Introduction to the Gut Microbiome and Microbiota-Gut-Brain Axis (MGBA)

Part of the MGBA Series 

A traditional theory of mental health proposed a very brain-centric view; that is, people believed they experienced feelings like anxiety, stress, or depression because something was going wrong in their brains. However, in the twenty-first century, researchers are realizing that mental health is much more than just what is going on inside of your head. Mental health can be impacted by a plethora of factors, both related to and beyond the brain. One such factor is the gut microbiome.

What Is the Gut Microbiome?
Let’s start with defining a microbiome. A microbiome is a community of tiny organisms, called microorganisms or microbes, that live together in a particular environment. These organisms can include fungi and bacteria. Amazingly, we have microbiomes all over our bodies, both inside and out, many of which are essential to our bodies operating properly on a daily basis. The gut microbiome is the community of tiny organisms that live in the “gut” or digestive system (think stomach and intestines).

In a healthy microbiome – whether on the skin or in the intestines – has two essential characteristics:

1. There are a large number of good microorganisms, which are microbes that promote your health and help your body function properly.
2. There is a lot of diversity in your microbiome, meaning there are many different kinds of microbes present in the gut. 

There can also be bad microorganisms in the microbiome; bad microorganisms are those that prevent the body from functioning properly and promote infection and disease. Ideally, the good microbes vastly outnumber the few bad microbes in a healthy microbiome. However, this is not always the case. A variety of lifestyle factors, including a high-fat diet, can disrupt this balance and allow bad microbes to outnumber good microbes. This disruption is commonly called “gut dysbiosis,” and is shockingly common in Western populations. 

That brings us to the question: how is dysbiosis connected to mental health? Enter the microbiota-gut-brain axis (often abbreviated MGBA). Think of it like the highway between two cities – the MGBA is what links the gut and the brain together and allows them to interact. The tiny organisms in the gut interact with the brain by influencing both hormones and the nervous system, the two main signaling systems in your body. This creates a “bottom-up” impact—what’s happening in your gut can affect your mood and mental state. When your gut microbiome is balanced (with good microbes outnumbering bad ones), it can have a profoundly positive impact on your mental health. When your gut microbiome is unbalanced, like in the case of gut dysbiosis, it can wreak havoc on your body, both physically and mentally. Recent studies have implicated the MGBA and gut dysbiosis in conditions including anxiety, depression, and chronic stress.  

What Does the Gut Microbiome Do?
The gut microbiome is best known for working behind the scenes to help us digest fiber, but it also plays many other roles. 

Producing Neurotransmitters:
The gut microbiome is involved in the production of neurotransmitters. Neurotransmitters are the brain’s communication molecules; they deliver messages within the brain and to different parts of the body. You can think of them as the brain’s version of energy. We need to have enough neurotransmitters to function, and the balance of neurotransmitters in the brain and body can influence how we feel and how we act. Some of the main neurotransmitters that the body uses are serotonin, dopamine, GABA, glutamate, and noradrenaline. 

The microorganisms living in your gut can do two things: impact your body’s natural production of neurotransmitters and produce neurotransmitters themselves. Serotonin is largely produced within the gut, and its production is controlled by the gut microbiome; serotonin has roles both in the gut and in the brain. In the gut, serotonin impacts the physical movements of the intestines and secretion of molecules that enable digestion. In the brain, serotonin impacts your mood and cognitive abilities; a lack of serotonin in the brain is associated with mood disturbances like depression and anxiety. 

When the gut microbiome is imbalanced, the production of neurotransmitters, such as serotonin, is thrown out of whack. This can result in both gastrointestinal and mood disturbances as too much or too little serotonin enters the body and brain. This connection explains why mood disturbances such as anxiety, stress, and depression are often associated with gastrointestinal pain and gastrointestinal disorders.

In addition to neurotransmitters, the good microbes in the gut microbiome also produce two additional types of molecules – brain-derived neurotrophic factor (BDNF) and short-chain fatty acids (SCFAs). While these are not neurotransmitters, both types of molecules have a demonstrated positive impact on brain health.

Managing Inflammation:
The gut microbiome manages inflammation within the body. Inflammation is a normal process when confined to physiologically appropriate processes such as wound healing or fighting an infection. Chronic inflammation, however, is not good for the body.

