The Microbiome, The Brain & Mental Health
Let’s get right to the point: I’m a germaphobe, especially around this time of year.
Any chance I get, I’m rubbing hand sanitizer between my hands, or using a pencil to press the buttons on an elevator. Yes, I’m that kid. The word “bacteria” makes me cringe. 😬
For me, it’s about not getting sick. I hate being sick, mainly because it means I can’t get work done. But what scientists have been finding out over the past several years is that bacteria, along with other microbes, actually prevent us from getting sick.
In fact, there are around 39 trillion microbes living in and on our body right now. To put this into perspective, that’s 9 trillion more cells than cells that are our own! (You can imagine my reaction when I found this out…)
But seriously, researchers are figuring out that these trillions of microbes are vital to our health and wellbeing, and are linked to certain diseases, even neuropsychiatric disorders. The human microbiome has the potential to transform our understanding of mental illnesses and open the door to a new world of treatments that we have just started exploring.
The Human Microbiome
The human microbiome is the collection of all of the microbes living in and on us, like bacteria, viruses, archaea, fungi, etc., as well as all of their genetic makeup.
These microbes live everywhere, from our skin to our nose, vital to the proper functioning of bodily processes. A few include:
- Providing nutrients for our cells
- Helping in digestion
- Programming the immune system
Pretty much all processes in the body rely on the microbiome in one way or another.
Microbiome composition differs from person to person, and depends on the location in the body you’re looking at. While we’re still exploring this fascinating field of science, we are beginning to understand how the microbiome is shaped by our early life, diet, environment and genes.
Studies have found that microbiome composition, particularly the gut microbiome which includes the microbes and their genes in the gastrointestinal tract, is significantly correlated with diseases like irritable bowel syndrome and diabetes.
And what’s even more interesting is that we’re beginning to see the role of the microbiome in our brain health and in neuropsychiatric diseases.
The Microbiome-Gut-Brain Axis
When you think about the brain or mental health, the gut microbiome probably isn’t the first thing that comes to mind… But studies are uncovering the complex communication pathways between the gut microbiome and the brain. The results we’re finding are so intriguing that funding agencies are pouring millions of dollars into understanding this communication pathway.
The brain and gut are connected via a direct line of biochemical communication, created by immune pathways and nerve cells called the gut-brain axis. The brain can also send signals to the gut to stimulate or suppress digestion.
There are 4 main ways our brain and gut microbiome communicate:
- Microbes interact with immune cells and cause them to release cytokines (signaling proteins secreted by cells of the immune system). The cytokines circulate from the blood to the brain.
- Microbes interact with enteroendochrine cells of the gut wall that produce neuroactive compounds. These compounds interact with the vagus nerve, the most complex cranial nerve in the human body, which sends signals to the brain. They interact with the vagus nerve through way of the enteric nervous system, a massive web spread over the entire digestive tract made up of more than 500 million neurons. Research has found that an estimated 80 to 90 percent of the vagus nerve’s neurons transmit sensory information from the stomach and intestines to the brain.
- Microbes produce metabolites and neurotransmitters. These molecules circulate to the brain where some are small enough to enter through the blood-brain barrier.
- While this isn’t a direct pathway of communication, we have actually found human gut bacteria in brain tissue… weird, but true.
And our understanding of the microbiome-gut-brain axis continues to evolve as we study the complex molecular pathways:
The mechanisms by which bacteria access the brain and influence behavior include:
- Bacterial products that gain access to the brain via the bloodstream and the area postrema
- Cytokine release from mucosal immune cells
- Release of gut hormones such as serotonin, also known as 5‑hydroxytryptamine (5‑HT), from enteroendochrine cells
- Afferent neural pathways, including the vagus nerve
The microbiome-gut-brain axis is bidirectional, meaning that the brain also influences microbiome composition.
Stress and emotions can influence the gut microbiome via the release of stress hormones and sympathetic neurotransmitters. Human stress hormones like noradrenaline via adrenergic nerves might influence bacterial gene expression or signaling between bacteria, changing gut microbiome composition and activity.
Although in the preliminary stages, research like this is already changing our understanding of different neuropsychiatric disorders.
Anxiety, Depression & Schizophrenia
Around 1 in 5 U.S. adults experience mental illness each year. However, our current scientific understanding of mental illnesses is lacking, which makes them especially difficult to diagnose and create effective treatments for.
