Gut-Brain Axis: Understanding The Gut-Brain Connection

This "gut-brain connection" has become a popular area of investigation and has had immense implications for mental health. It is now evident that there is a distinct biological and physiological basis for psychological, neurodevelopmental, age-related, and neurodegenerative disorders that originates in the gut shifting the viewpoint of psychiatric illness.

Over the past 15+ years, research has been emerging to clarify how these trillions of the microorganisms within and on our bodies (microbiota) are key regulators of mood through their interaction with the brain.

In this article, we dive deep into how our gut microbiome affects our mood in both positive and negative ways.

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What is the Gut-Brain Axis

This dynamic bi-directional relationship between our bellies and brains is termed the "gut-brain axis."  

As humans provide a home for the microbes that inhabit the gut, these microorganisms have evolved to return the favor and establish a mutually beneficial (symbiotic) relationships with their hosts. As they digest our food to meet their own nutritional needs, they also provide energy, nutrients, and neuroactive metabolites, such as neurotransmitters and their precursors, which serve as signaling molecules to the brain. In response, the brain translates these signals and sends chemical messages to modify the nervous system, inflammation, and other bodily processes.

The little microbes that inhabit our body impressively produce over 90% of the body's serotonin and a majority of other metabolites and neurotransmitters that influence cognitive health. They also interplay with our nervous system and minds in many other ways.

How Our Gut and Brain Communicate

The communication between our microbiota and our brain occurs via several mechanisms. These include the routes of (1, 5, 7-10)

The Immune System

70% of immune cells are present in the gut. An individual's diet and lifestyle directly influence the gut microbiome. The foods we eat affect the diversity and composition of bacteria in the gut, which in turn influence immune cells. A healthy diet and lifestyle support good bacteria that increase immunity. While on the other hand, stress and an inflammatory diet can increase harmful bacteria lowering systemic immune response and increasing inflammation.

Tryptophan Metabolism

The digestion of dietary proteins in the small intestine leads to the release of tryptophan, which can be absorbed through the intestinal wall and then enters the bloodstream. Tryptophan is a precursor to serotonin and the building block to melatonin and vitamin B3, which are essential in sleep and brain function.

Vagus Nerve

The vagus nerve extends from the brainstem through the neck down to the abdomen. It is similar to a "highway system" that transports communication from the gut to the brain and vice versa.

Enteric Nervous System

The enteric nervous system is the neurons and supporting cells of the gastrointestinal tract. Because the enteric nervous system relies on the same type of neurons and neurotransmitters found in the central nervous system, some medical experts call it our "second brain."

The gut-brain axis is a communication highway between the central and the enteric nervous system, linking stress responses to intestinal functions. This is commonly associated with "nervous gut" or "that gut feeling."

Short Chain Fatty Acids

Microbial metabolites from fiber (short-chain fatty acids SCFAs), protein (branched-chain amino acids), and peptidoglycans (components of the bacterial cell wall). These breakdown products serve as signaling molecules that impact various processes in the body.

Gut Bacteria and Neurotransmitters Production

Our gut bacteria and brain both produce and respond to the same neurochemicals. These include GABA, serotonin, norepinephrine, dopamine, acetylcholine, and melatonin (a byproduct of serotonin), which all play a role in mood and cognition.

Below is an overview of these different neurotransmitter and neurohormones and which gut bacteria produce them.

Serotonin

Serotonin, and its precursor, 5-hydroxytryptamine (5-HT), have a toning effect on the nervous system. It is an inhibitory neurotransmitter because it decreases the signaling propagation down the nerve. It is believed to play a role in emotion, mood, digestion, appetite, sleep, sexual behavior, temperature regulation, pain perception, blood clotting, and bone health. It also can act as a hormone. (12-13)

Our gut microbiota produces over 90% of the body's serotonin. Impaired absorption and breakdown of food reduce our ability to build serotonin.

