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Depression is a complex disease with multiple contributing causes, involving both genetics and the environment. In this article, we discuss genetics, gut microbes, the gut-brain axis, as well as links between depression and inflammation.
What is Depression?
Depression (also named Unipolar Depression, Major Depression, and Major Depressive Disorder) is a complex disease with many contributing factors, including both the genetics and the environment. We still don’t completely understand what causes depression.
Conflicting results have arisen from studies that look at the effectiveness of antidepressants for the treatment of depression.
The only effective treatments, neurotransmitter reuptake inhibitors, have low efficacy since 30 – 40 % of patients do not respond to these drugs and 60 – 70% of patients do not experience remission (R, R).
In addition, patients typically experience many severe side effects while these medications can take a long time to see an improvement in mood.
Diagnostic Criteria for Depression
Diagnostic criteria for depression include (R):
- Depressed or irritable mood
- Decreased interest in pleasurable activities and ability to experience pleasure
- Significant weight gain or loss (>5% change in a month)
- Insomnia or hypersomnia
- Psychomotor agitation or retardation
- Fatigue or loss of energy
- Feelings of worthlessness or excessive guilt
- Diminished ability to think or concentrate
- Recurrent thoughts of death or suicide
Risk Factors for Depression
Known Risk Factors for Depression include (R):
- Females are approximately twice as likely to have depression than males.
- Highest risk age group is between 25 – 30
- People who are divorced, separated, or widowed have higher risks of depression than married or people who were never married
- Lower income than $20,000/year, and rates of depression decline as income increases.
- Having relatives with early-onset major depression
- Personality: middle-aged adults (31 – 41 years old) with decreased emotional strength and no interpersonal dependency
- Stressful life events
- Early trauma
- Cardiovascular disease, AIDS, respiratory disorders, cancer, Parkinson’s
Is Depression Really Caused by Low Serotonin?
Most antidepressants aim to increase the amount of the neurotransmitters serotonin and norepinephrine in the synaptic cleft.
Neurotransmitters are chemicals in our body that transmit signals from one nerve cell to another nerve, muscle cell, or gland cell. They play a major role in shaping everyday life and functions. There are over 100 neurotransmitters, including dopamine, norepinephrine, and serotonin.
However, it remains an unanswered question whether low serotonin and norepinephrine cause depression, because numerous attempts to find confirm that depressed people have low serotonin and norepinephrines have failed (R1, R2).
Furthermore, while most selective serotonin reuptake inhibitors immediately increase serotonin in the brain, patients don’t experience an improvement in the mood until weeks after starting the medication (R).
Although antidepressants have established biochemical bases such as inhibition of monoamine oxidase or reuptake of specific neurotransmitters, diagnoses, and treatment of depression are subjectively based on symptoms and not on measured biochemical imbalances (R).
The fact that this is a complex disease with many different contributing causes but one treatment may account for low treatment response rates.
Genetics of Depression
Attempts to identify genes or genetic mutations responsible for depression have been met with limited success, possibly because different cases of depression may be caused by mutations in different genes as well as the environment (R).
Several comprehensive studies (genome-wide association, familial and twin studies) indicate that interactions of multiple genes, and interactions of these genes and environmental factors are responsible for depression (R, R2).
A systematic genomic study identified genes related to immune function and inflammation as genetic causes of depression (R).
Another comprehensive genetic study identified genes related to serotonin functions, circadian rhythm, and other neurotransmitter genes as a risk factor for depression, as listed in this table (R):
|Gene Name||Variant||Minor Allele Frequency|
|5HTTLPR/SLC6A4||44 bp ins/del||0.43|
|intron 2 VNTR||0.35|
|ACE||Ins/del intron 16||0.45|
|DRD4||48 bp ins/del||0.45|
|GABRA3||CA repeat intron 8||0.29|
|ACMSD (R)||rs2121337 (increased suicidal risk, Quinolinic)|
Family studies of major depressive disorder-recurrent unipolar (MDD-RU) disorder have shown that first degree relatives are at increased risk (R).
Serotonin transporter gene (SLC6A4) is associated with MDD (R). The serotonin transporter gene and other genes involved with the serotonergic system are candidate genes for susceptibility to depression since several antidepressants act on this system.
Six other MDD susceptible genes are APOE (Apolipoprotein E), DRD4 (Dopamine receptor D4), GNB3 (Guanine nucleotide binding protein subunit beta 3), MTHFR (methyl tetrahydrofolate reductase), SLC6A3 (sodium-dependent dopamine transporter) and SLC6A4 (R).
If you have had your DNA sequenced, such as by 23andme, you can also input your genetic data into SelfDecode to learn more about how these genes affect your health and depression risks.
The Gut Microbiome
For every cell in a human body, there are ten cells of gut microorganism. The average human gut is inhabited by about 10,000 – 100,000 billion microorganisms like bacteria, fungi, and viruses. Together, the gut microbiome (all genes of these microorganisms) contains 150 times as many genes as the human genome (R).
