The Gut-Brain Axis: The Human Gut Microbiome and Anxiety and Depression
Introduction
By Samantha Lee
Humans have evolved throughout the many years with microbes. Microbes play an important role in not only human health but also human disease. The human intestinal tract contains a wide variety of microorganisms, all of which have a large impact on health and disease [1]. This microbiota has recently been studied more in depth as researchers discovered that microbes have a larger impact on human health than once understood. Antibiotics and diet have been shown to alter the diversity of the gut microbiota, leading to the possibility of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) since patients with IBS and IBD have been shown to have unstable gut microbial populations [2].
The human gut contains a large number of microbes that live in the gastrointestinal tract of humans and other animals [53]. These microbes play an important role in digestion, metabolism, and immune function. They can ferment food and supply nutrients and energy to a host and to its immune systems [44]. The intestinal microbiota has a wide diversity of microbial species, and this community of bacteria colonizes the gastrointestinal tract after birth [2]. There are around 40,000 bacterial species that are influenced by vertical transmission from one’s mother, genetic makeup, diet, medications, gastrointestinal infections, and stress [2].
The human gut microbiota can be grouped by three major bacteria enterotypes: Bacteroides, Prevotella, and Ruminococcus [9]. Bacteroides are Gram-negative, obligate anaerobic bacteria. They make up a significant portion of the human fecal bacterial population [54]. Prevotella is another Gram-negative bacteria, and it is thought to have a common ancestor with Bacteroides [55]. It is more common in the gut of individuals who eat primarily a diet filled with carbohydrates, since it is able to break down fibers and plant glycans [56, 57]. Ruminococcus, on the other hand, is an anaerobic, Gram-positive bacteria. Certain species of Ruminococcus have been found to be less prevalent in individuals with IBD [58]. Treatment with antibiotics can affect the intestinal gut microbiota and can cause lifelong changes to the makeup of this community.
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Mood Disorders
Mood disorders are mental health conditions that affect one’s emotions and behaviors[49]. They include depression disorders, anxiety disorders, and manic disorders. The development of mood disorders is not fully understood, but genetics and environmental factors seem to play a role in the progression of these forms of disorders [7]. Additionally, there is evidence suggesting one’s neuroticism is a predictor for the development of a mood disorder [67].
There are differences in prevalence of mood disorders based on sex. For example, in the United States, women are more likely to be diagnosed with a stress-related mood disorder than men [68]. All diagnoses of mood disorders come from the DSM-5, the standard manual of mental disorders with the diagnostic criteria and treatment options for every form of mental disorder known. It was published by the American Psychiatric Association in 2013, and a revised version of the DSM-5 was published in 2022.
Depression
Major depressive disorder is one of the most common mood disorders. It can be present in 121 million people at once [3] and symptoms include low mood or anhedonia and changes to physical and physiological functions [7]. Many people with depression have episodes beginning during adolescence, and these episodes are recurrent [4, 7].
Depression can develop for a multitude of reasons. “Susceptibility genes, neurochemical imbalances, brain circuitry dysfunction, faulty information processing, negative cognitions, social or environmental sources of vulnerability, and precipitating stressors” [7] are all potential reasons for the development and progression of depression.
One of the key causes of depression is through genetics. Genetic influences are similarities of depression measures that increase with shared genes [7]. Families are used to study this cause of depression by comparing parents with depression and the number of their offspring with depression [7]. Twin studies compare behavior between identical and fraternal twins. Since both twins have the same family or possible common environment, this form of study shows the overall impact of genes and is the strongest piece of evidence for the heritability of depression [7]. In major depressive disorder, the most common genetic markers are involved in serotonergic neurotransmission [7]. Serotonin is a neurotransmitter that is involved in mood, reward, and memory [50]. Abnormalities in serotonin have been linked with the pathophysiology of depression [7].
Anxiety
While day to day anxiety is common, anxiety disorders are another common mood disorder, characterized by uncontrollable feelings of anxiety and fear that impair one’s social, occupational, and personal activities [64]. It affects about 16.4% of the population or around 40 million people in the United States [20]. Symptoms of anxiety include fatigue, restlessness, difficulty concentrating, increased heart rate, and chest pain [64]. There are many types of anxiety disorders, including generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, panic disorder, and post-traumatic stress disorder.
