Gut Microbiota and Mental Health
The gut has over a long period evolved to contain several microorganisms whose functions are cross-cutting. At different sites of the gastrointestinal system, there different types of microorganisms that have been isolated, and they play different essential roles. In their large numbers, the diversity is composed of bacteria, protozoa, viruses, helminths among other organisms. There are even current studies that have alluded to a possibility that the number of microorganisms that exist in the gut is more than the number of human cells in the ratio of about 1.3: 1 (Butler, Mörkl, Sandhu, Cryan, & Dinan, 2019a).
There is no dispute over what roles these microorganisms play in the health of human beings. Some of the areas of function in the body include metabolism, regulation of the immune functions, satiety, and even mood behavior (a recent finding). Microorganisms isolated from the human gut have been shown to break down some of the food materials in the body that have over the past been thought to be indigestible by human hosts, hence a role in metabolism (Butler et al., 2019a). The human genome is relatively stable for any external changes that would influence structure and function.
However, the genome of most microorganisms in the gut is dynamic and tends to respond to external changes like medication, the status of health, exercise, stress, and age. The dynamic nature of the microorganisms, therefore, makes them be able to survive in different environmental conditions of the gut. For instance, the colony of bacteria that inhabits the gut gets established in the early stages of human life, and they become sensitive to manipulation by varying environmental conditions. The gut is an independent system, and despite this, it is linked to the central nervous system, and therefore, this affects the function (Clapp et al., 2017). The hormones, immunological factors, and neurotransmitters, once released, are thought to send signals to the CNS and therefore affecting the function.
The function of the gut, in coordination with the brain, is usually mediated via the autonomic nervous system. There are different hypotheses put forward to explain the role played by the microbiota in the gut. However, the current evidence suggests that interaction between the gut and microbiota leads to the secretion of chemokines, cytokines, neuropeptides, neurotransmitters, microbial byproducts, and endocrine messengers. The released products have the capability of being secreted into the blood as well as the lymphatic system. Afterward, the products influence how the neural messages are carried via the vagal nerve and the afferent neurons into the brain, thus regulating the mood or behavior of a person.
The brain has been shown to hold very close communication with the gut through several means, which include the ANS, the hypothalamus-pituitary axis, among other connections. Findings have shown that exposure to stress causes the release of catecholamines, and some of them like norepinephrine get released into the gut (“(PDF) Gut-microbiota and mental health: Current and future perspectives,” n.d.). The secretion of the hormones then functions to regulate the secretory and motility functions of the gut. There seems to be a complex and not a single class of compounds that are responsible for the mediation of the unified purpose of the gut and brain.
The Microbiota-Gut-Brain Axis
The axis depicts a term that offers the description of the bidirectional link that exists between the gastrointestinal system and the central nervous system, thus playing a significant role in the body homeostasis (Treisman, 2017). There is a network that is formed, and the ANS system branches mainly the parasympathetic and sympathetic complex with the enteric nervous system together with neuroimmune and neuroendocrine portions of the central nervous system.
The intricacies of the working mechanism of the network remain unresolved. Still, it is thought that communication entails the neural mechanisms, neurotransmitters, the immune response, and the release of the neuropeptides. When the materials are released, they can initiate communication with neighboring environments, and this affects function (Treisman, 2017). Some of the molecular components, though, to take part in the communication include the short fatty acids, endocrine hormones, bile moieties, immune-modulating agents, and neuropeptides.
The dysregulation of the microbiota-gut-brain axis has been explored for the sake of several psychiatric disorders, which include depression, anxiety, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. The axis has, therefore, also been associated with the other number of functions, including regulation of both fat and glucose metabolism, satiety and food intake, secretion of insulin and sensitivity to it, lifespan, and bone metabolism.
Communication in the Microbiota-Gut-Brain Axis
The primary function of the gut microbes is to put an evident barrier at the level of the host and the microbiota, and this hinders the occurrence of infections. The walls of the gut have a lining of epithelial cells, which are made up of secretory cells, the chemosensory cells, and the enterocytes as well as gut-associated lymphoid tissues (Rea, Dinan, & Cryan, 2020). The components can maintain the leaky nature of the gut, and this limits the intestinal microbiota from having direct contact with the visceral tissues.