Although serotonin cannot cross the blood-brain barrier, its precursor, tryptophan, can. Cells within the intestine (enterochromaffin cells) break down dietary protein containing tryptophan to convert it to serotonin through various enzymatic pathways.

Spore-forming bacteria in the gut (predominantly Clostridia) and staphylococci both have been shown to make serotonin as a result of chemical signals in the body that indicate alterations in serotonin. (2, 14)

Dopamine

Dopamine is a neurotransmitter made from l-tyrosine that produces both excitatory and inhibitory effects on the nervous system. It impacts both physical and behavioral functions. Dopamine is involved in motor control, motivation, reward, cognitive function, maternal, and reproductive behaviors. It also plays a role in reward, anticipation, motivation, alertness, focus, mood, memory, addiction, lactation, pain processing, heart rate, and kidney function. (15-17)

As a hormone, dopamine and its precursor, one of our main catecholamines (made by the adrenal glands), norepinephrine (NE), are released into the body in response to stress.

Besides its function in the fight-or-flight response, as a hormone, dopamine also causes blood vessel vasoconstriction or vasodilation, slows gut transit time, protects the gastrointestinal lining, and regulates immune function. (16, 18)

Like serotonin, dopamine cannot pass through the blood-brain barrier. It is made within the brain in the substantia nigra and ventral tegmental areas. The gut is responsible for 50% of dopamine synthesis, and dopamine receptors are found throughout the intestine, impacting its function. Dopamine production has been detected in Staphylococcus, which converts its precursor, l-3,4-dihydroxy-phenylalanine (l-DOPA), to dopamine by an enzyme expressed by these bacteria.

GABA

GABA (gamma-Aminobutyric acid) is the most common inhibitory neurotransmitter, slowing down signals in the central nervous system. It has a calming effect and is thought to dampen nerve cell hyperactivity linked to fear, stress, and anxiety. GABA also plays a role in sleep and is related to attention and alertness.

GABA has two forms of receptors, GABA A and GABA B. Both decrease nerve cell responsiveness. GABA can reduce Beta brain waves, which are linked to focus and concentration, and increase Alpha brain waves which are associated with a relaxed state.

In the brain, GABA is produced by GABAergic neurons that convert glutamate into GABA using the enzyme glutamic acid decarboxylase. Bacteroides fragilis, Parabacteroides, Eubacterium, and Bifidobacterium also synthesize GABA in the gut.

Since GABA does not cross the blood-brain barrier, gut microbe-derived GABA is believed to act locally on the enteric nervous system or the vagus nerve. Furthermore, carbohydrate metabolic byproducts of microbiota in the colon, such as acetate, can cross the blood-brain barrier. These metabolites can be incorporated into the GABA metabolic cycle, preferentially in the hypothalamus in the brain.

Acetylcholine

Acetylcholine is an excitatory neurotransmitter that affects both parts of the nervous system, the central and peripheral nervous systems. It is the primary neurotransmitter of the parasympathetic nervous system, a part of the autonomic nervous system (a branch of the peripheral nervous system related to regulating automatic body processes such as digestion and breathing). It plays a role in contracting smooth muscles and dilating blood vessels. It also increases bodily secretions and slows the heart rate. It also is involved in various mental processes, such as memory and cognition. Imbalances in acetylcholine have been linked to dementia and Alzheimer's disease. (3, 20-21)

Acetylcholine is synthesized from the nutrient choline. Like the previous neurotransmitters, acetylcholine must be synthesized in the brain from choline transported through carriers in blood cells. Acetylcholine has been shown to be produced by multiple bacteria in the gut, including Bacillus acetylcholine. Lactobacillus plantarum, Bacillus subtilis, Escherichia coli, and Staphylococcus aureus. B. subtilis forms larger quantities of acetylcholine than E. coli or S. aureus. This form of acetylcholine acts in the enteric and peripheral nervous systems.