Norepinephrine and serotonin are two important neurotransmitters for anxiety disorders. Norepinephrine is a neurotransmitter involved in the fight or flight response, or the acute stress response, and it has been shown to increase alertness and to constrict blood vessels [52]. It is involved in the pathogenesis and regulation of anxiety disorders. Serotonin, in addition to its involvement in major depression disorder, is involved in the pathophysiology of OCD and other anxiety disorders [21].
Treatments
Treatment options for both anxiety and depression disorders are similar, including various therapies, medications, and lifestyle changes. The first line of treatment is typically some form of therapy, whether it be cognitive behavioral therapy (CBT) or more specific forms, like exposure and response prevention (ERP). CBT is focused on changing cognitions, such as thoughts, beliefs, and attitudes, and behaviors associated with those cognitions while also developing coping strategies [65].
Due to the involvement of serotonin, selective serotonin reuptake inhibitors, or SSRIs, are one of the common drugs used for the treatment of depression and anxiety disorders. These drugs work by blocking the reuptake molecules responsible for bringing serotonin molecules back into the neuron [51]. This allows serotonin to stay outside of the neuron for longer periods of time and have more effects on the brain.
SNRIs are another common form of medication. These are selective norepinephrine reuptake inhibitors and have a similar mechanism of action as SSRIs [66]. While there are a variety of treatments available for both depression and anxiety, there are forms of mood disorders that are treatment resistant, meaning they do not respond to any form of treatment available.
The Gut-Brain Axis
The enteric nervous system (ENS) is a portion of the autonomic nervous system that produces over 30 neurotransmitters and has more neurons than the spine, with around 100 to 500 million neurons [25]. It is made up of plexes, which are networks of interlacing neurons. The submucosal plexus of the enteric nervous system regulates gastrointestinal blood flow and controls epithelial cell functions and secretions [27]. The myenteric plexus regulates relaxation and constriction of the intestinal wall [27], or peristalsis. Serotonin also plays a key role in peristalsis by activating neurons involved in initiating relaxation and constriction [36]. Using GABA, dopamine, norepinephrine, serotonin, and other neurotransmitters, the gut bacteria can interact with intestinal cells and ENS and with neuroendocrine and metabolic systems while also communicating with the CNS through the ENS [37]. These signals are transported to the CNS through the afferent vagus nerve fibers [37].
The vagus nerve is the tenth cranial nerve and has a large role in the relationship between the gut, the brain, and inflammation [25]. It travels from the brainstem, through the neck and thorax, and down to the abdomen [25]. It is responsible for regulating internal organ function [26]. The most important function of the vagus nerve is to bring information from the inner organs to the brain [25]. It is one portion of the gut-brain axis.
The vagus nerve afferent pathways regulate hypothalamus-pituitary-adrenal (HPA) axis activity [29]. The HPA axis is the primary pathway activated during a stressful situation. Cortisol is the hormone released that is associated with stress. The production of cortisol leads to the availability of glucose and the suppression of immune responses [63].
The gut-brain axis is composed of the brain, the spinal cord, the autonomic nervous system (sympathetic, parasympathetic, and enteric), and the HPA axis [28]. There have been many studies looking at the relationship between the gut and mental health. One study, looking at the relationship between diet and depression, showed that depression in females was associated with increased fermentation of carbohydrates [12]. This fermentation indirectly implicates changes in the gut microbiota composition, since more fermentation means more bacteria needed for these processes.
When looking at specific bacteria that have possible influences on mental health, a variety of bacteria have some effects on mental health. Mice have been shown to have altered, anxiety-like behavior when infected with Campylobacter jejuni [13], triggering activity of vagal nerve ascending pathways [14]. These pathways include the nucleus tractus solitarius and lateral parabrachial nucleus [14]. Additionally, chronic Helicobacter pylori infection changes gastric physiology, leading to delayed gastric emptying and visceral sensitivity, and abnormal feeding behavior [15], accompanied by the down-regulation of Proopio-melanocortin (POMC), a regulatory peptide, and the upregulation of TNF-ɑ [2].
Bifidobacterium and Anxiety and Depression
With chronic infection from a non-invasive parasite and chemically-induced colitis, there was an increase in anxiety and depression-like behavior in mice [17]. However, these symptoms were normalized by treatment with probiotic Bifidobacterium longum NC3001 [2]. B. longum is a Gram-positive bacterium that is sometimes added to food products [60] and can produce lactic acid [61]. B. longum was not found to improve gut inflammation, but there was a reduction in anxiety behavior in the mice [2]. Neurons treated with B. longum fired fewer action potentials when reacting to a depolarizing current [17].