Three major phyla (groups) of bacteria: Bacteroides, Firmicutes, and Actinobacteria live in the large intestine. Most of these bacteria don’t need oxygen to grow (anaerobic).
The composition of our gut bacteria is mainly influenced by (R):
- Our mother’s gut bacteria
- Our diet
The composition of our gut bacteria readily changes in response to the environment, while our genes remain unchanged. This is because the bacteria have very short lifespans and also compete for resources and interact among themselves.
Diet Changes the Microbiome
In mice, dietary changes such as including 50% lean beef comparing to normal chow significantly change fecal bacteria composition and also reduce anxiety-like behaviors within three months (R).
When a human goes from meat-eating to a vegetarian diet, the gut biome can rapidly switch between carnivorous and herbivorous profiles within one day (R).
Neurotransmitters and Hormones vs the Gut Microbiome – A Two-Way Interaction
Changes in neurotransmitter or hormonal environment can also affect the gut microbiota as mice that experienced social disruption exhibit less microbial diversity and richness than the same mice at baseline or control mice (R).
In addition, germ-free mice show elevated turnover rates of many neurotransmitters and altered expression of synaptic plasticity-related genes, suggesting that normal gut microbiota modulates brain development and behavior (R).
Humans and the gut microorganisms have a two-way relationship.
Diseases Influenced by gut microbial metabolism
How the Gut Microbiome Influences Depression
Gut Bacteria Influence Brain Development
Rodents that have grown without gut bacteria (germ-free rats and mice) lack a mature enteroendocrine system (the hormone production system of the gastrointestinal tract). They also differ in neurotransmission compared to their counterparts with gut bacteria. (R).
Manipulation of Gut Bacteria in Mice Changes their Brain and Behaviors
Mice without gut bacteria exhibit increased spontaneous movements and are anxious which is accounted for by increased turnover rates of neurotransmitters like noradrenaline, dopamine and serotonin and the brain (R).
Newborn rats undergo stress and become depressed when separated from their mothers. The addition of Bifidobacterium to their diet reverses the stress and depression both behaviorally and neurochemically. However, the Bifidobacterium is less effective than the antidepressant citalopram (R).
When two types of germ-free mice are fed with feces from the other type, they start behaving like the other type of mice from which the feces was taken (R).
Feeding mice with antibiotics temporarily change the gut bacteria. It increases the expression of BDNF in the brain (hippocampus) and changes their exploratory behaviors (R).
Probiotic Supplementation Alleviates Depression in Humans
Probiotics significantly decreased depression scores in both healthy individuals and patients with major depressive disorder under 60 years of age (R).
L. helveticus and B. longum reduced depression in healthy volunteers when they were taken regularly (R).
A mix of L. acidophilus, L. casei and B. bifidum decreased depression, and in addition lowered insulin levels, insulin resistance, and hs-CRP and increased glutathione levels in patients with major depressive disorder (R).
Read this post to learn more about how probiotics improve mood and brain function.
The Gut Microbiota-Brain Connection and Depression
The Gut-Brain Axis
The gut-brain axis represents the 2-way communication between the gut and gut microbiota, and the brain (R).
It includes neural, chemical, humoral and immunological signaling between the organ systems involved as well as the gut microbes.
Inflammation May Contribute to Depression
The cytokine hypothesis of depression came about with the observation that several symptoms of depression resemble that of sickness behaviors, including lethargy, fever, reduced appetite, decreased interest in exploration or sexual activity and increased time spent sleeping (R).
Also, patients treated with cytokine therapy, such as interferons and interleukin-2 often experience depression as a side effect (R).
Sickness behaviors can facilitate healing. The seclusion of sick individuals reduces the odds of spreading the infection (R, R2).
There are also higher incidences of immune activation in depressed patients (R).
Furthermore, patients with cytokine-induced depression typically respond well to SSRIs. However, there are several nuanced differences between the diagnostic criteria (also called Diagnostic and Statistic Manual of Mental Disorders or DSM) for depression and sickness behavior and evidence is conflicting regarding whether inflammation really causes depression (R).
Not all ill patients have depression, and not all depression patients have high inflammatory markers. Altogether, this suggests that inflammation (as much as serotonin deficiency) may be a contributor, rather than a direct cause of depression (R).
Nevertheless, regulation of inflammatory cytokines may simply be one piece of the puzzle.
Intestinal Permeability and Depression
The intestinal mucosal barrier and the mucosal immune system keep the gut microbes inside the gut lumen from the gut immune system. Compromised gut barrier allows the bacteria to activate the immune system, which can raise inflammation (R).
When bacteria move through the intestinal barrier, activation of the gut immune system can increase the inflammatory cytokines. This process leads to anxiety behaviors in mice, which goes away when the gut barrier function is restored, or when probiotics are introduced (R).
In the presence of leaky gut, bad gut bacteria may trigger the inflammation through the TLR4 receptor (R).