The visceral tissues are charged with secreting a layer of mucus from the goblet cells, and they increase the thickness of the wall as they travel from the proximal to the distal region of the gut. The luminal-mucosal interphase forms the part where most of the microbes and the host interact. The exchange of the materials back and forth via the mucous layer and the epithelium facilitates the proper communication that occurs between the microbiota-the gut and the brain. The colonization of the gut by the microbes is kept under check by the help of the antimicrobial peptides, being expressed by the Paneth cells located in the crypts of the intestines.
More host protection is assured by the defensins, the antibacterial lectins, and goblet cells, which then shield the epithelial lining from any direct contact with microbes. It also protects the cells from the innate and adaptive immune system. The secretory cells are also known to control the production of substances from the enteroendocrine cells like somatostatin, ghrelin, peptide YY, and serotonin. In as much as many microbes are located along with the mucosal layer, some are restricted to the gut and perform their functions at that point.
The enterocytes are mainly associated with the expression of innate immune receptors and the moment they are activated, and they facilitate the release of chemicals. Some of the chemicals released include chemokines and cytokines as well as chemosensory cells whose functions include defense against other microbes like helminths. The gut also possesses polysaccharides that coat and prevent degradation, although they also identify the string of bacteria present in the host. The host immune system is, therefore, able to scavenge and regulate the commensal strain of bacteria while marking the invading ones.
Another communication in the microbiota-gut-brain axis occurs via the regulation of the response of the gut microbiota to stressful conditions. Stress leads to the activation of the HPA axis as a quick response to disturbance in the environment. Once the HPA is activated, there is an alteration of the behavior that then alters endocrine messengers, which include the mineralocorticoids and glucocorticoids and the catecholamines. The existence of long periods of stress is then related to an increased likelihood of disorder like anxiety, bipolar disorder, and depression. Over long periods, the effects of stress on the composition of the microbiota have been studied, and it has been established that stress changes the composition of the microbiota.
There are other studies that have been done to determine the effect on different roles of the microbiota in regulating the response to stress. There are limited studies that have found that in as much as microbiota in the GI tract and stress interact through an immune relationship. The interaction affects the immune system and makes it possible for biochemical processes.
Another aspect of communication regards the regulation of the neuroinflammatory response by the gastrointestinal microbiota. The movement of the immune cells like the chemokines, the cytokines, the endocrine messengers as well as the byproducts of microbes to the brain is regulated tightly by the blood-brain barriers. The BBB is under the surveillance by the macrophages and other cells called the microglia. It has also been determined that the diversity of the GI microbiota is essential to maintain the maintenance and maturation of the microglia in the healthy state and is regulated. Further, studies have revealed that there is a multimodal effect of the microbiota on the physiological activities in the central nervous system. The physiological influence takes place by the recruitment of the local immune regulators from the peripheral region of the brain.
The role of the GIT microbiota and Mental Health
The microbiome, deemed as all microorganisms in the human GIT together with their genetic materials. The studies have shown that the microbiome is responsible for its effect on the number of CNS disorders. The disorders include schizophrenia, depressive disorders, autism, and anxiety. To prove the role of the microbiome in psychiatric disease is given by the ability to alter the diversity of microbiota and complexity when compared to others in healthy individuals.
The modulation of the positive effects of the gut microbiota by the living organisms has been shown to decrease the adverse effects of several mental disorders. There are, however, several practical challenges that affect the therapeutic approach. The moment the microorganism is ingested, they move through the different environments of the gut, even the regions with high enzyme concentrations and low pH levels. Together with the increase in the levels of the immune cells and cytokines, there is an increase in the permeability of the BBB, and this enhances the effects of the molecules through the permeable gut. The released molecules affect the brain function, and this could lead to, among other conditions, depression, anxiety, and memory challenges.
