Mental illness might not all be in your head…

Current research suggests a new way to look at mental illness may be through the gut microbiome

The human gastrointestinal tract (GIT) contains a diverse collection of microorganisms known as the gut microbiota. Trillions of bacteria, protozoa, fungi, and archaea, currently reside in the GIT and have been linked to play a critical role in gut-brain communication via immune, neural, and endocrine pathways. Due to these observed interactions between the gut microbiome and the brain, the therapeutic benefits of targeting the composition of bacteria in the GIT is of interest to the psychiatric community for the treatment of mental illness.

Patients with autism spectrum disorder, depression, schizophrenia, and bipolar disorder have been shown to have significant differences in the diversity and composition of their microbiomes. The media has also brought attention to this topic, as there have been claims that there are great benefits in altering the gut microbiome through probiotics, prebiotics, and/or dietary modifications in order to alleviate symptoms of mental illness. Understanding the underlying interactions between the gut-brain network in various psychiatric disorders as well as the benefits and limitations of using supplements that help diversify the microbiota in the GIT is part of the puzzle to understanding the complexity of mental illness.

The whole concept of the “gut-brain” axis is not a new phenomenon. Gastrointestinal issues have long been linked to psychiatric illness. For example, appetite changes have been linked to major depressive disorder (MDD), whereas nausea and diarrhoea symptoms were reported with those with anxiety disorders. Mood disturbances, anxiety, and stress are recognized as playing a role in irritable bowel syndrome (IBS) and irritable bowel disease (IBD). Even those who do not experience mental illness have probably had feelings of an upset stomach associated with nerves or stress. While this idea of the gut and brain being intricately linked has been around for a while, it is not until relatively recently that considerable research has been performed in investigating the role of the gut microbiome in this “gut-brain” axis. 

“Stark differences in the composition of the microbiome between those with plant-based versus animal-based diets have been observed.”

The colonisation of bacteria in the gut is understood to begin during birth since the uterus is a sterile environment. Interestingly, the neonatal microbiome has been shown to vary depending on the method of delivery with caesarean section infants having a microbiome more resemblant to the mother’s skin and those born naturally with a microbiome having a closer resemblance to the mother’s vaginal microbiome. However, these differences tend to resolve quickly and by one year, infants exhibit a diverse and adult-like microbiome in their GIT. 

As adults, the most significant determinant of the composition of the microbiome is diet. It has been shown that shifts in composition of microorganisms present in the gut occur in response to dietary changes. Additionally, stark differences in the composition of the microbiome between those with plant-based versus animal-based diets have been observed. With the healthiest microbiome being a diverse collection of “healthy” microbes, maintaining this diversity is often the purpose of treatments with probiotics, as they are living bacteria that benefit the host when administered in correct amounts. 

The communication between the gut and the brain is a complex bidirectional system where information is transmitted, interpreted, and responded to. The microbiome of the GIT has been shown to have a critical role in this communication network and the mechanisms by which the bacteria of the gut are interacting and influencing the central nervous system are being uncovered. Studying the microbiome and its communication along the “gut-brain” axis has been performed through manipulation and altering the microbiota of rodent models. 

“Not much work has been done with using phage therapy, but it does provide a promising future avenue in research.”

As previously mentioned, observing the impact of manipulation due to probiotics is one means of studying this complex relationship, but studies can also examine the effects of prebiotics which are found in plant fibres that confer and stimulate the growth of healthy bacteria and fungi in the gut. They can also be administered through “synbiotics”, combinations of probiotic and prebiotic, in order to increase their efficacy in altering the microbiome composition. Another buzzword in this research is “psychobiotic” referring to a pro-, pre-, or synbiotic that has been shown to demonstrate a positive effect on mental health.

Another common and useful method of studying the effects of these types of supplements in order to benefit those with mental illness is through faecal microbiota transplantation (FMT). Essentially, this is the transfer of one’s microbiota to another to replicate the microbiota composition for study. It has been used to transfer the diseased phenotype of a donor patient, like someone with anxiety or depression, to a model organism for investigation. This methodology has proven successful in treating those with gastrointestinal infections like Clostridium difficile which is a common hospital-acquired infection. It has also been used for investigation with IBS and has been correlated with increased mood for those afflicted.