How Gut Inflammation Affects Mood

The fascinating role that inflammation plays in psychiatry has recently received increasing attention. Studies have established a link between higher inflammatory markers and their metabolites and depression. It has also been demonstrated that the administration of inflammatory triggers has been associated with the development of depressive symptoms.

These inflammatory mediators have the potential to interact within multiple pathways that can result in mood shifts and depression. These include their effects on monoamine neurotransmitter metabolism, neuroendocrine function, synaptic plasticity in the neurons, and the various neurocircuits related to mood regulation. For these reasons, pharmacological treatments that aim at modulating inflammatory mediators have been under investigation for the treatment of depression. (22)

Various factors such as psychosocial stress, diet, inflammatory adipose tissue, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells can all contribute to inflammation in the brain. This low-grade chronic neuroinflammation is believed to play a crucial role in forming a basis for the interaction between psychological stress, impaired gut microbiota, and major depressive disorder. (22-23)

Microbes can produce metabolites that enter circulation, alter the inflammatory tone in the gut, periphery, and central nervous system (CNS), and signal the trafficking of immune cells into the brain. Furthermore, the vagus nerve has been shown to modulate brain immune responses.

Some specific bacteria in the gut have been shown to have an essential role in the immune response, including inflammation. This is more evidence of when dysbiosis (an imbalance in commensal microbes, including an overgrowth of pathogens) can cause inflammation in the gut and eventually lead to a leaky gut, causing systemic inflammation. Gut dysbiosis and leaky gut have both been linked to psychiatric disorders.

Functional Medicine Lab Test to Consider When Focusing on Gut-Brain Axis

Comprehensive Stool Test

Assessing for dysbiosis and digestive health is imperative to establish a healthy microbiome that can foster a balanced mood via the gut-brain connection.

Comprehensive stool tests offer a complete look at gut health by measuring pathogens and analyzing digestion, nutrient absorption, inflammation, and immune function, all of which impact the gut-brain axis.

Neurotransmitter Test

Due to the bi-directional relationship between the gut and the brain, calming the mind by supplying it with proper neurotransmitter balance can modulate mood and may impact the gut through the vagus nerve pathway.

Micronutrients

Over time, micronutrient-related malnutrition can lead to mental health and mood disorders. Micronutrients serve as cofactors in enzymes that help produce amino acids and neurotransmitter formation in the gut and brain. (26-27)

The Cellular Micronutrient Assay by Cell Science Systems includes measurements of nutrients implicated in balancing mood, including B vitamins.

Omega Index

A large body of research demonstrates correlations between essential fatty acids, brain development, and mood and behavior outcomes. Furthermore, lower levels of omega-3s have been shown to impact the brain's dopaminergic centers. Omega-3s are also being studied for their role in serotoninergic signaling. Finally, they play a role in modulating inflammation affecting mental health (31-32), and fatty acids have been linked to microbiota diversity. (33-34)

Measuring Fatty Acids, and the Omega-3 index can indicate dietary intake and if one needs additional supplementation.

3 Types of Food That Help Increase Mood

Foods High in B Vitamins (Neurotransmitter Precursor)

In a recent review, B vitamins were also shown to modulate stress response and benefit people at risk for mood issues due to deficiencies. In one study, vitamin B6 was shown to reduce anxiety symptoms believed to be related to its role in GABA production. (26-27) Furthermore, B vitamins, especially vitamin B12, have been linked to better memory. (33-35)

Foods high in B vitamins include: (33)

• Whole grains
• Eggs (especially high in pantothenic acid (B5) and Cyanocobalamin (B12))
• Legumes
• Citrus fruits
• Avocados (1 cup of avocados contains 30% of the daily requirements for folate requirement and 23% of vitamin B6.)
• Meat, Poultry, Fish
• Liver
  

Food High in Magnesium (Neurotransmitter Precursor)

Magnesium supports nerve transmission and neuromuscular conduction and plays a protective role against excessive neural excitation. Magnesium levels have been linked to various mental and neurological health conditions.