In depression, there are organizational changes, neuroplastic changes, and neurochemical dysfunction. The onset of the illness is when there is dysregulation of the system, and this is attributable to the release of the cytokines as a result of the secondary influence of the systemic response to the stressors, which is exaggerated. The involvement of probiotics like yeast and bacteria has been under utility together with other medications in the treatment of depression and anxiety (Lu et al., 2019). The probiotics have also been thought to alter the inflammatory processes that are initiated by the cytokines.
Some of the patients who have had inflammatory-related suffering have been shown to benefit highly from the use of probiotics. The probiotics would also work to decrease the production of the TNF-a. In other evidence, probiotics have been shown to influence synaptic plasticity and neurogenesis in the hippocampal region, which then allows for the differentiation of the neural cells. In the study using mice, there was a production of fewer amounts of the stress hormones and, after that, preserving the permeability of the intestines.
Also, the probiotics serve a neuroprotective role through the prevention of the dysfunction between the neurons (the stress-induced synaptic dysfunction). There is a further reduction in the amounts of the ACTH and corticosterone that is produced while at the same time depressing the activity of the HPA axis. Therefore, when probiotics are ingested, they have the potential to reduce the effect of the HPA axis on stressors, thus reducing physiologic damage.
The probiotics containing L. acidophilus, L, B. bifidum, B. lactis, L. lactis, L. salivarius, L. plantarum, B. lactis, and L. casei, paracasei, are some of the strains that have been shown to affect the mental disorders through the activation of some regions of the brain (Flowers, Ward, & Clark, 2020b). The probiotics used have been shown to improve the mood, manage anxiety and excess fatigue, and reduce any abdominal discomforts, allowing for a consistent and right length of sleep when exposed to stress.
In another case scenario, the alteration of the GI microbiota has also been applied in the management of bipolar disorders. The occurrence of bipolar disorder has been notably shown to cause a decrease in the levels of Fermicutes, more so the Faecalibacterium that is a symptom reporting tool that is personalized (Butler, Mörkl, Sandhu, Cryan, & Dinan, 2019b). The use of probiotics has recently been credited for the reduction of the frequencies of re-hospitalization over 24 hours when they are used as adjunctive therapy options.
The risk of bipolar disorder has been thought to occur as a result of the response of the immune system and the process of inflammation. Other risk factors are linked to the genes, but in this condition, they only account for a small portion of disease occurrence (Flowers, Ward, & Clark, 2020a). The explanation for the mechanism of the microbiota in handling BD is not spelled out. However, there is an explanation that can be done since the disorder is associated with an increase in the levels of proinflammatory mediators.
Considering schizophrenia, several mechanisms have been postulated. The first mechanism is linked to the biochemical process as the different molecules travel between the brain and the gut. The molecules affect the immune system, the vagus nerve, and the endocrine system (Szeligowski, Yun, Lennox, & Burnet, 2020). The microbiota is produced either directly or indirectly, and therefore invoking the gut-brain axis would play a role in altering the pathogenesis.
To add, products formed from the bacterial fermentation of the carbohydrates like the short-chain fatty acids offer protective effects. The SCFAs protect against the inflammatory status both in the central nervous system and peripheral regions. Other metabolites like polyamines, formyl peptides, D-glycerol-B—D-mannoheptose-1, 7-biphosphate, and polysaccharides A contribute to the modulation of the inflammatory process.
Other bacteria strains like Lactobacillus can regulate one’s emotions through the vagus nerve. In another mechanism, there are the enteroendocrine cell release mediators (Szeligowski et al., 2020). The mediators include the cholecystokinin, 50htydroxytryptamine (5-HT), the peptide YY and the glucagon-like peptides that help in with the mechanism of disease causation. All these mediators are affected and regulated by the contents and constituents of the intestines.
