How Psychobiotics Support the Gut-Brain Connection

What Are Psychobiotics?

Psychobiotics are health-promoting microorganisms (probiotics) or compounds that support such microorganisms (prebiotics) which, when ingested, confer cognitive and mental health benefits to the host through their interaction with the gut microbiota [1]. To put it simply: psychobiotics are probiotics and prebiotics for the brain. 

Psychobiotics are probiotics and prebiotics for the brain.

Psychobiotics are able to influence brain function because the brain and the gut microbiota (good bacterias that help you digest food) are in constant crosstalk through the gut-brain axis. By modulating the composition or the metabolism of the gut microbiota, psychobiotics change signaling from the gut to the brain. And because this signaling impacts brain activity, it is a gateway to brain function, allowing psychobiotics to influence it in ways that may support cognition, healthy stress responses, mood, and emotional regulation. 

What Is the Gut-Brain Axis?

The gut-brain axis (also known as the gut-brain connection or microbiota-gut-brain axis) is a pathway of communication and mutual regulation between the brain, the gut, and the microbes in the gut (the gut microbiota). It’s an intricate system that involves the nervous, endocrine, and immune systems, as well as the gut microbiota and its gene products, metabolites, and signaling molecules (the gut microbiome) [2,3]. 

While the microbiota in our gut may seem innocuous, it actually plays a crucial role in our health. The sheer abundance of microbes in the human body, equaling the number of human cells, and their collectively vast genome [4] highlight the microbiota's significant impact. Their relevance goes beyond viewing it as a mere collection of harmless bacteria.These microbes are not just passive inhabitants of the gut, they’re collaborators with which we have a mutually beneficial relationship. The gut-brain axis is a key signaling system because it allows the brain to keep tabs on an immense ecosystem that contributes actively to human health. 

The gut-brain axis also links cognition and mental health to gut functions and microbial metabolism. It’s in this crosstalk that psychobiotics intervene.

In a sense, the gut microbiota is an extension of the human body, and therefore, the brain monitors and regulates its activity, as it does with any other part of the body. But the gut-brain-microbiota connection is about more than just housekeeping and maintaining homeostasis. Because it allows the gut microbiota to influence brain function [5], the gut-brain axis also links cognition and mental health to gut functions and microbial metabolism. It’s in this crosstalk that psychobiotics intervene. 

[For a more in-depth discussion of the gut-brain axis, check out our article series covering its communication pathways, its role in metabolism and energy homeostasis, and the influence of the gut microbiota on the immune system.]

How do the Gut and Brain Communicate?

The nervous, endocrine, and immune systems are the three major signaling systems that participate in the back and forth between the brain and the gut and in their mutual regulation [2,3,6,7]. 

The nervous system plays a particularly important part in this network. The gut has its own nervous system, the enteric nervous system (ENS), often called our “second brain.” In addition to controlling gastrointestinal functions, the ENS has an important role in sensing microbial, endocrine, and immune molecules and in signaling the physiological state of the gut to the central nervous system (CNS) [3]. 

Gut bacteria can either produce or stimulate the production of several neuroactive molecules that may activate the Vagus nerve.

The Vagus Nerve is the main route of communication between the ENS and the brain [8]. In addition to receiving input from the ENS, vagal nerve terminals can sense dietary components, microbial compounds, and other cues about microbial composition and activity [8,9]. Furthermore, gut bacteria can either produce or stimulate the production of several neuroactive molecules that may activate the ENS and Vagus nerve and influence brain function and behavior [10–12]. 

Role of the HPA Axis in the Gut-Brain Connection

The hypothalamic–pituitary–adrenal (HPA) axis is one of the main neuroendocrine pathways in the human body. The hypothalamus and the amygdala are two brain regions that receive and integrate information about the status of tissues and organs and devise responses to adjust physiological processes. Along with the adrenal gland, they form this signaling system that has a key role in maintaining homeostasis [13]. 

Among its many functions, the HPA axis is probably most recognized for its role as the primary neuroendocrine response system to stress and for its influence on mood and emotional regulation. The HPA axis can also modulate the activity of the immune system, regulate gut physiology and health, and influence the gut microbiota’s composition and activity in ways that are linked to its stress response actions [6,14–16]. 

This is also a two-way street. Microbial signaling molecules can also influence the activity of the HPA, either through activation of the ENS and the Vagus nerve or by direct action on relevant brain regions, such as the hypothalamus, which they may reach through the bloodstream [6,17,18]. They also influence neuroendocrine function indirectly by modulating the activity of the immune system and the production of immune signaling molecules that impact the activity of the HPA axis [5,14,19]. By influencing HPA axis signaling, the microbiota has a way into our mood and stress responses.