Foods high in magnesium include:

• Nuts and seeds
• Legumes
• Fiber-rich grains
• Green leafy veggies
• Dark Chocolate
  

Foods for Feeding the Microbiome

Fermented foods, such as yogurt, kefir, kimchi, tempeh, and sauerkraut, contain microbes that support healthy brain activity.

High fiber foods, including whole grains, fruits, vegetables, nuts, and seeds, contain prebiotics which are good for your bacteria and help to produce short-chain fatty acids. Fiber is a form of prebiotics that can feed the bacteria that modulate brain activity and neural signaling. (39-40)

Polyphenol-rich foods, including cocoa, green tea, olive oil, and coffee, contain plant chemicals digested by your gut bacteria to support healthy microbe balance and brain health. (41-42)

Herbs & Supplements That Help the Gut-Brain Axis

Probiotics

Several studies have supported the role of probiotics in modulating mood and brain health. (43-49 ) A team of researchers reviewed 21 studies that included 1,503 people. 14 of the 21 studies used probiotics as interventions, and seven chose non-probiotic interventions, such as diet, to regulate intestinal microbiota (IRIFS).

A more recent study showed that an eight-strain probiotic supplemented with treatment as usual (TAU) produced better results than TAU and placebo for depression.

Finally, in another study, "probiotic administration for four weeks was associated with changes in brain activation patterns in response to emotional memory and emotional decision-making tasks, which were also accompanied by subtle shifts in gut microbiome profile." (49)

Specific probiotics have been labeled "psychobiotic," "a live organism that, when ingested in adequate amounts, produces a health benefit in patients suffering from psychiatric illness." These bacteria can produce neuroactive substances, including GABA and serotonin, and act on the gut-brain axis. (50-51) They have produced positive effects in some clinical trials in patients with irritable bowel syndrome (IBS), including Bifidobacterium infantis.

Herbs

Recently it was found that there is an interaction between the gut microbiota and herbal medicines through two pathways. First, the gut microbiota "digests" the herbal medicines into absorbable, active small molecules which produce biological changes. Secondly, herbal medicines alter the composition of the gut microbiota and its secretions, leading to physiological changes.

For example, many herbs contain polysaccharides which cannot be digested by regular digestive processes. Therefore, specific microbes, such as Bifidobacterium and Bacteroides, can secrete various enzymes to break them down into smaller metabolites that can have various impacts on the body.

Some herbs that have shown to benefit mood include ashwagandha for stress and anxiety, St. John's Wort for depression (showing superiority to placebo and equal effectiveness to medications), Rhodiola for stress and depression, and saffron for depression (56-57).

Supplements

Supplements to support mood that also supports the gut include the nutrients mentioned above: b-vitamins (26-27, 33-35) and precursors, magnesium (36), and fish oils (28-34).

Lifestyle Changes That Help the Gut-Brain Axis

Exercise

Exercise has been shown to alter the microbiome and has evidence for changing brain neurochemistry to support mood. (58-60)

Sleep

Sleep has been found to alter the microbiome and is very important for overall mental health. At least 7-8 hours of sleep are optimal for most adults.

Stress Reduction

A recent review found that stress management techniques had beneficial effects on inflammatory activity, anxiety status, and quality of life in IBD patients. The gut-brain connection significantly impacts irritable bowel disease (IBD) patients.

Summary

Our moods are not just stemming from our brains. We literally have "gut feelings" that are not human-oriented but rather microbial-based. Bi-directional communication from our gut to the brain occurs through various pathways, including how microorganisms produce and assimilate neuroactive compounds, modulate inflammation, and interplay with the vagus nerve.

Integrative medical practitioners can now work with conventional mental healthcare to ensure that the biological and neurological support of the gut-brain is addressed to improve efficacy in treatment. This can be done through diet, nutrients, herbal approaches, and lifestyle.