Schizophrenia is characterized by the occurrence of both negative and positive symptoms. The mechanism of management is often complex and lengthy dueling; therefore, using the microbiota approach would provide an alternative pathway. The use of microbiome has also been used as a viable approach to the diagnosis of schizophrenia. In particular consideration, there have been demonstrable changes occurring in the levels of Gammaproteobacteria, Enterobacteriales, and Bacteroides fragilis, and this has been used to distinguish the patient from the controls (Zheng et al., 2019). There is, however, some overlap between schizophrenia and other mental disorders like depression.
The inflammatory process has also been likened to the occurrence of schizophrenia, although this mechanism is not fully understood. In schizophrenia, there are elevated levels of IL-6, TNF-a, IL-8, and reduced amounts of IL-10, which is an anti-inflammatory mediator. Besides, the intestinal lining of the people with schizophrenia has been found to have elevated levels of Saccharomyces cerevisiae, which is one of the markers of the intestinal inflammatory markers (Rodrigues-Amorim et al., 2018). Dysbiosis is, however, likely to cause an increase in the inflammation and inflammation of the intestines and hence permeability. More evidence shows that Dysbiosis could lead to bacterial infections and contribute to the occurrence of schizophrenia.
The gut microbiome is also associated with an increase in the permeability of the BBB. In the end, Dysbiosis would facilitate infection of the CNS, and this is a risk factor in schizophrenia. In other evidence, the immune system has a link with the conversion of tryptophan to form kynurenate. The kynurenate is a known glutamate receptor antagonist, and whenever there is hypofunction of the N-methyl-D-aspartate receptor, schizophrenia is more likely. When post mortem is conducted in those who succumbed to schizophrenia, there has been evidence of elevated kynurenate (Rodrigues-Amorim et al., 2018). The effect of the gut microbiome on the balancing of tryptophan can occur either directly or indirectly.
The Brain-Derived-Neurotrophic Factor is also vital in the learning and memory processes of schizophrenia. The BDNF levels have also been sampled out from the hippocampus of people with schizophrenia, especially in the drug naïve patients (Rodrigues-Amorim et al., 2018). The low levels of the BDNF are often associated with inadequate response to the antipsychotic medications in diagnosed cases.
Since schizophrenia is associated with impairment in cognitive abilities, the use of prebiotics has been evidenced to improve cognition and flexibility. In as much as a decline in cognitive skills is not just unique to the occurrence of schizophrenia, cognitive flexibility leads to an improvement in the global cognitive performance measurements. Augmentation of therapy with the prebiotics has been shown to increase the responses of the pyramidal neurons to NMDA and hence increase the response of the NMDA receptors. The prebiotics have also been linked to increased levels of BDNF (an essential component in the pathogenesis of the disease).
Another mental condition that has been of great concern in anxiety and the manipulation of the microbiota has been useful in the management of this condition. The principle behind the influence of the disease is based on the fact that when there is an imbalance of the microbiota, mood changes and anxiety are more likely alongside stress occurrence (Yang, Wei, Ju, & Chen, 2019). Just like other mental conditions, microbiota enhances the resilience of the human body to different stressful environments.
Whenever food is chewed and then swallowed, there are metabolites like butyrate that are produced, and they are sensed by the vagus nerve that then sends signals to the brain to regulate the digestive process. The gut is also responsible for the production of several hormones and neurotransmitters like serotonin, which is then able to influence the physiology of the body (Forbes et al., 2018). Adequate levels of the serotonin in the body can potentiate the effects of anxiety, mood, happiness, and serotonin on the lower side. Serotonin acts as a link between the gut, and the brain is involved in the processes like gut movement, bone health, nausea, and sleep.
In another explanation, whenever there is hyperactivation, the neurotransmitter GABA plays a role of inhibition this resulting in a calming effect that improves mood and reduction of anxiety. In the presence of stress, the vagus nerve is inhibited, and this impairs the performance of essential functions. The moment the vagus nerve becomes inactive, the anti-inflammatory molecules are not released. Since the gut microbes are sensitive to stress and inflammation, the ecosystem is significantly affected (“Anxiety might be alleviated by regulating gut bacteria: Review of studies suggests a potentially useful link between gut bacteria and mental disorders — ScienceDaily,” n.d.). Similarly, when the vagus nerve is shut down, it can control the permeability of the gut wall. When the gut wall is more porous, there is a high risk of metabolites, more external bacteria, and toxins to get access to the body, and this finds its way to the brain. In this occurrence, therefore, the incidence of discomfort and anxiety are more likely.
