Gut Microbiome (Gut-Brain Axis) and Depression – Pathophysiology | Role of Pre and Probiotics

In the human gut, there are 12 different phyla of which over 90% is made up of Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes.

Firmicutes, in particular, have been shown to have significant phyla differences between patients with depression and healthy controls. [Jiang et al. 2015]

Although there is a paucity of data from studies that have enrolled patients with psychiatric illness, the first population-based study was published in February 2019. This study investigated whether there were any correlations between specific gut bacteria and depression in a Flemish population cohort (n=1,054). [Valles-Colomer et al. 2019] In this study:

• Faecalibacterium and Coprococcus bacteria were consistently associated with higher levels of quality of life.
• In addition, Dialister and Coprococcus were significantly depleted in cases of depression.
• These results were also validated in an independent population (n=1,063) from the Netherlands and a cohort of depressed patients from a hospital in Belgium.
• Furthermore, the investigators detected the presence of the microbial dopamine metabolite, 3,4-dihydroxyphenylacetic acid, and showed that its presence correlated with a better quality of life scores.

Other evidence suggests that certain bacterial strains are associated with specific depressive symptoms. [Liu L & Zhu G, 2019]

• The total number of bacteria are predictive of insomnia and high depression score on QIDS-SR (Quick Inventory of Depressive Symptomatology)
• Reduced Enterobacteriaceae is predictive of high anxiety scores on GAD7 (Generalised Anxiety Disorder -7)
• Lactobacillus/Enterococcus is positively related to psychomotor agitation items in QIDS-SR and GAD-7 in depressed patients.

A systematic review by Cheung et al. examined 5 phyla in depression —Bacteroidetes, Firmicutes, Actinobacteria, Fusobacteria, and Proteobacteria. They found:

These findings add considerable weight to the unique dysbiotic relationship between the gut microbial community (and microbial metabolites) with intestinal inflammation and reduced quality of life and mental wellbeing.

The microbiota hypothesis posits that MGB axis dysfunction forms an important part of the pathological basis of MDD.

The bidirectional relationship between the gut and brain (down-top influence) and the brain and the gut (top-down influence) highlight that MDD is a systemic disease characterized by both brain and peripheral dysfunction. [Maqsood and Stone 2016]; [Yarandi et al 2016]; [Liang et al 2018]; [Liu and Zhu 2018]

1.HPA Axis

The gut microbiota are mediators of the stress response and their associated sequelae.

Although the microbial ecosystem is remarkably resilient (state of equilibrium), persistent stress may disturb their relative stability as the community shifts over time to a new equilibrium.

Stress-induced changes can collectively alter the composition, function, and metabolic activity of the gut microbiota.

Cortisol release during acute stress is a natural biological response to the presence of stressors whereas chronic stress is a maladaptive process characterised by a dysfunctional HPA axis. Acute stress has a limited effect on the gut microbiota however chronic stress may cause a clinically meaningful imbalance in the microbial community [O’Mahony et al 2009]; [Allen et al 2017]:

• With increased levels of cortisol, there is an increase in the permeability of the gut wall (leaky gut), which then facilitates a systemic inflammatory response.
• A leaky gut drives a proinflammatory state as evidenced by increased levels of circulating TNF-α, interferon-γ, and IL-6.
• IL-6 is known to activate the HPA axis and over time it also down-regulates glucocorticoid receptors. These receptors are a feedback mechanism that suppresses the HPA axis, however, their downregulation results in a hyperactive and overly sensitive HPA axis.
• Evidence also suggests that these changes cause a reduction in hippocampal serotonin as well as a reduction in BDNF expression, all of which increase the susceptibility to depression. [Liang et al 2015]

Finally, it has also been shown that stress can directly model the gut microbiota composition. Evidence suggests that maternal stress can alter vaginal microbiota, which then has downstream implications for the microbiota profile in the offspring. [Jašarević et al 2015]

2. Bioactive Neurotransmitters

There is accumulating evidence that bacteria secrete neuroactive compounds that have psychiatric properties that can affect sleep, appetite, mood, and cognition. [Tang et al 2014]

These neuroactive compounds can act locally on the enteric nervous system as well as act directly on the brain either by crossing the blood-brain barrier or communicating through vagal chemoreceptors. [Vitetta et al 2014]

• Lactobacillus can secrete acetylcholine
• Candida, Streptococcus, Escherichia coli, and Enterococcus can secrete serotonin
• Bacilli and Serratia can secrete dopamine

Although much of this research has taken place in the laboratory, the evidence seems to suggest that these neurotransmitters can modulate synaptic activity.