Phage therapy is another exciting technique used in this research that alters the microbiota through the use of bacteriophages or viruses that infect bacteria. Using this along with FMT could help make the transfer of microbiotas more efficient and accurate. Not much work has been done with using phage therapy, but it does provide a promising future avenue in research. Lastly, there are also “postbiotics” which can alter the microbiota. “Postbiotics” are bacterial products or metabolites that have activity in the host, so those most interested in looking at effects on the brain would be short-chain fatty acids (SCFA). SCFAs like acetate, butyrate, and propionate are produced by those bacteria which often colonise the gut. They produce these SCFAs in response to non-digestible carbohydrates, suggesting why a high-fibre diet is associated with health benefits.

All of these research techniques that have been used to study the “gut-brain” axis have helped understand how the GIT and brain interact with each other in a complex manner and how mental illness plays a role in altering this communication network. Understanding the research methods provides insight into how to interpret results correctly and informatively. Researchers are looking for ways to help those struggling with mental illness, but it is imperative to follow the evidence and the effectiveness of altering the microbiota and its impact on psychiatric conditions.

The gut microbiota has also been linked to the immune system’s induction and development. When the microbiota is abnormal, there is an increase in immune system molecules called pro-inflammatory cytokines that help drive inflammation. Many of the uncomfortable symptoms associated with GIT issues are due to inflammation in that region. Usually, the microbes from the gut are prevented from going into the bloodstream by the intestinal epithelium barrier, but stress has been shown to disrupt this barrier and cause a “leaky gut” allowing the movement of microbes and stimulating an inflammatory immune response. There are many psychiatric conditions associated with chronic inflammation and increased levels of pro-inflammatory cytokines, although the source is not known. This link with chronic stress and a “leaky gut” could provide one explanation for the production of these cytokines and mental illnesses like depression.

Events in early life and chronic stress are deemed risk factors for depression, anxiety, and other psychiatric conditions. The hypothalamic-pituitary-adrenal (HPA) axis controls and mediates the stress response in the body through many reactions ultimately netting the production of cortisol, the body’s primary stress hormone. There has been substantial experimental evidence that the gut microbiome plays a role in this stress response as a regulator of this pathway. Dysfunction in this HPA axis is common among psychiatric illnesses, especially mood and anxiety disorders. Interestingly, several prebiotics and probiotics have been demonstrated to reduce cortisol levels, possibly providing a means of intervention for these illnesses.

More traditionally implicated in psychiatric disorders are neurotransmitters in the brain. The body’s “chemical messengers” that communicate along the central nervous system. Specifically, GABA, serotonin, acetylcholine, noradrenaline, and dopamine are of major interest with mental illnesses. The bacteria in the gut are able to directly produce all of these neurotransmitters as well as those SCFAs previously mentioned, which are thought to be important for the maintenance of neurons. Unfortunately, the quantities of these messengers produced by the gut bacteria are relatively small, but this again demonstrates how intricately linked the microbiota and the brain truly are.

“Recent studies have demonstrated that psychotropic medications can alter the composition of the microbiome.”

Serotonin especially is the most studied neurotransmitter in relation to mental illness for its implications in anxiety and depressive disorders. Tryptophan, an essential amino acid obtained from the diet in eggs, fish, and nuts, is a precursor for serotonin synthesis in the brain, although most of it is metabolised with the help of the microbiota in the gut via the kynurenine pathway. Certain metabolic intermediates of this pathway, specifically kynurenic acid and quinolinic acid, are neuroactive. Kynurenic acid has been shown to have neuroprotective properties, whereas quinolinic acid and kynurenine have been implicated as depressogenic. Therefore, an imbalance in these intermediates of the kynurenine pathway may play a role in depression.

Lastly to highlight the bidirectional characteristic of the “gut-brain” axis, more recent studies have demonstrated that psychotropic medications can alter the composition of the microbiome. Of most relevance is that serotonin-specific reuptake inhibitors (SSRIs) antidepressants appear to alter the microbiota. This research is still in its early stages and no clear evidence exists, but it is something to remain aware of with alterations in the composition of neurotransmitters of the brain affecting the gut microbiome. 

In order to put the complexity of this topic all into perspective, the genome of the bacteria in the human gut massively exceeds the amount of human DNA present in the whole body or every one human gene, there are over 100 bacterial genes. Understanding the complexity of the interaction between our bodies and these resident bacteria in the gut is essential for the future of physical and mental health. Hopefully, further research will be performed in this field and more correlations drawn between psychiatric illness and microbiota composition, but for now, the future looks promising. 

Shannon McGreevy

Shannon McGreevy is the Online Editor of Trinity News, and a Junior Sophister student of Biochemistry.