A healthy microbiota can produce more butyrate, which is a short-chain fatty acid that protects the gut lining by making a proper barrier lining. In line with the vagal nerve activity, there is the prevention of the microbe-produced metabolites from affecting the normal function, this being able to modify the mood and anxiety states. When there is Dysbiosis, it means the balance is concerned, and there is a lower production of butyrate, which therefore makes one more prone to anxiety.
Whenever Dysbiosis is evident, the growth activity of the opportunistic bacteria is not controlled, and this means the immune system is triggered to fight off. When the resultant inflammatory process activates the immune system, the body’s stress response is heightened, and anxiety increases (“Anxiety might be alleviated by regulating gut bacteria: Review of studies suggests a potentially useful link between gut bacteria and mental disorders — ScienceDaily,” n.d.). On the other hand, high anxiety and stress levels affect the central nervous system and could adversely lead to other conditions like depressions. The probiotics supply essential bacteria and offer useful protection of the gut wall lining, and this, in the end, produces a soothing effect, which in the course time reduces potential anxiety.
Conclusion
The gut is a very diverse and complex system that is independent and organized to discharge its functions properly. It works to facilitate digestion and eventually make available nutrients to the body. The gut has a self-preserving mechanism, where it possesses several microorganisms that constitute the structural integrity, which adds up to the functionality. There are different microorganisms, including bacteria, viruses, and protozoa, among others, which coexist to play a common role in protection. Growing evidence has made it possible to discover that despite just these microorganisms offering protection to the gut, they have a role in the mediation of several mental disorders. The microbiota also can improve normal mental functioning and well-being.
However, despite usefulness in the provision of nutrients, it has been shown to play crucial roles in potentiation of the mental conditions. To confer functions, the system works in another complex network called the gut-brain axis. To make possible the connection, the gut executes its function that affects the brain through the branches of the autonomic nervous system (parasympathetic and sympathetic nervous system). The autonomic nervous system extends the connection to the CNS through the vagus nerve.
The gut microbiota enhances numerous mental health conditions, and this has gone a long way to offer alternative therapy options that are often curtailed by adverse effects. Some of the common diseases include anxiety, depression, schizophrenia, and even bipolar disorders. All the conditions are affected through different mechanisms through which the gut works, but importantly, the interventions take advantage of the gut-brain axis.
Another relevant and useful mechanism to explain the role of gut microbiota on the brain is through modulation of the immune system. The microbiota plays an essential role in ensuring physiology, and whenever it is not conferred, inflammation is likely. The process of inflammation is preceded by the release of the inflammatory mediators, which increases the permeability of the walls, and this increases the possibility of attack by external pathogens. Increased permeability also makes it possible for the brain to be attacked by pathogens, and this makes mental conditions to be more likely.
Therefore, in as much there is a promise on the effect of gut microbiota on the influence of mental health, there is still ongoing research to establish the molecular basis of the mechanism. The evidence on mood and behavior currently holds in the face of continuing research. There are other hormones and catecholamines like norepinephrine that have also been used in the explanation of the existing link between the gut and brain.
