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Microbiome and Mental Health

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History of the gut microbiomeEdit

Before Antonie van Leeuwenhoek first discovered bacteria in a sample in 1676, though the connection between microbiome and mental health has recently come to the attention of public media with articles about it published in the New York Times[1], Scientific American[2], Huffington Post[3], and Nature[4], the history of research in this area has deep roots in the science field. Scientists have been pondering and writing on the connection between the brain and the body for centuries. For instance, in 1759, Laurence Sterne said in reference to “a man’s body and his mind" that if you "rumple the one, -you rumple the other" in his book The Life and Times of Tristan Sterne.

The human gastrointestinal tract alone contains a delicately balanced ecosystem of 100 trillion microorganisms, nearly ten times the number of cells in the entire human body. [5] These bacteria in our gut, which are collectively called the gut microbiome, play many physiological roles in the body, for instance synthesizing vitamins, developing the immune system, aiding digestion to name a few, and managing the stress response.[5] Beyond involvement in somatic processes, bacteria within the body are so interwoven in our systems that impact our behavior and cognition. One study even found that when the gut contents of two mice were swapped, including all of their gut microbiome, the mice's personalities switched; for example, stress-prone mice became calm and calm mice became stress-prone.[5]

Even without the context of disease, humans and animals alike have very diverse interpersonal compositions of their microbiomes. Thus, it has been difficult for researchers to discern the difference between unbalanced, or dysbiotic, microbiome and a healthy microbiome.[6] Over the past decades, researchers have found hundreds of bacteria strains in the human gut; however, only a handful amongst such are ubiquitous[6]. Some of these ubiquitous bacteria include: anaerobic cocci and Bacteroides--which are prevalent in high abundance--and Clostridium, Bifidobacterium, Eubacterium, Lactobacillus, Escherichia coli and Streptococcus--which are prevalent in lower abundance[6].

Acquisition and development in humansEdit

Bacteria begin to form an inextricable link to us shortly before birth when they colonize our guts within the womb.[5] By the time we are 3-5 years old, we have developed a full adult microbiome and a gut-brain axis. Once the microbiome is established, it is relatively stable throughout life. [7]

The gut-brain axisEdit

The gut-brain axis describes the connection between the gut in the brain via many different body systems, such as the immune system, nervous system, and endocrine system. In much the same way that proprioceptors help gauge the state of muscle tension and stress, provide feedback to the brain, which in turn changes the state of muscles to prevent damage, the gut and brain have similar systems of providing dual-direction feedback and change. Many factors throughout the body have a significant impact on the state of one's mental health[8]:

  • Excessive bodily inflammation
  • Poor absorption of nutrients and medication in the gut
  • Gut serotonin imbalance
  • Leaky gut syndrome, which causes nutrients to leach into the blood stream rather than being absorbed by the intestines
  • A dearth of brain serotonin, dopamine, and other neurotransmitters
  • Hormonal imbalance
  • Deficiencies in certain vitamins and minerals (A, B, C, D, E, K, Calcium, Iron, Magnesium, Phosphorus, Sodium, and Zinc, among others)

Although these varied systems may seem disparate, they are largely interconnected through the gut-brain axis. The gut-brain axis (GBA) is a set of mechanisms through which the gut and brain communicate bidirectionally. Three of the main communication routes are the immune system, the nervous system, and the endocrine system. Through these mechanisms, the information in the gut can affect behavior and cognition, although not necessarily in a negative way. For instance, one study found that when the gut bacteria from two different mice were swapped, the personality traits of those mice also swapped. stress-prone mice became calm and calm mice became stress-prone[5].

Immune system interactionEdit

The first mechanism through which bacteria in the gut interact with our brain is through inflammation. The mechanisms that cause the brain to convert typical chronic inflammation into depression and anxiety symptoms are a result of typical immune system function. During a regular immune response to an infection, there is an increase in pro-inflammatory cytokines, such as interleukin-1 and interleukin-2. In immune response, cells throughout the body release cytokines that mediate and regulate immunity, inflammation, and hematopoiesis (induced blood cell destruction in case of infection)[9]. Pro-inflammatory cytokines seek infected cells and signal other cells to destroy them, as well as induce other biological responses to infection like inflammation. Anti-inflammatory cytokines release signaling compounds that cause biological processes that inhibit further inflammation. In a mentally and physically healthy person, anti-inflammatory cytokines are in equilibrium with pro-inflammatory cytokines[9]. However, when someone becomes infected with deleterious bacteria, the body produces more pro-inflammatory cytokines, as inflammation will stop the bacteria from infecting the whole body. Research has found that increased levels of pro-inflammatory cytokine activity in the brain lowers metabolism of neurotransmitters, specifically that of GABA; GABA, when in lower levels, causes depressive symptoms[8].