Role of the Immune System in Microbiota-Gut-Brain Communication

The gut is a very important organ from an immunological perspective. Not only does it contain trillions of friendly microbes (which, despite being friendly, still need to be kept under surveillance), it is also constantly exposed to possibly harmful microbes we may ingest. That’s why around 70–80% of the body’s immune cells are found in the gut, where they defend us against harmful microbes, but also allow the beneficial ones to thrive [20,21]. The immune system and the gut microbiota develop in parallel throughout life and form a close relationship of mutual influence and support.

70–80% of the body’s immune cells are found in the gut, where they defend us against harmful microbes, but also allow the beneficial ones to thrive.

However, the influence of the microbiota on the immune system goes beyond the gut. Microbial metabolites influence the development, maturation, and function of circulating and tissue-resident immune cells in different organs, and fine-tune immune responses throughout the body [22–24]. This includes the brain, where microbial metabolites are able to influence the activity of microglia, the predominant resident immune cells of the CNS [23]. Among their many functions, microglia regulate brain immune signaling, support neural function and communication, support synaptic plasticity, and are essential for cognition and mental health [23,25–27]. 

Figure 1:  Pathways of microbiota-gut-brain communication. Source: Del Toro-Barbosa, M. et al (2020). Nutrients, 12, 3896. Licence: CC BY 4.0

How the Gut Microbiota Influences Brain Function 

The gut microbiota produces a variety of molecules that may influence nervous, endocrine, and immune signaling. By doing so, it can modulate different aspects of brain function, including cognitive and mental health [2,5,7,28].  

For example, several gut microbes have the ability to either produce or influence the brain levels of neurotransmitters such as serotonin, dopamine, norepinephrine, and GABA, all of which have important roles in the regulation of mood, emotion, stress responses, and cognition [10,11,29–34]. 

Several gut microbes can either produce or influence the brain levels of neurotransmitters such as serotonin, dopamine, norepinephrine, and GABA, all of which have important roles in the regulation of mood, emotion, stress responses, and cognition.

The microbiota may also influence behavior by modulating brain-derived neurotrophic factor (BDNF) production in the CNS. BDNF is a neurotrophin well-known for its role in supporting neuroplasticity and cognitive function, but that also plays an important part in mood regulation [10,35–37]. 

Figure 2. Diagram of preclinical and clinical tests used to evaluate psychobiotic potential. GABA, gamma-aminobutyric acid; SCFAs, Short Chain Fatty Acids; MRI, magnetic resonance imaging. Licence: CC BY 4.0.

Gut microorganisms create a variety of important metabolites. Short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate, are one of the most studied metabolites. SCFAs have been linked to the modulation of mood and stress responses [38,39]. SCFAs may influence neural function by modulating neurotransmission, influencing levels of neurotrophic factors, and by stimulating the production of neuroactive gut hormones [10,40–43]. 

Unhealthy changes in the gut microbial ecosystem may manifest as poorer cognitive performance, impaired emotional regulation, negative mood states, and unhealthy stress responses.

Molecules produced by a healthy and balanced gut microbiota are part of normal neuroendocrine and neuroimmune processes and thus contribute to healthy brain function. However imbalances may dysregulate those same processes and lead to the activation of the HPA axis, increased production of stress hormones, changes in immune signaling, and changes in neurotransmitters and neuromodulator levels. This is why unhealthy changes in the gut microbial ecosystem may manifest as poorer cognitive performance, impaired emotional regulation, negative mood states, and unhealthy stress responses [6,44–49].

How Psychobiotics May Support Brain Function and Mental Health

Just as imbalances in the gut microbiota may impair brain function, restoring its balance or promoting the growth of beneficial microbial communities may help to support mental health, mood, and cognition. Stimulating the development of a healthy gut microbiota with psychobiotics can be the means to that end. 

Psychobiotics are a subset of probiotics and prebiotics that support brain function. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host [50]. Prebiotics are substrates that are selectively utilized by host microorganisms conferring a health benefit [51]. In the case of psychobiotics, the support they provide leads to health benefits specifically associated with brain function [5,28,52]. 