References
(PDF) Gut-microbiota and mental health: Current and future perspectives. (n.d.). Retrieved May 12, 2020, from https://www.researchgate.net/publication/260425062_Gut-microbiota_and_mental_health_Current_and_future_perspectives
Anxiety might be alleviated by regulating gut bacteria: Review of studies suggests a potentially useful link between gut bacteria and mental disorders — ScienceDaily. (n.d.). Retrieved May 12, 2020, from https://www.sciencedaily.com/releases/2019/05/190520190110.htm
Butler, M. I., Mörkl, S., Sandhu, K. V., Cryan, J. F., & Dinan, T. G. (2019a, November 1). The Gut Microbiome and Mental Health: What Should We Tell Our Patients?: Le microbiote Intestinal et la Santé Mentale : que Devrions-Nous dire à nos Patients? Canadian Journal of Psychiatry, Vol. 64, pp. 747–760. https://doi.org/10.1177/0706743719874168
Butler, M. I., Mörkl, S., Sandhu, K. V., Cryan, J. F., & Dinan, T. G. (2019b, November 1). The Gut Microbiome and Mental Health: What Should We Tell Our Patients?: Le microbiote Intestinal et la Santé Mentale : que Devrions-Nous dire à nos Patients? Canadian Journal of Psychiatry, Vol. 64, pp. 747–760. https://doi.org/10.1177/0706743719874168
Clapp, M., Aurora, N., Herrera, L., Bhatia, M., Wilen, E., & Wakefield, S. (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
Flowers, S. A., Ward, K. M., & Clark, C. T. (2020a). The Gut Microbiome in Bipolar Disorder and Pharmacotherapy Management. Neuropsychobiology, 79(1), 43–49. https://doi.org/10.1159/000504496
Flowers, S. A., Ward, K. M., & Clark, C. T. (2020b, January 1). The gut microbiome in bipolar disorder and pharmacotherapy management. Neuropsychobiology, Vol. 79, pp. 43–49. https://doi.org/10.1159/000504496
Forbes, J. D., Chen, C. Y., Knox, N. C., Marrie, R. A., El-Gabalawy, H., De Kievit, T., … Van Domselaar, G. (2018). A comparative study of the gut microbiota in immune-mediated inflammatory diseases – Does a common dysbiosis exist? Microbiome, 6(1). https://doi.org/10.1186/s40168-018-0603-4
Lu, Q., Lai, J., Lu, H., Ng, C., Huang, T., Zhang, H., … Hu, S. (2019). Gut Microbiota in Bipolar Depression and Its Relationship to Brain Function: An Advanced Exploration. Frontiers in Psychiatry, 10. https://doi.org/10.3389/fpsyt.2019.00784
Rea, K., Dinan, T. G., & Cryan, J. F. (2020, January 1). Gut microbiota: A perspective for psychiatrists. Neuropsychobiology, Vol. 79, pp. 50–62. https://doi.org/10.1159/000504495
Rodrigues-Amorim, D., Rivera-Baltanás, T., Regueiro, B., Spuch, C., de las Heras, M. E., Vázquez-Noguerol Méndez, R., … Agís-Balboa, R. C. (2018, November 17). The role of the gut microbiota in schizophrenia: Current and future perspectives. World Journal of Biological Psychiatry, Vol. 19, pp. 571–585. https://doi.org/10.1080/15622975.2018.1433878
Szeligowski, T., Yun, A. L., Lennox, B. R., & Burnet, P. W. J. (2020, March 12). The Gut Microbiome and Schizophrenia: The Current State of the Field and Clinical Applications. Frontiers in Psychiatry, Vol. 11, p. 156. https://doi.org/10.3389/fpsyt.2020.00156
Treisman, G. J. (2017). The Role of the Brain-Gut-Microbiome in Mental Health and Mental Disorders. In The Microbiota in Gastrointestinal Pathophysiology: Implications for Human Health, Prebiotics, Probiotics, and Dysbiosis (pp. 389–397). https://doi.org/10.1016/B978-0-12-804024-9.00042-2
Yang, B., Wei, J., Ju, P., & Chen, J. (2019, April 1). Effects of regulating intestinal microbiota on anxiety symptoms: A systematic review. General Psychiatry, Vol. 32, p. e100056. https://doi.org/10.1136/gpsych-2019-100056
Zheng, P., Zeng, B., Liu, M., Chen, J., Pan, J., Han, Y., … Xie, P. (2019). The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice. Science Advances, 5(2), eaau8317. https://doi.org/10.1126/sciadv.aau8317