Effects of Gut Microbiome on Depression

Nolan Brady
WRTG 3030
University of Colorado Boulder

Abstract
Depression has a long, complicated history in medicine. For being one of the oldest
recorded diseases, with its first apparition occurring in the second millennium B.C.E, it remains
one of the least understood [8]. Unlike many other diseases being researched, depression has
many different potential origins, with many potential avenues for treatment. The complications
in approaching depression occur in both the interconnectedness that is involved in the causation,
and the lack of a “silver bullet” treatment pathway. Said another way, there are too many
variables in both diagnosis and treatment to assert an explanation with any sense of certainty.
Previous research has focused on neurochemical relationships between neuroreceptors and the
endocrine system in an effort to pinpoint the neurochemical imbalance that has been proven to
exist. Unfortunately, these explanations have gotten treatments no closer to a statistically
significant solution. Recent research involving the gut microbiome has made compelling
progress towards linking neurological effects of the gut microbiome and overarching depressive
episodes. Most importantly, fecal transplants from rats with major depressive disorder (MDD)
showed an onset of depressive symptoms. Equally as important, a rat placed under conditions to
induce a state of MDD showed a dramatic reduction in gut microbiome biodiversity [9].
Mechanisms of action such as the hyperactive effects of the gut microbiome on the vagus nerve,
limbic system and endocrine system highlight the importance of a more broad spectrum
approach to analyzing the source of chemical imbalances within the brain.

Introduction
In 2017 the National Institute of Mental Health released a study stating that in the United
States alone 11 million people suffered from a depressive episode [7]. Of those 11 million
approximately 64% were classified as having suffered severe impairment [7]. Severe
impairment is defined as a depressive condition being impactful enough to limit or prevent the
individual from performing daily tasks such as work or school [7]. The data being produced in
these studies leave little room for interpretation; this disease is one to take seriously. Despite
the complexity that surrounds the causation and potential treatment of these conditions, it is
pivotal to understand the basics of the pathophysiology behind depression. Over the course of
this review, we will cover in detail the main neurotransmitters such as dopamine, serotonin,
norepinephrine, and gamma-aminobutyric acid (GABA) that are thought to be partially
responsible for MDD. Next, we will take a look at the receptors for these neurotransmitters
since the interaction between both of these has interesting and unique ways in which it can both
aid in and/or cause depressive episodes. Understanding both neuroreceptors and
neurotransmitters in tandem will greatly aid in understanding how different regions of the brain
are involved in different aspects of depression. With all this background covered, the final
section of this review will be dedicated to linking gut microbiome to the neurologic effects that
we previously discussed. When speaking about the gut microbiome the focus will be on the gut-
brain axis (GBA) with respect to how it interacts with the endocrine, autonomic nervous
system, limbic system, and the hypothalamus. While the health of the gut microbiome joins the
rest of the potential solutions to treating depression, it may well add a critical vantage point by
which to view the disease. It is only in understanding all potential factors of such a nebulous
disease that we can ever hope to begin effectively treating it.

Physiology of Depression
Depression has long been understood as being a “chemical imbalance in the brain”. While
this is mostly accurate, it lacks a great deal of detail as to what chemicals are out of balance and
how these different chemical imbalances might manifest into observable symptoms. The
chemicals in question are the neurotransmitters serotonin, dopamine, norepinephrine and
GABA. Each of these has a specific role in aiding neurons transmit impulses in the brain by
impacting action potentials across neurons. The relationship these neurotransmitters have with
their respective receptors will highlight how imbalances or other abnormalities with respect to
these neurotransmitters may play a role in depressive episodes.