However, further research is necessary to determine whether these compounds have psychotropic properties at pharmacological concentrations in humans.

3. Short Chain Fatty Acids (SCFAs):

Short-chain fatty acids (SCFAs) are the main metabolites produced by the microbiota in the large intestine through the anaerobic fermentation of indigestible polysaccharides such as dietary fibre and resistant starch.

SCFAs serve a number of functions:

• SCFAs influence intestinal mucosal immunity, and barrier integrity and function.
• SCFAs interact with receptors on enteroendocrine cells which release gut hormones (e.g glucagon-like peptide 1 (GLP1), peptide YY (PYY)) and neurotransmitters (5-HT, GABA).
• SCFAs induce T-regulatory cells (Tregs) differentiation and influence inflammation by regulating interleukin secretion.
• SCFAs influence systemic inflammation mainly by inducing T regulatory cells (Treg) differentiation and by regulating the secretion of interleukins.
• SCFAs can cross the blood-brain barrier (BBB) and influence neuroinflammation by affecting glial cells, modulating levels of neurotrophic factors, increasing neurogenesis, contributing to the biosynthesis of serotonin, and improving neuronal homeostasis and function. [Silva Y et al., 2020]

4. BDNF

Brain-derived neurotrophic factor (BDNF) is an important neurotrophic substance vital to the survival and maintenance of neurons associated with emotion and cognitive functioning.

There is clear and consistent evidence that alterations to BDNF levels in limbic structures play a key part in depressive neurobiology. [Duman and Monteggia 2006]; [Dawood et al 2007]; [Duclot and Kabbaj et al 2015]

• Bifidobacterium can increase BDNF in the hippocampus
• Increasing Lactobacillus levels can increase BDNF expression in the brain
• Administering prebiotics (i.e. fructo-oligosaccharide and galacto-oligosaccharide) can increase BDNF levels in the hippocampus

5. Vagus Nerve

The intestinal nervous system consists of 200-600 million neurons. It has therefore been given the term ‘Second Brain’. 

These neurons are controlled predominantly by the vagus nerve and thus the vagus nerve acts as the primary connection between the brain and proximal intestinal tract.

• L. rhamnus regulated behavioural and physical reactions through the vagus nerve, by regulating GABAAα2, GABAAα1, GABAB1b receptors mRNA expression which are anxiety-related receptors.
• Increased intestinal vagal nerve activity can lead to enteric neuroinflammation which can lead to anxiety
• Probiotics administration in animal studies showed antianxiety effects mediated by vagal nerve.

6. Lipopolysaccharides

Lipopolysaccharides (LPS) are a proinflammatory endotoxin that is a component of the outer membrane of Gram-negative bacteria.

LPS can trigger an inflammatory response that has been associated with anxiety, depression, cognitive deficits, and visceral pain. [Maes 2008]; [Stevens et al 2018]

• If too much LPS passes the intestinal barrier (leaky gut) and into circulation, then there is an inflammatory cytokine cascade characterized by the production of IFN-γ.
• The inflammatory response caused by LPS increases indoleamine 2,3 dioxygenase (IDO), an antimicrobial enzyme that catabolises tryptophan (tryptophan is an essential amino acid for many microbial pathogens).
• Tryptophan is degraded by IDO into kynurenine and the kynurenine pathway has been connected to a number of psychiatric disorders, including depression.
• Not only does the kynurenine pathway reduce tryptophan availability for serotonin but there is also the production of oxygen radicals and potent neurotoxins. [Reus et al 2015]

7. Micronutrients: 

Gut microbiota produces water-soluble vitamins and affects the intestinal absorption of micronutrients.

Dysbiosis therefore could result in a deficiency of micronutrients contributing to depression.

• For example, Bifidobacterium, among the genera that were less abundant in MDD in reviewed case-control studies, can synthesize riboflavin, niacin, and folate.
• Folate deficiency is associated with depression and methyl folate augmentation is efficacious in depression.