Desbonnet et al. (2008) looked at the potentially antidepressant effects of Bifidobacterium infantis on rats [18]. Following treatment with B. infantis, rats underwent forced-swim tests, while also being tested for immune, neuroendocrine, and monoaminergic activity [18]. While rats treated with B. infantis had no change in swim behaviors, there was an increase in the concentrations of serotonin and dopamine metabolites in the frontal and amygdaloid cortex and a decrease in pro-inflammatory cytokines [18]. Serotonin and dopamine, as well as pro-inflammatory cytokines, have potential effects on the development of depression, indicating that B. infantis may have antidepressant properties.
Lactobacillus and Anxiety and Depression
Lactobacillus rhamnosus is a Gram-positive bacterium that can be found in the female urogenital tract [62]. In relation to the gut-brain axis, L. rhamnosus has been found to have an impact on GABA, an inhibitory neurotransmitter. L. rhamnosus treatment in mice promoted exploratory behavior and decreased depression-like behavior, along with alterations in the brain of mRNA for GABA(B1b) and GABA(Aɑ2), both of which are receptors for GABA molecules [19]. GABA is an inhibitory neurotransmitter that decreases activity in the following neuron. The change in GABA(B1b) and GABA(Aɑ2) mRNA being associated with decreased depression-like behavior indicates that GABA has possible effects on the development of depression. Additionally, L. rhamnosus has altered the expression of GABA receptors in the brain, leading to a decrease in anxiety-like symptoms [38]. This aligns with the previous piece of evidence to indicate the relationship between GABA with both anxiety and depression disorders. When looking at a specific type of anxiety, Obsessive-Compulsive Disorder (OCD), mice treated with L. rhamnosus had a decrease in OCD-like symptoms, and these findings were similar in humans when treated with L. helveticus [42, 43].
HPA Axis and Anxiety
The HPA axis is active in acute anxiety situations, due to cortisol reducing the perception of fear by hindering memory retrieval [71]. However, in chronic anxiety, a disconnect develops between the stressor and the behavioral consequence, allowing individuals to function normally while still having anxiety-like feelings [72]. The HPA axis ends up being chronically active in these cases of persistent anxiety and can cause harm by decreasing hippocampal serotonin receptors from the high amount of corticoids released during HPA activation [73]. These effects then lead to further impairment of coping mechanisms, thus prolonging the cycle and leading to more long-term damage.
In rodents, maternal separation and social isolation are common behavioral stressors used to understand the effects of long-term stress on the brain. When looking at early maternal separation, rodents showed changes in the brain circuitry involved in stress reactivity, specifically with an exaggeration of HPA axis activity [74]. When looking at social isolation, rodents showed abnormalities in behavior that reflects that of human depression and anxiety disorders [75]. While animal models are not fully accurate, they provide significant results that can further the understanding of human behavior.
Patients suffering from anxiety have been shown to have chronic stress-induced adrenal hyperactivity and elevated cortisol levels, indicating an overactive HPA axis [76]. Long-term exposure to elevated cortisol levels can cause damage to hippocampal receptors and hippocampal neurons [77], which would lead to higher cortisol concentrations, furthering the damage to the hippocampus.
Changes in the HPA axis may be due to the exposure to stressful situations during critical development stages. For example, rates of childhood abuse have been associated with patients suffering from anxiety disorders [76]. These stressors during important developmental stages can cause long-term changes in the HPA axis during these critical periods, leading to chronically low basal cortisol levels and impacting mood and mood disorders during adulthood [78].
Other Evidence of the Gut-Brain Axis
Evidence connecting the gut microbiome to the development of anxiety and depression suggests that overall diversity in the gut microbiome has associations with the presence of anxiety and depression-like symptoms. Individuals suffering from depression had less diversity in stool samples than normal individuals [45]. This suggests that lower diversity of microbes in the gut can lead to the development of depression. Similarly, in patients suffering from Generalized Anxiety Disorder, stool samples showed lower diversity in the microbial community [46].
Irritable Bowel Syndrome (IBS) and Irritable Bowel Disease (IBD) have been shown to have instability in gut microbiome populations [2]. This instability can indicate lower diversity in the gut, which has been associated with depression and anxiety. When looking at potential comorbidities for IBS patients, around 50% of patients had a comorbidity with depression or anxiety disorders [48].
Current Research
Vagus Nerve Stimulation
Conclusion
References
Authored for BIOL 238 Microbiology, taught by Joan Slonczewski,at Kenyon College,2024