General Function of Neurotransmitters and Neuroreceptors

Neurotransmitters play a very active role in the way the brain works. Much as the name
implies, neurotransmitters are instrumental in neuronal communication. Despite the umbrella
term there are two main types of neurotransmitters. There are inhibitory and excitatory
neurotransmitters [4, 11]. Inhibitory receptors such as GABA receptors act as suppressors for
neuronal signals and in turn decrease the nervous system activity [4, 11]. Excitatory
neurotransmitters do the opposite. These are chemicals such as norepinephrine which increase
the magnitude of certain brain signals and increase nervous system activity on the neurons or
neuronal areas they are found [4]. To help in understanding these effects it’s important to know
how neurons transmit signals. In an overly simplistic explanation, neurons carry signals by way
of a binary chemical charge (either positive where the neuron is actively signaling, or negative
where no signal is being transmitted) within the neuron. The binary system we use in computers
was modeled after the humble neuron after all. In any case, this charge is achieved by the
neuron either taking on or expelling charged ions [12]. The polarization from negative to
 positive of these neurons is referred to as an action potential. The inhibitory properties of
GABA and the GABA receptors essentially work to silence different neuronal signals, or, in
other words, prevent the ionization of the neuron. Therefore, having more GABA manifests
itself as a calm or less anxious state of being. Norepinephrine on the other hand does the
opposite, this neurotransmitter essentially boosts signals and creates hypersensitivity within the
neuron. Interestingly enough, norepinephrine is a derivative of dopamine. A higher than normal
level of circulating norepinephrine often manifests as a higher level of anxiety in affected
individuals. Knowing how a neuron interacts with the likes of GABA or norepinephrine isn’t
complete without mentioning serotonin or dopamine. These two neurotransmitters are
responsible for carrying the action potential between neurons. These chemicals bind to receptor
sites on the receiving neuron and allow for ion channels to open in order to change the
polarization of the neuron. Normal levels of serotonin and dopamine, much like GABA and
norepinephrine are vital for regular signaling across the neuronal pathways.

Examining Brain Regions and Systems Involved in Depressive Episodes

Having gone over the smaller scale aspect of how messages are carried around the brain,
it’s important to zoom out and look at the brain as a whole. In doing so, there are areas with
particular importance to depressive symptoms. These areas include the endocrine system, the
limbic system, and a brief look at the stress steroid family of glucocorticoids (such as cortisol).
The endocrine system is known to most as the system in the body that regulates hormones. This
includes but is not limited to the production of cortisol, norepinephrine and other glucocorticoids
[12]. As was discussed in the previous section, an over or under production of hormones such as
norepinephrine can be very problematic to overall brain function. The same goes for cortisol and
glucocorticoids with respect to the limbic system. To those unfamiliar with the limbic system,
it’s a group of structures in the brain that include the amygdala, hippocampus, hypothalamus
(which acts as the liaison between the nervous system and the endocrine system), and other
structures that fall out of the scope of this review. The amygdala is the primary region of the
brain responsible for fear, anger and aggression [12,13]. The hippocampus is in charge of
cataloging memories and works in conjunction with the amygdala to process learning from fear
[13]. It may have become apparent that a lot of these systems interact with one another.
Something to the order of the endocrine system regulates the brain function of the limbic system
which in turn regulates the endocrine system. This recursive nature is where the true complexity
of depression becomes apparent. Take for instance cortisol (which is produced from the
hippocampus as a response to stress) and its effects on the amygdala and hippocampus. Studies
have shown that cortisol actually causes the amygdala to enlarge. This enlargement has been
linked to problems sleeping and changes in how other key hormones are regulated (namely
within the glucocorticoid family) [13]. Interestingly enough the hippocampus is also impacted by
its release of cortisol. It’s been shown that cortisol can actually impede the neuroplasticity within
the hippocampus leading to issues with memory.

The Gut Microbiome and Gut-Brain Axis

The gut microbiome is probably something that most people have written off as being a
pawn of the probiotic marketing world. Until more recently it hasn’t made its way into the more
conventional science world. In short, the gut microbiome is a collection of an astounding number
of microorganisms that live in the human gut. It’s estimated there are about 10❑14
microorganisms that reside within the gut [10]. These organisms have a far larger impact on
general well-being than was previously understood.