In humans, the presence of serum antibodies (IgA and IgM) against harmful gut bacteria, which indicate that they have leaky gut, can predict depression with 90% accuracy (R).
Gut Bacteria Influence the Stress Response System
Many depressed patients have dysfunctions of the stress response system (HPA axis dysfunction), and resolution of the HPA axis dysfunction correlates well with remission of the disease (R).
Monoamine reuptake inhibitors are also found to decrease glucocorticoid receptor resistance, thus reducing HPA axis dysfunction, so drugs that target HPA axis dysfunctions may be effective treatments for major depression (R).
In addition, early life stress has been associated with an increased risk for depression at least partly because early life stress can make the person more sensitive to stress later on (R).
Colonization of the gut flora influences changes the stress response setpoint. Adult mice without gut bacteria exposed to mild restraint stress exhibit stronger stress response than mice with gut bacteria (R). This stronger stress response in the mice without gut bacteria could be reduced by giving it a probiotic bacteria called Bifidobacterium infantis (R).
The Gut Microbe Influences Neurotransmitter Production
Bacterial Waste Chemicals can Act as Neurotransmitters
The gut bacteria are major modulators of chemicals (metabolites) in the blood. Some of these are neurotransmitter precursors or may influence neurotransmitter levels in the brain, while others may have neuroactive properties.
Carbohydrate fermentation by gut microbes results in short-chain fatty acids such as propionates and butyrates. These metabolites may have neuroactive properties which have been implicated in autism spectrum disorder (R).
Gut Bacteria and Inflammation Affect Serotonin Metabolism
Kynurenine of the tryptophan metabolic pathway from (R).
While tryptophan depletion does not always lead to depression, low serum tryptophan may precipitate depression in susceptible individuals (R).
An increase in inflammatory cytokines such as IFN-α, IFN-γ, and TNF-α can increase the activity of the enzyme indoleamine-2,3-dioxygenase (IDO), which increases tryptophan conversion into neurotoxic compounds including kynurenine and quinolinic acid (R).
Neurotoxic substances, rather than tryptophan depletion, may cause depression (R).
Rats treated with Bifidobacterium infantis have reduced inflammatory cytokines, increased tryptophan and kynurenic acid (a neuroprotective metabolite of tryptophan), and reduced kynurenine levels in comparison to untreated rats (R).
In addition, these effects of B. infantis on tryptophan metabolism may be strain-specific as it was not observed in other B. longum. However, B. longum reduced depression and increased BDNF in rats (R).
While this study presents promising evidence that gut bacteria may help modulate tryptophan metabolites and prevent depression, more rigorous studies are required to support this mechanism.
How the Gut Bacteria May Affect the Brain
One of the ways that the gut content can communicate with the central nervous system is through enterochromaffin cells and the vagus nerve.
It is believed that enterochromaffin cells and vagus nerve are involved in the communication between the gut bacteria and the brain, although we still don’t completely understand how (R).
Enterochromaffin Cells (ECC) Sense Gut Bacteria and Secrete Serotonin
- Are present throughout the digestive tract
- Detect the types of bacteria and foods in the gut with Toll-like receptors
- Secrete serotonin and signaling peptide in response to stimuli, i.e. foods, microbial factors, bacterial toxins
- Serotonin secreted by ECC cells increases motility, so pathogenic bacteria tend to increase serotonin signaling in the gut to induce a flushing motion which can induce diarrhea or vomiting.
- Harbor receptors for corticotropin-releasing hormone, and neurotransmitters including GABA, adrenaline and acetylcholine
The Vagus Nerve May Link Between the Gut and the Brain
- Controls intestinal peristalsis as well as secretions, and communications among gut cells and with the gut microbes
- Controls how ECC cells secrete serotonin
- Innervates (controls) many regions of the brain, including the raphe nuclei, which is responsible for producing serotonin for the rest of the brain
- Although this is not always the case, cutting the vagus nerve often diminish the effects of the probiotic on depression and anxiety in mice, such as in these two studies:
- Introducing Lactobacillus rhamnosus (JB1) altered gamma-aminobutyric acid (GABA) receptor function in the brain of mice, resulting in mice with higher anxiety and reduced depression (R).
- Mice with infectious colitis also experience anxiety-like phenotype, which could be normalized by introducing Bifidobacterium longum NCC 3301. B. longum decreased anxiety-like phenotype reduced but had effects on the colitis (R).
- The FDA approved vagus nerve stimulation as a treatment for treatment-resistant depression in 2001. In a small trial of severely ill treatment-resistant patients, the long-term response rate to this treatment was around 44%, with a remission rate at about 29% at 1 year (R). We still don’t completely understand how vagus nerve stimulation helps with depression. However, the successful treatment outcomes of vagus nerve stimulation implicate the vagus nerve as a key modulator in the communication between the gut and the brain, although other organs controlled by the vagus nerve could also contribute to this pathway.
- Another study which tracks HPA axis dysfunction in depressed patients treated with VNS found that HPAA dysfunction also resolved as the depression resolved-post VNS (R).
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