The Gut-Brain Axis
Introduction
Did you know that less than half the cells in the body are human? The other half is largely composed of microbes, which collectively form the human microbiome. The microbiome has many functions - it helps humans digest food, fight against infection, and can impact reproductive health by affecting the frequency of menstrual cycles and sperm quality (Horn et al., 2022). A large portion of the microbiome is concentrated in the gut and recent studies have connected an imbalance of gut microbes with a negative effect on mental health. This topic is referred to as the gut-brain axis. The purpose of this literature review is to explore current research on how the brain and gut are linked, as well as to understand how this connection impacts mental health. Recent research has focused on how mental health treatments, such as cognitive behavior therapy, could be a useful way to treat the symptoms of various chronic disorders linked to the gut-brain axis, including gastroesophageal reflux disease (GERD) and irritable bowel syndrome. The gut microbiome plays an important role in overall health, so it’s important to learn about its functions and be able to recognize when the gut microbiome could be imbalanced.
The Gut Microbiome
The microbiome is affected by age, diet, people, and medication. By the age of three, most children have a microbiome that is comparable to adults (Clapp et al., 2017). A major part of microbiome development is the interactions the child has with different parts of the mother's body. Variations in these factors can contribute to differences in the bacterial composition of the microbiome. For example, fetuses delivered vaginally are reported to have higher amounts of gut bacteria than fetuses delivered via Cesarean section. Infants who were breastfed (as opposed to formula fed) had an increased number of overall bacterial species in their bodies.
Later in life, the gut microbiome is particularly affected by diet. Studies have shown that a diet rich in fiber, polyphenols, and micronutrients has a positive effect on gut microbial composition (Horn et al., 2022), leading to a higher abundance of beneficial bacteria. Processed foods negatively affect the gut microbiota by causing inflammation and developing higher levels of destructive bacteria. The image below shows the microbiome of United States residents compared to Malawians (in East Africa) and Amerindians (indigenous Americans). We can see that the US gut microbiome is quite different, and the reason could be the high amount of industrialized foods that Americans eat every day (Yatsuneko et al., 2012).
This image shows how different the US gut microbiome is compared to Malawians and Amerindians.
What is the Brain-Gut Connection?
Hidden in our digestive system, we have a little brain called the enteric nervous system (ENS). The ENS consists of two thin layers of more than one hundred million nerve cells lining the gastrointestinal tract from the esophagus to the rectum (“Gut-Brain Connection,” 2020). The gut is a part of the ENS. While this little brain isn’t capable of thought, it can communicate with the brain in our skull, which is part of the central nervous system. Together, the brain and the spinal cord make up the central nervous system (CNS). The National Institutes of Health (NIH) defines the gut-brain axis as a “bidirectional communication between the central and the enteric nervous system, linking emotional and cognitive centers of the brain” (Carabotti et al., 2015). The picture shown on the right summarizes this bidirectional relationship (Ahmad, n.d.)
The exact pathway that links the gut and brain has not been confirmed yet, but there are several theories. A possibility is that microbes interact with enteroendocrine cells in the gut, which would have peptides and other neuroactive molecules that can interact with the vagus nerve (which runs from the brain to the abdomen). The vagus nerve then sends signals to the brain (Uematsu et al., 2010). In 2018, scientists at the University of Alabama, Birmingham discovered gut microbes in cross sections of human brain tissue (Roberts et al., 2018). While they were unable to discover the pathway of entry that the microbes could have used, this opens up the possibility that microbes are somehow making their way from the ENS to the CNS.
How the Brain-Gut Connection Impacts Mental Health
The brain-gut connection has several implications on our mental and physical health. Many gastrointestinal disorders that stem from gut inflammation, such as irritable bowel syndrome, have been linked to the gut-brain axis. Furthermore, inflammation of the gut due to microbe imbalance (dysbiosis) has also been linked to anxiety and depression. Probiotics that heal the gut have the potential to restore balance in the gut microbiota and researchers are investigating this as a potential treatment for these disorders.
The gastrointestinal (GI) tract can become inflamed due to a variety of reasons, but the most common is a diet high in processed foods and red meat and low in fruits and vegetables (McDonald, 2020). When the GI tract becomes inflamed, the intestines become more permeable. Everyone’s GI tract is semi-permeable; it allows us to absorb water and nutrients from our food.