Nervous system interactionEdit

Through various mechanisms, including the vagus nerve and through the release of neurotransmitter precursors, the enteric nervous system is connected bidirectionally with the central nervous system. A second communication system the gut and brain have with one another is through the nervous system and the brain. As previously mentioned, bacteria become incorporated in the human gut before birth in the womb. Bacteria also become enmeshed within the nervous system in addition to the gut, strengthening specific neural pathways and lines of communication between the gut and brain and causing the development of signaling mechanisms in the central nervous system that irrevocably affect behavior and cognition (Forsythe & Bienenstock, 2008). Thus, our normal nervous system function is dependent upon the bacterial balance and correct functioning. Normally, information is sent from the heart, lungs, pancreas, liver, stomach, and intestines to the brain (including the cerebral cortex, medulla oblongata, limbic system, etc.) via sensory fibers in the vagus nerve (Forsythe & Bienenstock, 2008). From the medulla oblongata, the afferent inputs go to the locus ceruleus in the brain stem, from which the inputs send signals to widespread areas of the CNS that commence a stress response (Forsythe & Bienenstock, 2008). If the locus ceruleus, an area responsible for coordinating stress response, is activated repeatedly, permanent changes occur in the way neurons activate and interact with one another that are in line with anxiety and depressive disorders (Forsythe & Bienenstock, 2008). This is also known as a hyperactive HPA axis, and it is activated similarly in the inflammatory aspect of the gut-brain axis, resulting in elevated stress response and anxiety. Elevated stress and anxiety has been shown to deplete ones microbiome of bacteria that produce anti-inflammatory cytokines, thus resulting in the biological effects inherent in inflammatory response and subsequent depression

Endocrine system interactionEdit

Research has be conducted on the interactions between neuroendocrine hormones, and specifically on the relationships between hormones and the gut microbiota. Findings show that stress-induced neuroendocrine hormones can influence bacterial growth[10] and that gut microbiota may play an important role in hormone regulation such that endocrine effects of bacteria may influence host responses ranging from behavior to metabolism and appetite, and even immune responses.[11]

Microbiome in physical illnessEdit

For years, research has been underway to uncover the relationships between microbiome dysfunction and conditions such as colorectal cancer, inflammatory bowel disease, and immunologically mediated skin diseases. While associations have been established, causal relationships between the microbiome and these diseases have not been supported.[12]

Microbiome and mental illnessEdit

Anxiety and depressionEdit

Depression is known to be closely related to elevations in C-reactive proteins, inflammatory cytokines, and oxidative stress.[13] Current research is being done on the relationship between fecal bacteria (which served as a proxy to analyze the gut microbes) and depression, showing that the presence of certain bacteria are correlated to symptoms of depression.[14] One such study examined the role of switching the gut contents of two mice with distinct personalities, with one very stress prone and the other not. Researchers found that when the gut contents were switched, the non-stressed mouse became stress prone and stressed mouse became more calm[5].

Schizophrenia and bipolar disorderEdit

Schizophrenia is a neuropsychiatric disorder which can appear during adolescence and usually persists throughout an individuals' life. There are varying degrees of Schizophrenia, with characteristic symptoms such as hallucinations, delusions, apathy, and social withdrawal. Bipolar disorder (BD) is a complex and multifaceted disorder with a wide range of manifestations. Bipolar Disorder varies greatly and is defined by the presence of mania or depression in different regards. Previous studies have demonstrated that both schizophrenia and bipolar disorder are associated with alterations of the systemic immune system including low-grade chronic inflammation (increased plasma cytokines, soluble cytokine receptors, chemokines, acute phase reactants) and T-cell activation features.[15][16][17] In addition, elevated antibodies to S. cerevisiae were also found in increased levels in individuals with schizophrenia and bipolar disorder [18] The gut microbiome can influence brain function, thus playing a role in mental diseases such as Schizophrenia. Specifically, humoral immunity to food antigens, intestinal inflammation, exposure to the parasite Toxoplasma gondii, endothelial barrier defects and microbial dysbiosis consistent with a physiological model where gut-bases processes create a systematic state of immune dysregulation.[19][20] A variety of factors influence GI function and environment, and while no known medication exists to completely suppress GI trauma, practicing psychiatrists should consider complementing treatment with probiotics, herbal remedies, vitamins, and minerals that improve GI symptoms in individuals with schizophrenia and bipolar disorder.[21]

Autism spectrum disorderEdit

Links between particular bacteria and phenotypes relevant to ASD raise thequestion of whether microbial dysbiosis (imbalances of the microbiome) plays a role in the development or presentation of ASD symptoms.[22] Studies of fecal DNA have found over represented clusters of Clostridium or Desulfovibrio in children with ASD and gastrointestinal complaints as compared to children with typical neuro-behavioral development and similar GI complaints.[23][24][25] A study found that children with autism have increased incidences of GI problems such as constipation and food selectivity, suggesting that neurobehavioral etiology may account for the higher incidences of the GI symptoms in children with autism.[26]

Anorexia and bulimiaEdit

Because of the growing evidence suggesting the importance of the microbiome in weight regulation and its relationship to anxiety and depression, research into gut-brain interactions may be important to the treatment of anorexia and bulimia. [27]

Probiotic and prebiotic interaction with microbiomeEdit

Anxiety and depressionEdit

Lactobacillus and Bifidobacteria are common anti-inflammatory probiotics that have been shown to reduce anxiety and behavioral signs of distress.[28] A recent study found that probiotics decrease ruminative, negative thoughts in humans, and that the introduction of prebiotics (or fibers that promote the growth of beneficial bacteria decrease anxiety.[29]

Use in clinical practiceEdit

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