The Microbiome-Gut-Brain Axis

What happens in our gut may have a profound impact on what happens in our brain. The relationship is thought to be so profound that the term microbiome-gut-brain axis has been coined to describe it.

You’ve probably heard before that migraine has strong ‘genetic’ links. Which is true, however genes are only part of the puzzle when it comes to migraine. [1]

In identical twins for example, only in 20% of cases will you see both twins suffer from migraine attacks. [2] That leaves a huge component up to other environmental factors.

An environmental factor that could be playing a significant role are the microorganisms in our gut called the gut microbiota (previously known as ‘gut flora’). [1]

Researchers are edging closer to understanding how gut microbiota can potentially influence conditions like depression, autism, epilepsy, and migraine.

What is the microbiota?

Microorganisms like bacteria are invisible to the naked eye, but we contain trillions of them on and inside us

Like other mammals, humans literally have trillions of microorganisms which live on our skin and inside our bodies.

The entirety of all these microorganisms that live on and inside us are called our microbiota.

Now before you run off to have a long shower to begin scrubbing urgently to try to get rid of them… It’s important to understand that having microorganisms is entirely normal and even important to our health.

The microbiota is made up of trillions of cells including bacteria, viruses, and fungi.

Note: the gastrointestinal (GI) tract is referred to here as the “gut” for simplicity in this article.

What is the microbiome?

In the same way that humans have genes which tell our cells what to do, so does each microorganism.

The collective genomes of all the microorganisms in our microbiota is the microbiome.

The microbiota are the cells of microbes or microorganisms (same thing). The collective genome of all them together is the microbiome.

This is a great 4 minute video explanation with visuals that make it easy to understand:

Why do we have gut bacteria?

Rapid colonization of the gut bacteria and microbiota is an inevitable consequence of living as a mammal. All mammals share this in common.

In humans, it is currently debated whether an infant’s gut is completely sterile at birth. Nevertheless, a rapid increase in microbiota begins from childbirth.

An infant’s gut microbiota is also influenced by breastfeeding. For example Gut Microbiota Worldwatch claims that breastfed babies have Bifidobacteria – considered a friendly bacteria which benefits the gut – whilst babies reliant on formula are likely to have less of these bacteria.

Our microbiota will continually evolve from birth through to old age and will be influenced by things like the food we eat, the air we breathe and other environmental factors.

We share a symbiotic relationship with our microbiota. Having microorganisms is beneficial for us and the more diverse our microbiota, the better.

A Canadian study found that infants with less diverse gut microbiota at 3 months were more likely to have food sensitivities to eggs, milk, and peanuts by 12 months. [42]

This indicates that a lack of diversity may lead to food allergies later in life. [42]

3 benefits of the microbiome

The microbiome is considered to have 3 major categories of functions. [12]

1. It defends against pathogens or bacteria or viruses which can cause disease by providing competition for nutrition in the gut. It also helps prevent pathogens from colonizing the gut through the production of antimicrobial substances and it helps detoxify harmful compounds.
2. It strengthens the intestinal walls called the epithelial barrier which limits bacterial penetration into tissues as well as mucus secretions of substances (IgA) to protect the intestinal walls from toxins and pathogenic microorganisms.
3. It helps absorb nutrients by metabolizing indigestible food compounds. It also helps produce vitamins and other nutrients; it keeps our gut healthy and balances our immune system.
   • Interestingly, studies conducted in germ-free animals found lower digestive activities and muscle wall thickness. [13]
   • The most recent trend of research has focused on the fourth role of the gut microbiome.
4. Guiding the mature development and functionality of the immune system

Facts about the microbiome & microbiota

• We have around 100 trillion of these microorganisms on or inside us.
• They outnumber our human cells by at least 10 to 1.
• The biggest microorganism habitat resides in our gut. Other locations include our skin and mouth.
• Much of the microbiota live with us in a symbiotic relationship that is mutually beneficial. There are also opportunistic pathogens that can invade us and cause disease or other health problems.
• Two-thirds of the gut microbiome is unique to each individual.

How the microbiome can impact our health & brain

The science in this field is still in its infancy but there are some very interesting initial findings.

We know that over 25 different diseases are associated with changes in the composition of the gut microbiota.  [1] These include inflammatory bowel disease (IBD), allergy, diabetes, IBS, and obesity.

A growing body of research is mounting mostly from animals, showing that microbes in the gut can influence behavior and alter brain physiology and neurochemistry. [37]

In humans, researchers have drawn links or correlations to conditions such as: [37]

• anxiety
• depression
• autism
• schizophrenia
• multiple sclerosis [38]
• neurodegenerative disorders

How does the gut affect the brain?

Think back to the last time you had butterflies in your stomach… you might be at a job interview, speaking to a large audience or just really excited about something…

That sensation in your gut is coming from a commonly overlooked network of neurons which line our intestinal walls. This mass of neural tissue is so extensive that some scientists have nicknamed it the second brain “second brain”.

This second brain controls digestion which is a complicated and sometimes dangerous business. As well as controlling the entire digestion process and internal muscle coordination, it also maintains the biochemical balance and composition required for the digestive enzymes to function.

Where things can be dangerous is with what we eat and drink. Potentially harmful bacteria or viruses need to be stopped before they penetrate the body. If a pathogen crosses the intestinal walls, immune cells in the gut lining secrete inflammatory substances including histamine. These are picked up by the second brain and can trigger diarrhea and/or vomiting.