Increased permeability can lead to a “leak,” which means that along with nutrients and water, the GI tract will let in other larger molecules that can potentially be toxic.
A leaky GI tract will lead to the gut microbiome experiencing stress and releasing cytokines and neurotransmitters. Cytokines mediate responses of the immune system, and although they are detectable in normal gastrointestinal tissue, in increased numbers they can cause tissue damage. These molecules filter through the intestines and into the bloodstream. Our brain is typically protected from harmful molecules by the blood-brain barrier - a network of blood vessels and tissue that is made up of closely spaced cells. Increased levels of cytokines and neurotransmitters in the blood increase the permeability of the blood-brain barrier; rogue molecules that influence brain function and lead to anxiety, depression, and memory loss increase in quantity (Clapp et al., 2017).
A recent study investigated the link between childhood microbe development and anxiety by testing if early life probiotics, specifically Lactobacillus rhamnosus GG (LGG), could relieve anxiety in adulthood via regulation of the gut brain axis (Zhou et al., 2022). LGG was given to mice from day 18 of pregnancy to birth and then to the newborn mice for 5 days. Behavioral tests demonstrated anxiety relief symptoms in the adult LGG colonized group. The researchers believe that LGG colonization increases intestinal proliferation and creates a better protected intestinal barrier at the age of three weeks old in the mice. With lower intestinal permeability, anxiety-inducing molecules are less likely to find their way through the blood-brain barrier. While we normally think of our mental health as being impacted primarily by our thoughts, feelings, and experiences, it’s important to keep in mind that physical health and mental health are intricately connected and changes in one can affect the other.
Irritable Bowel Syndrome and the Gut-Brain Connection
Irritable bowel syndrome (IBS) is a chronic disorder that affects the stomach and intestines. This disorder has traditionally been studied as a gut disorder, but there is also a psychological component. Research from the University of Missouri has shown that IBS can be linked to anxiety, depression, and suicidal ideations (Irritable Bowel Syndrome Patients Suffer High Rates of Anxiety and Depression, 2023). Individuals with IBS have a risk of anxiety and depression that is 3 times higher than healthy individuals. These psychological symptoms could be related to the gut-brain axis. This possibility arose when several human studies reported that the fecal microbiome of individuals with depression is different from that of healthy individuals. Samples from depressed individuals had a lower abundance of the bacteria Parevotellacae and Faecalibacterium. Further studies have shown that mice can exhibit behavioral and gastrointestinal characteristics of individuals with anxiety and IBS via the transfer of the microbiome. This hypothesis has been supported by several medical professionals. Dr. Tarar, a professor at the University of Missouri School of Medicine, said “We’ve long suspected that dysfunction of the brain-gut axis is bidirectional, such that IBS symptoms influence anxiety and depression, and on the other hand, psychiatric factors cause IBS symptoms. Medical professionals need to treat both ends of the axis.” (Irritable Bowel Syndrome Patients Suffer High Rates of Anxiety and Depression, 2023). Dr. Tarar reinforces the idea that mental and physical health are connected. While the idea of medical professionals recommending psychiatric treatments for physical disorders might sound strange, recent research has shown that this is an option worth exploring.
Cognitive Behavioral Therapy for IBS and the Gut-Brain Axis
Cognitive behavioral therapy (CBT) is a common form of psychotherapy that is used to treat a variety of disorders, including anxiety and depression. This is a problem oriented type of therapy that focuses on identifying harmful thoughts/behavior habits and working to reverse them (“Cognitive Behavioral Therapy,” 2022). Recent research has found that CBT can reduce IBS symptom severity.