8. Antibiotics

In a large population study, researchers examined the risk of depression, anxiety, and psychosis after a single antibiotic course. What they observed was that microbiota dysbiosis caused by recurrent antibiotic exposure increased the risk of depression and anxiety but not psychosis. [Lurie et al 2015]

In general, antibiotic usage reduces gut microbiota diversity and increase the susceptibility to pathogen colonisation. Different antibiotics differentially affect the gut microbiota although most antibiotics will induce a stress response in commensal bacteria. [Maurice et al 2013]

• Ciprofloxacin reduces diversity and depletes the abundance of multiple beneficial taxa including Bifidobacterium. These effects can persist for several weeks to a year in healthy adults.
• Azithromycin causes a transient reduction in the diversity of the Firmicutes phylum in adults, although this effect is more pronounced and deleterious in children.
• Maternal intrapartum antibiotic prophylaxis (ampicillin and gentamicin) for Group B Streptococcus is associated with long-term infant gut microbiota dysbiosis regardless of the mode of delivery. [Azad et al 2015]

The evidence in the literature therefore suggests that broad-spectrum antibiotic administration can induce perturbations to gut microbiota composition and that this can persist for months to years.

Antibiotics and gut microbiome 

Dietary prebiotics are defined as

The following criteria are used to classify a compound as a prebiotic:

• Should be resistant to acidic pH of the stomach, cannot be hydrolyzed by mammalian enzymes, and also should not be absorbed in the gastrointestinal tract.
• Can be fermented by intestinal microbiota
• The compound can selectively stimulate growth and/or activity of the intestinal bacteria, and this process improves the host’s health.

Probiotics: 

• That microbes must be alive in an adequate number when administered.
• Strains must be identified genetically, classified using the latest terminology, and designated by numbers, letters, or names.
• Appropriately sized and designed studies must be performed to designate a strain as probiotic and using the strain(s) on the host to which the probiotics are intended (human, livestock, companion animal, etc.).
• Strains shown to confer a benefit for one condition may not be probiotic for another application.
• Strains that are probiotic for humans but are being used in animal studies should be clearly designated as human probiotics under experimental testing.

Potential mechanisms of action for pro and prebiotics include:

• Regulating the capacity of intestinal microbiota
• Preserving the integrity of the intestinal barrier (preventing leaky gut)
• Preventing bacteria translocation and regulating local inflammatory reaction through the intestinal related immune system

Evidence suggests that daily consumption of a probiotic supplement could have a positive effect in improving the mood, anxiety, and cognitive symptoms present in MDD.

Probiotics may have the most significant effect on symptoms of anxiety, which is often co-morbid with MDD. [Wallace & Milev, 2017].

According to the systematic review: 

A more recent systematic review in 2020 of 7 studies which included 12 probiotics concluded: [Noonan et al., 2020]

1.Isolate Prebiotic Therapy for patients with clinically recognised depression:

• unlikely to affect an individual’s experience of their condition in a quantitatively evident way

2.Isolate or adjuvant probiotic/combined prebiotic–probiotic therapy

• may offer a quantitatively measurable improvement in parameters relating to depression.

No worsening of parameters of anxiety or depression were observed in any of the studies.

The gut microbiota is strongly associated with MDD and this relationship stems from the bidirectional MGB axis that connects the brain with the gut.

It is hypothesised that alterations to the diversity and composition of the gut microbiota may be a risk factor for developing MDD, which in turn may play a role in symptom severity.

Research supports the notion that specific bacterial species are linked to depressive behaviours and therefore there is substantial clinical potential for the development of gut microbial profiles related to depressive disorders.

Prebiotics and Probiotics may be potential treatment options for depression however more reseach is needed.

Furthermore, no consensus has arisen about specific bacterial strains and depression, some authors suggest that studying microbial functioning may be more productive than a purely taxonomic approach to understanding the gut microbiome in depression. [Cheung et al., 2019]

Learn More: 

1. Simplified Guide to the Gut-Brain Axis
2. Maternal – Infant relationship – The role of the Gut-Brain Axis. – Prof Anne Buist. (Video)
3. Diet and Gut Microbiome in Depression by Prof Michael Berk. (Video)