Technically, the second brain is known as the enteric nervous system. It contains around 100 million neurons. That’s more than the spinal cord or the peripheral nervous system.

It travels along the walls of the long tube of the gut all the way from our esophagus to the colon. The enteric nervous system enables us to control the daily grind of digestion independently of the brain.

Scientists were shocked to discover that around 90% of the fibers in the vagus nerve carry information from the gut to the brain and not the other way around.

The gut has been implicated in a variety of brain disorders.

Parkinson’s disease is where problems with movement and muscle control are caused by a loss of dopamine-producing cells in the brain. Interestingly, there is around the same amount of dopamine in the gut as there is in the brain, according to Emma Young from the New Scientist.

Researcher Heiko Braak at the University of Frankfurt, Germany found that it’s the clumps of protein that cause damage also appear in the dopamine-producing neurons inside the gut.

After performing several autopsies, Braak believes Parkinson’s may actually begin in the gut the result of an environmental trigger, like a virus, which then spreads to the brain via the vagus nerve.

Similarly, Alzheimer’s patients have plaques or tangles which characterize their condition. These are found in the brain and are also present in the neurons within the gut.

The gut-brain Axis

The brain and the gut are intimately connected through neural, hormonal and immune pathways. Not only does information travel from the brain to the gut. But we now know that information also passes from the gut to the brain. The transfer of information is bidirectional. [3,4]

How this works exactly is not 100% clear yet to scientists [37] even with the vagus nerve but there are a number of very exciting areas for researchers to pursue:

1. Neurotransmitters

Cells in the gut produce large quantities of serotonin which is a neurotransmitter. This may have a signaling impact on the brain. Serotonin is manipulated in several migraine treatments.

Another neurotransmitter that is heavily influenced by the gut is GABA. GABA inhibits signals from nerves cells which help calm down activity of the brain.

Researcher Philip Strandwitz from Northeastern University, Boston found gut bacteria which fed on GABA molecules. GABA has been implicated in neuronal hyperexcitability which is thought to play a key role in migraine. [40] Low levels of GABA have also been associated with anxiety and depression.

2. Immune System

The gut microbiota can prompt immune cells to produce chemicals called cytokines which can affect our neurophysiology in a variety of different ways.

Some cytokines can act on the pain receptors in the trigeminal nerve which can cause migraine. [1]

In times of stress, cytokines can keep our immune system on high alert.  This is ideal for short bouts of ‘fight or flight’ responses that our ancestors faced when attacked by a predator.  Today, however, chronic stress can keep inflammation cycling throughout the body. If left unabated it can lead to the development of depression, anxiety, high blood pressure, multiple sclerosis (an autoimmune disease) and potentially even cancer. [43]

Has being sick ever triggered a migraine for you? If so, there’s a good chance inflammation and stress played a role.

3. Bacterial molecules

Microorganisms can produce metabolites which can affect the activity of cells in the blood-brain barrier. Butyrate is one example. [37]

With so much potential and so much still unknown, research funding has ramped up.

• The US National Institute of Mental Health has funded 7 pilot studies to examine the ‘microbiome-gut-brain-axis’. The studies receive up to $1 million each over the past 2 years.
• The US Office of Naval Research in 2016 is investing $14.5 million over the next 6-7 years to evaluate the gut’s role of the in cognitive function and stress responses.
• The European Union is putting €9 million (US$10.1 million) into a 5 year project aimed at brain development and disorders called MyNewGut.

Can the microbiome affect stress, anxiety, and depression?

Emeran Mayer, Professor of Physiology, Psychiatry and Biobehavioral Sciences at the David Geffen School of Medicine at the University of California, Los Angeles (U.C.L.A.) suggests that “a big part of our emotions are probably influenced by the nerves in our gut”.

Everyday emotional well being may rely on messages from the gut. For instance, electrical stimulation of the vagus nerve is a useful treatment for depression and could be replicating these signals.

Depression treatments that target the brain may unintentionally impact the gut. 95% of the body’s serotonin is found in the gut. Antidepressant medications in the form of selective serotonin reuptake inhibitors (SSRIs) increase serotonin levels. It’s not surprising that these medications often provoke gastrointestinal (GI) issues and side effects.

Irritable bowel syndrome affects more than 2 million Americans and can arise in part from too much serotonin in the gut. Evidence is mounting that supports the theory that the gut may influence conditions like anxiety and depression. [12]

Animal tests have shown that probiotics can reduce anxiety-like behavior in mice. In another study a probiotic was compared to an antidepressant under stressful situations. Both the probiotic and drug were effective at increasing the animals’ perseverance and reducing levels of hormones linked to stress. Results were found to be similar for both the Bifidobacterium and Lactobacillus strains. [35]

Research has been extended to humans and has shown to reduce symptoms of anxiety and depression. [36]

Overall the research is promising but still preliminary. More research is required before clinically proven therapeutic probiotics can be formulated to treat conditions like anxiety or depression.

Implication for migraine patients

It’s important to realize that there is more speculation than strong conclusive evidence as at the time of writing (August, 2018).

We can clearly see that there are associations, links and proven models in animals. These findings are nothing less than remarkable. Whether or not these translate across to humans is yet to be proven.

It does highlight however that our gut may well be contributing to our condition without our knowledge and in much more profound ways that we could imagine.

This article is Part (1) of a (2) part series on the microbiome-gut-brain axis for migraine. See Part (2)  for tips on how to improve your gut microbiome and the conditions that link the gut with migraine specifically.