In 2021, researchers at the David Geffen School of Medicine at UCLA investigated whether analyzing the brain and gut microbiome of IBS patients can predict their response to CBT and if these responses were associated with changes in the brain-gut microbiome (Jacobs et al., 2021). After recruiting 84 IBS patients for the trial, the researchers assessed brain resting state functional connectivity (a neuroimaging technique also known as RSFC) at baseline and after two weeks of CBT. 58 of these participants (69%) were classified as CBT responders while 26 (39%) were non-responders. The gut microbiome composition was assessed via fecal sampling in 34 of these patients. This sample included 22 CBT responders and 12 non responders. The CBT responders had increased amounts of bacteria that belong to the Clostridiales order and decreased amounts of bacteria that belong to the Bacteroidales order. CBT responders also had increased fecal serotonin levels. These findings support the idea that the changes induced by CBT can occur via the gut microbiome and influence IBS symptoms. Furthermore, there was no clinical difference between the treatment that CBT responders and non-responders received. However, there were significant baseline differences in the gut microbiome of CBT responders vs. non-responders. As a result, it is possible that pre-existing differences of the brain-gut microbiome increased sensitivity to the effects of CBT in certain patients (Jacobs et al., 2021). Although further research should be done to confirm this association, it is possible that physicians can identify which patients are likely to respond to CBT for IBS by looking at their gut microbiome.
Conclusion
The gut-brain axis plays a vital role in our health. While there are many parts of the human body that continue developing for years, the gut microbiome is essentially set in stone by the time a child reaches the age of 3. Later in life, an imbalanced gut microbiome can affect both physical and mental health, which is seen when analyzing the mental health issues caused by several gastrointestinal disorders.
Recent research in the field of gastrointestinal disorders has shown that individuals with IBS have a fecal microbiome that is different from healthy individuals. Furthermore, a preliminary association has been made by researchers at UCLA between using psychotherapy to decrease symptom severity of IBS. Their clinical trial found that microbiome composition changed in IBS affected individuals when CBT was a part of their treatment. With further research, the gut-brain axis will ideally play a more significant role in the diagnosis and treatment of gastrointestinal disorders. Until then, it’s important to keep in mind the link between the gut microbiome and physical/mental health. While our gut bacteria are minuscule, the effect they have throughout our body is certainly not.
References
Ahmad, S. (n.d.) The Gut/Brain Connection and Your Mental Health. https://samoonmd.com/diet-and-mental-health-connection/
Carabotti, M., Scirocco, A., Maselli, M., & Severi, C. (2015). The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Annals of Gastroenterology 28(2).
Clapp, M., Aurora, N., Herrera, L., et al. (2017). Gut microbiota’s effect on mental health: The gut brain axis. Clinics and Practice. 7(4). https://doi.org/10.4081/cp.2017.987
Cognitive Behavioral Therapy (2022). National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK279297/
Gut Brain Connection (2020). Cleveland Clinic.
Horn, J., Mayer, D.E., Chen, S., & Mayer, E.A. (2022). Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders. Translational Psychiatry. 12(164). https://doi.org/10.1038/s41398-022-01922-0
Irritable Bowel Syndrome Patients Suffer High Rates of Anxiety and Depression (2023, February 22). University of Missouri School of Medicine. https://medicine.missouri.edu/news/irritable-bowel-syndrome-patients-suffer-high-rates-anxiety-and-depression#:~:text=This%20study%20looked%20at%20more,found%20in%20those%20without%20IBS.
Jacobs, J.P., Gupta, A. Bhatt R. et al. (2021). Cognitive behavioral therapy for irritable bowel syndrome induces bidirectional alterations in the brain-gut microbiome axis associated with gastrointestinal symptom improvement. BioMed Central: Microbiome Journal. 9(236). https://doi.org/10.1186/s40168-021-01188-6
McDonald, E. (2020, September 4). What foods cause or reduce inflammation? UChicago Medicine. https://www.uchicagomedicine.org/forefront/gastrointestinal-articles/2020/september/what-foods-cause-or-reduce-inflammation
Roberts, R.C., Farmer, C.B., Walker, C. K. (2018). The human brain microbiome; there are bacteria in our brains! Society for Neuroscience.
Uematsu, A., Tsurugizawa, T., Uneyama, H., & Torii, K. (2010). Brain-gut communication via vagus nerve modulates conditioned flavor preference. 31(6). https://doi.org/10.1111/j.1460-9568.2010.07136.x
Yatsunenko, T., Rey, F., Manary, M., et al. (2012). Human Gut Microbiome Viewed Across Age and Geography. Nature. 486. https://doi.org/10.1038/nature11053
Zhou, B., Jin, G., Pang, X., et al. (2022). Lactobacillus rhamnosus GG colonization in early life regulates gut-brain axis and relieves anxiety-like behavior in adulthood. Elsevier. 177. https://doi.org/10.1016/j.phrs.2022.106090