A healthy, balanced gut microbiome manages inflammation in a few ways:

1. It influences the actions of the immune system. The microbiome produces substances that impact how the immune system acts. Good microbes produce substances that strengthen the immune system, and bad microbes produce substances that incite excess inflammation. A healthy gut microbiome controls the number of bad bacteria in the gut and keeps both bad bacteria and harmful substances from entering the rest of the body. Bad bacteria are prone to producing inflammatory substances like lipopolysaccharides (LPS) and cytokines. The more good bacteria present in the gut, the less space bad bacteria have to grow and the fewer inflammatory compounds are produced.
2. It provides an extra layer of insulation for the intestine. Think of the intestine like a water pipe; it has multiple layers of cells that keep a tight seal, ensuring that only good substances are absorbed into the body and bad substances stay in the intestine to be excreted from the body. Keeping the intestine sealed is a group effort; good bacteria in the microbiome can help keep the intestine insulated and prevent harmful substances (like the inflammatory substances mentioned above) from entering the blood.
3. Having a balanced gut microbiome has been connected to having a secure blood-brain barrier and keeping inflammation out of the brain. The blood-brain barrier is like a shield for your brain; it operates similarly to security guards at an airport. It checks every substance that passes from the rest of your body into your brain, and it ensures that even if harmful substances are in your body, they cannot reach your brain. A lack of good microbes in the gut has been associated with a weaker blood-brain barrier that is less selective when letting molecules (including inflammatory substances) through to the brain.

Controlling Hormones:
The gut microbiome can play a role in regulating how sensitive we are to stress from an early age. A healthy gut microbiome can shield us from stress-related hormones like cortisol and adrenocorticotrophin, influence how our hormones work, and prevent excessive inflammation triggered by stress. In general, healthy gut microbes are a key part of regulating our hormones and preventing hyperactivity of our hormone systems.

The effect of the gut microbiome on hormones is still somewhat mysterious. Researchers speculate that the connection stems from intestinal permeability. We just discussed how good bacteria help keep the gut sealed and prevent bad bacteria and harmful substances from entering the blood. This is believed to have a connection to hormone control as well as general inflammation. 

How Does the Gut Microbiome Specifically Impact Anxiety?
Now that we’ve talked about some of the general ways that the gut microbiome influences your health, let’s dive into how your gut microbiome directly impacts anxiety. Your gut microbiome acts through two main pathways: communicating with the surrounding tissues and producing metabolites that impact your body as a whole.

Decreasing Inflammation in the Brain:
A healthy gut microbiome can reduce neuroinflammation, or inflammation in the brain. The gut microbiome has the ability to communicate with the brain’s specialized immune cells called microglia. When there’s an imbalance of bad and good microbes in the gut, the communication with microglia is disrupted.

Byproducts of the microbiome also play a role in inflammation. Bad microbes produce amyloids, which are substances that cause inflammation. Not only can amyloids escape the gut and head directly to the brain to wreak havoc, but they can also do damage within the gut. Amyloids can cause inflammation in the gut, which puts the whole body into a state of high alert. This inflammation will eventually reach the brain as well. Another substance that can cause inflammation is lipopolysaccharides (LPS), which are also produced by the bad microbes within the gut.

A healthy gut microbiome prevents neuroinflammation in two ways: it keeps the communication between microglia and good microbes intact, and it minimizes the production of inflammatory byproducts by bad microbes.

Increasing BDNF:
Brain-derived neurotrophic factor (BDNF) is a substance in the brain that helps brain cells to survive, grow, and replicate. BDNF also plays a role in synaptic plasticity—the brain’s ability to change its internal connections over time. Low BDNF has been associated with impaired memory and learning, as well as symptoms of depression and anxiety.

A healthy gut microbiome has been shown to increase BDNF in the brain and benefit synaptic plasticity, as well as the survival, growth, and replication of cells. The exact mechanism of interaction is not currently known, but it may be mediated through the products of microbes, like SCFAs, and the interactions between microbes and hormones.

Increasing NDMA receptors:
N-methyl-D-aspartic acid (NMDA) receptors are receptors in the brain that regulate brain activity and communication. NMDA receptors are known as “excitatory” receptors; this means that when the NMDA receptor receives a signal (usually in the form of the neurotransmitter glutamate), it turns a cell in the brain on or “excites” it. Having enough NMDA receptors is an important part of being able to balance activity and inactivity in the brain; NMDA receptors, similar to BDNF, are also involved in synaptic plasticity. 

