterium and Coprococcus bacteria were consistently associated with higher quality of life indicators. Dialister and Coprococcus were also depleted in depression.”13

This study is by no means a prescription for a one-size-fits-all gut microbiome to fight depression – everyone’s gut microbiome is unique and begins developing from birth. The findings do, however, point to the biological role of gut microbiomes in mental health. The major finding was the positive correlation between quality of life and the gut microbiome’s ability to synthesize the dopamine metabolite 3,4-dihydroxyphenylacetic acid – indicating a potential role of the microbial, γ-aminobutyric acid production in depression.

The above study was one of the first to find associations between specific gut bacteria and depression but has followed a growing body of literature over the past decade. A 2019 recent systematic review on gut microbiota and MDD pointed to the bacterial transplantation of feces from depressed patients to rodents.1 After transplantation, the rodents exhibited depressive behavior.

In human trials, nine specific gut bacteria genera were higher in those with MDD (Anaerostipes, Blautia, Clostridium, Klebsiella, Lachnospiraceae incertae sedis, Parabacteroides, Parasutterella, Phascolarctobacterium, and Streptococcus), six were lower (Bifidobacterium, Dialister, Escherichia/Shigella, Faecalibacterium, and Ruminococcus), and six were divergent (Alistipes, Bacteroides, Megamonas, Oscillibacter, Prevotella, and Roseburia).14 The clinical trials reviewed overall pointed to the importance of a balanced gut microbiome.

The psychiatric community is far from prescribing a specific gut bacteria to the general population; indeed, that is an unlikely solution as gut microbiomes are unique to individuals and their dietary patterns. However, the evidence does point to the role of an imbalanced gut in MDD and the potential for improved gut health to improve mental health.

Healthy Gut, Healthy Mind? Pathways to Intervention

With evidence just beginning to grow, how can clinicians treat the patient via the gut microbiome? Therapy can be geared toward the patient’s lifestyle and behaviors – an integrative form of CBT. Patient education on gut imbalance due to inflammation and the body’s maladaptive response can be addressed. In addition, providers can look for key risk factors tied to gut dysbiosis, such as:14

  • antibiotic use
  • high fat/high sugar diets
  • sedentary lifestyle
  • obesity
  • trauma and emotional stress

Clinicians may also consider recommending supplementation with pre- and probiotics to keep the patient’s system balanced and working properly. “Most research has been done on Lactobacillus and Bifidobacterium species. It is not yet known which ones work best for depression, but it has been shown that combinations of probiotic strains are more beneficial than just using a single strain probiotic,” says Dr. Mörkl.

For most patients with gut dysbiosis, supplementation with pre- and probiotics may be most beneficial, least invasive, and easiest to follow. Landau explains: “When we consume prebiotics, the probiotics in our gut ferment these, and the byproducts (short-chain fatty acids) are able to reduce inflammatory signals to our brain, thereby playing a preventative roll in mood management.” One of these short-chain fatty acids is butyrate, a metabolite produced by the Faecalibacterium and Coprococcus bacteria – noted to correlate with positive mood in the Flemish Gut Flora Project described above.

A few more tips from Landau:

  • When recommending a prebiotic, select those that provide a diverse array of prebiotics, rather than one in isolation – this allows a range of probiotics to be fueled.
  • The particular type of prebiotic included in a product should be supplied in the clinically proven dosage.
  • For patients new to prebiotics, or sensitive to soluble fibers, advise they build up use slowly to ensure tolerance
  • Select prebiotics that have lower dosage requirements to attain benefits with less chance of gastric distress.

But is there a best diet for mental health? For patients with depressive disorders, Dr. Mörkl recommends, dietary interventions, “such as the Mediterranean diet as an adjunct treatment, as there is enough evidence on the favorable effects. The major part of a Mediterranean diet consists of vegetables and fruit, which contain a range of prebiotics. Specific subtypes of probiotics and prebiotics are referred to as psychobiotics, which impact the gut-brain axis, and result in modifications of mood, anxiety and cognitive function.” Patients do not need to follow a one-size-fits-all dietary approach though, adds Dr. Mörkl, noting, “Possibly every other form of a balanced, plant-based diet with a basis of vegetables and fruit may have favorable effects (such as a traditional Norwegian or Japanese diet.”

Fermented foods may be recommended as well, including yogurt, kimchi, kefir, sourdough, tempeh, kombucha, and sauerkraut.14 Other foods that may help the body to produce prebiotics include dandelion greens, Jerusalem artichoke, garlic, leeks, asparagus, barley, oats, and flaxseeds.

While dietary intervention may be useful as an adjunct treatment for patients with MDD, Dr. Mörkl clarifies that they may be most helpful “as one of the first-line treatments for patients with mild depression, especially for that population for whom antidepressants seem to have little effect.”

She adds, “I think that dietary interventions should be used alongside psychotherapy and psychopharmacological interventions as an important pillar in the biopsychosocial treatment model for all forms of depression.”

Professional Takeaways

As research methodology improves and understanding of the gut health’s relation to not only inflammation but also to mood disorders grows, clinicians can incorporate measurable lifestyle interventions to guide patients toward sustainable improvements in both their physical and mental health. By working with the patient to improve gut health (in addition to ongoing therapy), there is potential to improve the individual’s quality of life while also treating the symptoms of major depressive disorder.

Key Points

  • The microbiota-gut-bran axis is composed of the central nervous system, neuroendocrine, and neuroimmune systems, and has garnered attention for its role in MDD via interaction with key neurological, immunological, and biological pathways.
  • Both animal and human research models point to the potential for an imbalanced gut microbiome to precipitate depression. More recent studies are beginning to link specific bacteria to mental health, with an emphasis on the ability of gut metabolites to synthesize monoamine neurotransmitters, such as dopamine.
  • Gut dysbiosis – the imbalance of good and bad bacteria in the human gut – has been linked to MDD. Dietary changes, combined with supplementation of pre- and probiotics may be a novel way to treat the whole patient, improving symptoms of depression and increasing markers of wellbeing.


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Last Updated: Dec 15, 2020