General Physiology of the Gut-Brain Axis With Relation To MDD

The microbiome and gut-brain axis (GBA) has far greater implications to wellbeing than
simple intestinal health as was previously thought. Recent research has shown that the gut
microbiome is capable of producing neurotransmitter molecules on their own in non-trivial
quantities [10]. Through these and other nervous system pathways these microorganisms are able
to directly and indirectly impact the brain systems discussed previously, namely the limbic and
endocrine systems. This is all done via the gut-brain axis. The GBA provides two way
communication between the central nervous system (CNS) and enteric nervous system (which
controls most of the autonomic intestinal function) [9,10]. A lot of this nervous system
stimulation from intestine to brain is actuated along the vagus nerve. This provides the
microbiome almost uninterrupted access to the hypothalamus and greater limbic system and vice
versa [10,14]. Because of this, irritation or neurologic signals initiated from the gut can cause
disruption within the brain. These disruptions can in turn affect other neurotransmitters that are
secreted within the brain leading to further imbalances down the line.
Another system that is prone to impact from the gut microbiome is the hypothalamic,
pituitary and adrenal axis (HPA). This system is essentially a feedback loop of different
hormones that are secreted by each gland that in turn regulate each other. It’s essentially a
complicated three way checks and balances system deep within the brain. With respect to MDD
the primary issue that can arise is hypersensitivity within this axis. This would lead to hyper
activation of the adrenal gland which will in turn flood the body with norepinephrine,
epinephrine and glucocorticoids. Research has shown that the microbiome can directly increase
that sensitivity thereby increasing the circulating hormone levels. This also has a number of
tangential effects. The most noteworthy of these effects being a reduction of serotonin within the
hippocampus. This leads to an even greater series of cascading effects within the HPA axis.
Other effects such as the sleep disruption that symptomatically occurs in patients affected by
MDD would also be caused by the increased glucocorticoids produced from HPA hyperactivity.
Implication of the GBA and General Takeaways

With the breakdown of this information there are a few important take away points that
need to be highlighted. Primarily the brain is a complicated and extremely interconnected organ.
There are far more intertwined systems than can be explained in an easily digestible manner.
Most crucial neurologic systems have both activatory and inhibitory effects on most other
systems. This leads to a network that may seem robust on the surface, but can easily be
manipulated at the introduction of outside stimulus. When examining these imbalances in
neurochemicals and neurologic impulses it’s important to understand that a small change in one
system can easily compound into a systemic issue. Accounting for these external factors clearly
shows how the gut microbiome can influence an individuals neurochemistry. Such a large
organism with several direct methods of engaging with neurologic systems at large can cause
major shifts in chemical balances. While the GBA is not inherently the cause (since after all it
can have many positive effects on mental health symptoms) it is important to look at the
incremental changes it can introduce, and furthermore, understand the cascading effects those
changes can have.

Moving Forward
The GBA and gut microbiome has potential for being a new frontier from which we can
fight mental disorders such as MDD. Understanding that there is an established pathway between
the gut microbiota and major regulatory systems in the brain is a major step in the right direction,
however furthering that knowledge into an actionable plan to help tackle the disease is truly
paramount. With more time and research potential there are a few aspects of the microbiome and
GBA that should be further investigated. The first is to develop a holistic view as to what a
healthy gut microbiome should resemble. Having a breakdown of what ratio of different
microbiota make up a healthy digestive tract would allow for a much needed baseline from
which to base diagnostic efforts or future research. Understanding if there are any pathogenic
bacteria that can or should be controlled may even lead to the discovery of another form of
antidepressant provided it’s efficacy is great enough. The second priority should be establishing
what environmental factors can be beneficial to maintaining the healthy bacteria while
eliminating the rise in pathogenic bacteria. This knowledge would further aid in the development
of sustainable preventative measures against a wide assortment of mental disorders. It could also
open the doors to minimally disruptive forms of treatment that don’t have the side effects and
stigmas of other drugs such as SSRIs or GABAergic reuptake inhibitors. Lastly a cohesion of our
knowledge of the GBAs affect on mental health disorders should be cross referenced with our
current understanding of mental health disorders. Taking a step backwards away from ultra
focused, and all too often miopic, research and examining the issue at large may reveal trends
that were previously missed. This may offer researchers clues as to where to look to next, or may
simply lead to a greater overall knowledge base from which the research community can build
on in the future.

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