Prebiotic consumption can lead to increased levels of NMDA receptors in the brain, which helps the brain to balance the “on” and “off” signals that it receives and is important for functions including learning, memory, and mood regulation. The mechanism by which prebiotics increase NMDA receptors in the brain remains elusive, but future studies hope to shed light on the subject.

Decreasing Cortisol Levels:
Cortisol is often mislabeled the “stress” hormone, but really, it is a hormone that primes the body to react to stressful situations. In small doses, it is good for you, but chronically elevated cortisol levels can have negative effects and contribute to feelings of stress and anxiety. 

Consuming prebiotics decreases the pro-inflammatory molecules produced in the gut, which can lessen the release of cortisol by the hormone systems in the body. Decreasing cortisol levels can help to reduce experienced stress and anxiety. 

The Vicious Cycle of Anxiety and “Leaky Gut”
We’ve discussed the role of the gut microbiome, but remember that the MGBA is a two-way street. Your mental state can also impact how your gut microbiome functions. 

Chronic negative emotion – like anxiety or stress – can directly harm the gut. It damages the lining of the intestine, changing how the intestine physically moves and secretes digestive substances. Think of this like tearing apart your gut microbiome’s home. When the intestines are degraded by anxiety and stress, the balance of microbes in the gut can shift, allowing bad bacteria to overtake the number of good bacteria and sending the body into gut dysbiosis. 

Part of the impact of anxiety and stress on the gut is that it weakens the junctions between cells in the intestinal lining – like tearing open holes in a water pipe. This is commonly termed “leaky gut” and allows the bad bacteria and inflammatory substances that would normally remain contained within the intestines to leak back into the body through the bloodstream. 

At the same time, stress can also weaken the blood-brain barrier – the special wall that protects the brain from toxins within the rest of the body. Weakening this barrier makes your brain more vulnerable to outside substances.

When anxiety weakens both the intestinal lining and the blood-brain barrier, a vicious cycle begins. Weakening the intestinal lining allows a larger amount of harmful substances to enter the bloodstream. Degrading the blood-brain barrier allows a larger proportion of substances in the blood to enter the brain. This process allows inflammation from an irritated gut to reach a uniquely susceptible brain, which can worsen existing symptoms of anxiety. With increased anxiety, the intestinal lining and blood-brain barrier degrade further.

This is just one example of how the two-way communication between the gut and the brain can create a self-reinforcing cycle in the context of anxiety. Anxiety harms the gut microbiome, which harms the brain, which worsens anxiety. 

How Do We Keep Our Gut Microbiomes Healthy?
The complexity of the gut microbiome, the relatively new nature of this field of study, and the fact that each person’s gut microbiome is unique, all make it challenging to fully understand how it interacts with mental health. However, researchers have made progress in figuring out how we can adjust our diets to promote the growth of beneficial gut bacteria and use the MGBA to our advantage. 

This is where psychobiotics (the main star of this series) come into play. The broad term “psychobiotics” encompasses dietary strategies aimed at influencing the MGBA and supporting the growth of beneficial gut bacteria. It includes probiotics (live microorganisms that promote gut health), prebiotics (substances that serve as food for beneficial gut bacteria), and synbiotics (supplements containing both probiotics and prebiotics). These psychobiotics can have various effects, such as influencing emotional and cognitive processes, regulating responses to stress and inflammation, and affecting the production of neurotransmitters and communication within the brain.

In simple terms, psychobiotics are foods and supplements that can help improve mental well-being by nurturing the right kinds of bacteria in the gut. In this series, I’ll walk you through the different types of psychobiotics (and the research that backs them up) and give you the tools to take care of your gut microbiome, so that it can keep taking care of you.

References:

1. National Institutes of Health (US); Biological Sciences Curriculum Study. NIH Curriculum Supplement Series [Internet]. Bethesda (MD): National Institutes of Health (US); 2007. Information about Mental Illness and the Brain.Available from: https://www.ncbi.nlm.nih.gov/books/NBK20369/
2. Segre, Julie. “Microbiome.” National Human Genome Research Institute. Updated January 24, 2024. Accessed January 20, 2024. https://www.genome.gov/genetics-glossary/Microbiome
3. Navarro-Tapia E, Almeida-Toledano L, Sebastiani G, Serra-Delgado M, García-Algar Ó, Andreu-Fernández V. Effects of Microbiota Imbalance in Anxiety and Eating Disorders: Probiotics as Novel Therapeutic Approaches. Int J Mol Sci. 2021;22(5):2351. Published 2021 Feb 26. doi:10.3390/ijms22052351
4. J. Lof, K. Smits, V. Melotte, L.E. Kuil. The health effect of probiotics on high-fat diet-induced cognitive impairment, depression and anxiety: A cross-species systematic review. Neuroscience & Biobehavioral Reviews. 2022;136. doi:10.1016/j.neubiorev.2022.104634.
5. Katarzyna Socała, Urszula Doboszewska, Aleksandra Szopa, Anna Serefko, Marcin Włodarczyk, Anna Zielińska, Ewa Poleszak, Jakub Fichna, Piotr Wlaź. The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders. Pharmacological Research. 2021; 172. Volume 172. doi:10.1016/j.phrs.2021.105840.
6. Jane A. Foster, Karen-Anne McVey Neufeld. Gut–brain axis: how the microbiome influences anxiety and depression. Trends in Neurosciences. 2013;36(5):305-312. doi:10.1016/j.tins.2013.01.005.
7. Neurotransmitters. Cleveland Clinic. Updated March 14, 2022. Accessed September 11, 2023. https://my.clevelandclinic.org/health/articles/22513-neurotransmitters#:~:text=What%20are%20neurotransmitters%3F,muscle%20cell%20or%20a%20gland.
8. Stewart I, Schluter PJ, Shaw GR. Cyanobacterial lipopolysaccharides and human health – a review. Environ Health. 2006;5:7. Published 2006 Mar 24. doi:10.1186/1476-069X-5-7
9. Cytokines and Their Side Effects. American Cancer Society. Updated December 27, 2019. Accessed February 8, 2023. https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/cytokines.html#:~:text=Cytokines%20are%20small%20proteins%20that,body%27s%20immune%20and%20inflammation%20responses. 
10. Foster JA, Rinaman L, Cryan JF. Stress & the gut-brain axis: Regulation by the microbiome. Neurobiol Stress. 2017;7:124-136. Published 2017 Mar 19. doi:10.1016/j.ynstr.2017.03.001
11. Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci. 2015;11(6):1164-1178. doi:10.5114/aoms.2015.56342
12. Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short-chain fatty acids in health and disease. Adv Immunol. 2014;121:91-119. doi:10.1016/B978-0-12-800100-4.00003-9
13. Butel MJ. Probiotics, gut microbiota and health. Med Mal Infect. 2014;44(1):1-8. doi:10.1016/j.medmal.2013.10.002
14. Solanki R, Karande A, Ranganathan P. Emerging role of gut microbiota dysbiosis in neuroinflammation and neurodegeneration. Front Neurol. 2023;14:1149618. Published 2023 May 15. doi:10.3389/fneur.2023.1149618
15. Agnihotri N, Mohajeri MH. Involvement of Intestinal Microbiota in Adult Neurogenesis and the Expression of Brain-Derived Neurotrophic Factor. Int J Mol Sci. 2022;23(24):15934. Published 2022 Dec 14. doi:10.3390/ijms232415934
16. Savignac HM, Corona G, Mills H, et al. Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-D-aspartate receptor subunits and D-serine. Neurochem Int. 2013;63(8):756-764. doi:10.1016/j.neuint.2013.10.006
17. Kao AC, Harty S, Burnet PW. The Influence of Prebiotics on Neurobiology and Behavior. Int Rev Neurobiol. 2016;131:21-48. doi:10.1016/bs.irn.2016.08.007
18. Frei, Remo; Akdis, Mübeccel; O’Mahony, Liam (2015). Prebiotics, probiotics, synbiotics, and the immune system: experimental data and clinical evidence. Current Opinion in Gastroenterology, 31(2):153-158.
19. Mörkl S, Butler MI, Holl A, Cryan JF, Dinan TG. Probiotics and the Microbiota-Gut-Brain Axis: Focus on Psychiatry [published correction appears in Curr Nutr Rep. 2020 Jun 5;:]. Curr Nutr Rep. 2020;9(3):171-182. doi:10.1007/s13668-020-00313-5.
20. Sarkar A, Lehto SM, Harty S, Dinan TG, Cryan JF, Burnet PWJ. Psychobiotics and the Manipulation of Bacteria-Gut-Brain Signals. Trends Neurosci. 2016;39(11):763-781. doi:10.1016/j.tins.2016.09.002
21. Sharma, R., Gupta, D., Mehrotra, R. et al. Psychobiotics: The Next-Generation Probiotics for the Brain. Curr Microbiol 78, 449–463 (2021). https://doi.org/10.1007/s00284-020-02289-5