RESEARCH AND IMPACTS OF PSYCHOBIOTICS

The mechanisms of action of psychobiotics have been studied mostly in preclinical research, where, in general, they act by activating the gut-brain axis through the pathways we’ve discussed above: 

• Enhancing neurotransmitter production in the gut and brain [11,29–31]
• Modulating neurotransmission in the ENS [1,53] 
• Activating Vagus nerve signaling [54,55]
• Influencing HPA axis activity and physiological stress responses [1,54,55]
• Supporting gut barrier function and decrease detrimental immune responses  [56,57]
• Stimulating the production of SCFAs and gut hormones [1,58,59]
• Influencing brain BDNF levels [60]
• Minimizing stress-induced deficits in neuroplasticity and cognition [60–62] 

Findings from clinical studies stand in line with the mechanisms described in preclinical research. In humans, psychobiotics have attenuated the HPA axis response to stress [63], reduced cortisol levels (associated not only with stress but also with emotional disturbances) [64–67], elevated plasma levels of BDNF [68], modulated immune signaling [69], and modulated brain activity in a functional network associated with emotional processing [70]. 

In humans, psychobiotics have attenuated the HPA axis response to stress, reduced cortisol levels and modulated brain activity in a functional network associated with emotional processing.

Clinical studies have also shown that, through these actions, psychobiotics may support mental health, positive mood, healthy stress responses, and cognition [46,71–74]. For example, psychobiotics have had beneficial psychological effects in healthy individuals with self-reported negative mood and distress [64], relieved abdominal distress in medical students facing examination for academic advancement [66], promoted feelings of happiness in individuals with low mood scores [75], and impacted reactivity to sad mood by reducing rumination and aggressive cognition [76]. 

Psychobiotic Support in Daily Life: Qualia Synbiotic 

Qualia Synbiotic is a combination of prebiotics, probiotics, postbiotics, fermented foods, herbs, and digestive enzymes that work complimentary to support digestive health, gastrointestinal performance, the gut microbiota, the gut-immune axis, and the gut-brain axis.

We developed Qualia Synbiotic first and foremost to support gut health and gastrointestinal performance. But because of the many ways gut health and the gut microbiota influence healthy brain function, we were also focused on the brain end of the gut-brain axis. When we researched ingredients, we cared about their impact in the gut …and on the brain, especially in areas related to supporting cognitive performance, emotions, mood, and stress resilience. As an example, we looked for a probiotic that was also a psychobiotic. Bacillus coagulans MTCC 5856, also known as Lactospore®, stood out because it’s a clinically-studied psychobiotic. In a placebo-controlled study, Bacillus coagulans MTCC 5856 supported both mood and gut health [77]. That’s the main reason why it’s included in Qualia Synbiotic.

Qualia Synbiotic also provides a number of ingredients that we believe complement the psychobiotic action of Lactospore® by supporting the gut-brain axis and contributing to healthy brain function:

• SolnulTM Resistant Potato Starch supports gut-brain signaling through the Vagus Nerve [78].

• Sunfiber® Partially Hydrolyzed Guar Gum supports serotonin and dopamine signaling [79].

• Celastrus paniculatus Seed Extract was traditionally used as a brain tonic as well as for gastrointestinal health; it supports neurotransmitter systems [80–84] (most of which are involved in gut-brain signaling), neuroprotective functions [84–87], positive behavioral responses to stress [83,88,89], and gastroprotective functions [90].

• Berriotics™ Fermented Berry Blend is a postbiotic produced by fermenting ten berries—acerola, black currant, bilberry, cherry, chokeberry, cranberry, gooseberry, mulberry, raspberry and strawberry. Berries are rich in polyphenols, particularly flavonoids such as anthocyanins, flavanols, and flavanones, which contribute to cognitive health [2] and support gut microbiota [91].

• Fermeric™ is a  Fermented Turmeric Rhizome Powder. Turmeric supports cognitive function [92,93], positive mood states [94], and mental health [95]. Like Berriotics™, Fermeric™ is a postbiotic; they are both fermented by Lactobacillus plantarum and contain cells and metabolites from the fermentation process. Heat-killed Lactobacillus plantarum supports healthy stress responses [96–98] and cognitive function [97,98].

• N-Acetyl-D-Glucosamine is used for a process known as O-GlcNAcylation, which can alter the activity of enzymes or transcription factors and which is important for healthy brain function [99–104].

• Magnesium (from Aquamin® Mg) is crucial for healthy brain function [105,106], and is associated with mental well-being [107,108] and healthy stress responses [109–113].

Optimal Gut-Brain Health

Qualia Synbiotic is a one-of-a-kind formula that doesn't just promote a healthy gut. It also helps support mood and brain performance by enhancing gut-brain connections that are also crucial for nearly every system in the body. There’s never been one simple scoop of supplemental nutrition designed to support so many aspects of gut health, including the gut-brain axis.* Shop now.

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