While there are hundreds of papers investigating the neurological causes of mental illness, most don’t capture the full picture, failing to take into account the factors and processes in our body that are affecting the brain. Emerging research on the gut microbiota’s role in mental illness is already beginning to strengthen our understanding of disorders like anxiety, depression and schizophrenia.
It’s known by many that serotonin (5-HT), regulating mood and social behavior, plays a significant role in anxiety and depression. But what’s less well known is that 90% of serotonin is produced in your gut!
The enterochromaffin cell (ECC) shown in green is the cell responsible for 5-HT synthesis. 5-HT synthesis is modulated by SCFAs (short-chain fatty acids) and 2BAs (secondary bile acids) produced by Clostridiales, which increase stimulatory actions on ECCs when there are high amounts of the amino acid tryptophan in your diet.
ECCs (68 of them, to be exact) communicate with afferent neurons like the vagus nerve, sending serotonin to the brain. The autonomic nervous system can also activate ECCs to release 5-HT into the gut lumen where it has the potential to interact with microbes.
It’s therefore possible that Clostridiales and other microbes in the gut microbiome could play a role in depression and anxiety by way of this pathway.
Another interesting team found that mice separated from their mothers, therefore causing anxiety, led to long-term changes in the microbiome.
This implies that the gut microbiome influences the HPA-axis, the central stress response system. They found that Lactobacillus rhamnosus JB-1, bacteria known to influence the immune system, decreased stress(less corticosterone) and brain chemistry changed, lowering anxiety. Mice with a severed vagus nerve did not receive this benefit.
Feeding mice Lactobacillus rhamnosus JB-1 additionally altered the amount of protein receptors in different parts of the brain. The altered protein receptors affected were both GABAa and GABAb which are associated with depression, anxiety and schizophrenia.
The microbiome of patients with First Episode Psychosis (FEP) has also been shown to be altered. The oropharyngeal microbiome had increased lactic acid bacteria in schizophrenia and more Lactobacillus phage. The gut microbiome had an increase of the phylum, Proteobacteria, accounted for by Succinivibrio. Numbers of Lactobacillus group bacteria were elevated in FEP patients and significantly correlated with symptom severity.
Another study found that the orders Clostridiales, Lactobacillales, and Bacteroidales and genera Lactobacillus and Prevotella were increased in FEP patients compared to healthy controls. They also found increased choline levels on imaging in FEP patients, a marker of cell membrane dysfunction. They suggested that the microbiome changes could, via changes in SCFA production, lead to microglia activation and cell membrane dysfunction, a conceivable, yet highly speculative, hypothesis.
A few other notable results:
- When mice are colonized with the microbiome from a depressed patient through the process of fecal microbiota transplantation (FMT), they begin to exhibit depressive-like symptoms
- The first population-level study on the link between gut bacteria and mental health found that the bacterial genera, Coprococcus and Dialister, were decreased in depression, while butyrate-producing Faecalibacterium and Coprococcus bacteria were consistently associated with higher quality of life measures. Butyrate is a short-chain fatty acid that is known to have antidepressive properties
- Lactobacillus helveticus R0052 affects neurons in the hippocampus and amygdala, and increased amount alleviates psychological distress
Treatments and Opportunity
As our understanding of the microbiome-gut-brain axis evolves, so will our treatments for mental illness.
- Researchers are currently studying the use of probiotics, prebiotics and synbiotics as potential treatments for depression, anxiety, and stress, being used as “psychobiotics.” While still preliminary, they have proved to be effective in studies.
- Another type of treatment is a fecal microbiota transplant (FMT) from a donor who has healthy gut microbiome, which is already being used to treat Alzheimer’s disease, and has been shown to affect the mood of mice.
- Phage therapy is the use of bacteriophages to treat pathogenic bacterial infections. Bacteriophages, known as phages, are a form of viruses. Phages attach to bacterial cells, and inject a viral genome into the cell to make it self-destruct. This therapy has been shown to be able to alter the gut microbiome.
While the field is still in its early stages, we’re already learning many new things about the gut microbiome and brain. With the potential to pave the way for new treatments and diagnostic methods, the emerging field of microbiomics will transform our understanding of neuropsychiatric disorders.
Hi! 👋 I’m Mikey, a student passionate about the intersections between exponential technologies, neuroscience, and mental health. My goal is to transform the diagnosis and treatment of neurological and psychiatric disorders. However, I’m pretty much interested in everything. Shoot me an email at email@example.com if you would like to further discuss this article, know of any cool opportunities, or just chat!