Ever since a 2004 study by Sudo and associates has shown that gut microorganisms affect the stress response in mice, the interest has been growing in uncovering the relationship between the gut with its microorganisms and the brain. The research in this field has accelerated over the past few years, partly due to the low price and easy conducting, and the results are more than interesting. What once may have sounded suspicious, to say the least, is now supported by a growing number of evidence that certain psychiatric conditions indeed are somehow linked to the microbial flora of the gut.
Did you know that the guts have their nervous system, the enteric nervous system, which contains over 100 million nerve cells? Due to its complexity and complex relations with the central nervous system, the enteric nervous system is sometimes referred to as the second brain! The communication between the brain and the gut nervous system is bidirectional – the brain influences the guts, and guts influence the brain too. The mediators of this communication are chemicals such as hormones, neurotransmitters, and cytokines.
But microorganisms that reside in the gut can produce chemicals that are the same or similar to the ones that the brain and the gut use for communicating. For this reason, they take an important part in this communication axis, which is now known as the microbiota-gut-brain axis. Diseases of the nervous system are usually multifactorial – they may have an inherited basis, but their development is also affected by different environmental factors, often not clearly defined. Well, imagine if one of those factors turned out to be the gut microbiota, which is easily modifiable. It is no wonder that the microbiota-gut-brain axis has been a hot topic in science in the past two decades!
It seems the microbiome plays a role in brain development. The evidence for this statement comes from animal studies, mostly on germ-free mice – mice without microbiota. Studies have shown that such mice have impaired metabolism of amino acid tryptophan, with higher circulating tryptophan levels, and lower levels of serotonin, the neurotransmitter that derives from tryptophan. At the same time, in male mice, the levels of serotonin were shown to be higher in the hippocampus, the part of the brain which is crucial for memory, learning, and emotions. Structural and functional changes were also reported in the part of the brain which regulates social and fear-related behavior, the amygdala.
Germ-free mice have distinct levels of other neurotransmitters too. Catecholamines, for example. Levels of tyrosine, an amino acid that makes up catecholamines, are lower in germ-free mice, while levels of catecholamines (noradrenaline and dopamine) are higher. Evidence indicates that microbiota also modifies histamine levels, GABA, oxytocin, and vasopressin, takes part in gut-to-brain satiety signalling, and plays a crucial role in forming new neurons. Germ-free mice show a decrease in expression of BDNF, a protein that promotes neuronal growth.
The listed neurochemical changes of the brain result in correlating changes of behavior. In a 2013 study by Cryer and associates, germ-free mice preferred spending time in an empty chamber or with an object than with another mouse. When they had to pick a mouse to spend time with, they went for the mouse they don’t know and not for the familiar one. It is considered abnormal social behavior for a social animal, and in the study, the behavior partially improved after administering probiotics. Administration of probiotics was also helpful for reducing anxiety- and depression-like behavior in healthy mice in several studies.
The abnormal behavior and neurochemical changes, similar to that noted in the studies on germ-free mice, are common findings in certain neuropsychiatric conditions. So, could this implicate that the composition of gut microbiota is somehow associated with psychiatric diseases? Many studies that have been performed on animals and humans so far suggest so.
Autism spectrum disorders are often associated with gastrointestinal diseases, and recent studies have shown changes in the gut microbiota of autistic children. Microbiota diversity was found to be increased in autistic children, with the excess of Bacteroidetes bacteria mainly being linked with the most severe cases. Fecal samples of autistic children had elevated levels of short-chain fatty acids (SCFAs) and ammonia, the products of gut bacteria. However, the significance of this finding is not fully understood.
Dopamine, the key neurotransmitter for the development and treatment of schizophrenia, is produced by gut microbiota, and gastrointestinal diseases and symptoms are often associated with this disease. This suggests a potential connection between gut microbiota alterations and the development and severeness of schizophrenia symptoms. This hypothesis is further supported by several studies that have associated increased incidence of schizophrenia symptoms with the usage of antibiotics, but further research in the field is needed.
The gut microbiota of people suffering from depression is significantly different from that of healthy people. The changes in gut microbiota diversity, the abundance of certain bacterial species, and the lack of others were strongly linked with depression in many studies, both on animals and humans. Antibiotics, stress, and poor diet (Western one, in particular) disrupt the microbiota, so they were shown to make a person more prone to developing symptoms of depression. On the other hand, probiotics, prebiotics, and a healthy diet (Mediterranean) restore gut microbiota and alleviate depression. Fecal transplantation studies are particularly interesting – when fecal microbiota of depressive patients is transplanted to germ-free mice, they develop depression too! This raises hope that the reverse process, transplantation of healthy microbiota to a depressive patient, could be a potential treatment strategy.
Like depression, anxiety is also associated with changes in microbiota composition, with the lack of certain bacterial species and the excess of others. Studies on young adults showed improved sleep quality and mental state under stressful conditions upon regulating gut microbiota. One of them, a2019 study by Hawley and associates, showed that the use of probiotics with several bacterial species improved panic and neurophysiological anxiety, worry, and negative mood in college students.
The drugs used to treat neuropsychiatric conditions have been targeting the brain only for a long time, with a limited effect. But what if another organ dysfunction is the missing piece to a more effective therapy?
The linkage between gut microbiota and brain development and functioning is proven, although a few question it. For some diseases, such as depression, disturbance of the microbiota-gut-brain axis is accepted as a potential cause or aggravating factor. For others, further research is needed, as most of the currently present findings come from animal studies. Nowadays, considerable effort is being put into developing more valuable studies on humans, broadening and fortifying current knowledge on the topic.
The term psychobiotic was coined to emphasize the potential role of prebiotics and probiotics in the treatment of psychiatric conditions and neurodegenerative disorders (such as Alzheimer’s and Parkinson’s). And indeed, in terms of treating depression, anxiety, and stress reactions, prebiotics and probiotics were found to be beneficial in many animal studies, and so were the fecal transplants. Although successful in several studies, this type of therapy is not yet officially in use when it comes to humans. Psychobiotics as such are currently only recognized as a therapy for irritable bowel syndrome. Progress is being made with incorporating them into the depression treatment guidelines. This therapy modality will sure become more broadly used after more evidence from studies is obtained.
Modifying gut microbiota is relatively simple and inexpensive – much easier than, for example, modifying genes. This is of incredible importance in a world of growing mental health issues incidence and giant economic and cultural gaps. If it turns out that the gut microbiota is what has eluded us for so long, it will be a major turning point in neurology and psychiatry – a turning point with the potential to change mankind.
