Austin Cobb
Campbell PA
Class of 2023
The Gut-Brain Axis and Gastrointestinal Microbiome
When an ovum is fertilized by a sperm and undergoes rapid cell division and
differentiation, the first structure to form is the beginnings of the gastrointestinal (GI) tract1.
Because of the importance of the GI tract, it is governed by its own enteric nervous system
(ENS) and influenced by the central nervous system (CNS), autonomic nervous system, and
hypothalamic-pituitary axis (HPA)2.
Within every human is a unique mixture of gastrointestinal microbes called the gut
microbiota or microbiome. While the majority of the bacterial species are the same, primarily
composed of anaerobic, rod-shaped Firmicutes and Bacteroides, the exact mixture of species
and amounts of each is unique to each individual - a bacterial fingerprint so to speak2.
A compelling relationship between the ENS, the CNS, and the gut microbiome was first
discovered in the 1990s with the discovery patients with hepatic encephalopathy often improve
dramatically with administration of oral antibiotics2. Additional relationships have emerged
between the composition of gut flora and the development of depression and anxiety 3.
Research has also shown a correlation between the severity of autism spectrum disorder (ASD)
and disturbance of the microbiome, specifically the ratio of Bacterioidetes to Firmicutes4.
Another interesting example of the gut-brain axis is that of functional gastrointestinal
disorders, of which irritable bowel syndrome (IBS) is perhaps the most well-known. Research
into these disorders has shown there is a link between psychiatric illness and functional
gastrointestinal disorders. Further, this link is believed to be bidirectional, with the ENS
influencing the CNS and vice versa5. The role of the microbiome in influencing this bidirectional
GBA is shown through multiple pieces of evidence: post-infectious IBS, small intestine bacterial
overgrowth, the effect of probiotics and antibiotics on symptoms, and many others all point to
a relationship2.
Knowledge of how the microbiome influences the GBA comes largely from germ-free
mice, which have been raised in sterile conditions to prevent colonization with a microbiome.
This lack of flora leads to alterations in the function of neurotransmitters in both the ENS and
CNS, delayed gastric emptying and gut motility, and neuromuscular abnormalities due to
change in gene expression for contractile proteins and neurotransmitters. Additionally, these
germ-free mice also showed alterations in the HPA axis, exhibiting anxiety-like behavior and
increased adrenocorticotropic hormone and cortisol2.
Also noted in germ-free mice was an increase in serotonin turnover and alteration in
synapse-related proteins. It was also shown that a commensal bacterium, Bifidobacteria
infantis, modulates tryptophan metabolism in the gut, possibly influencing the potential pool of
tryptophan available to be metabolized into 5-hydroxytryptamine, also known as serotonin6.
Memory dysfunction has also been noted in germ-free mice, possibly due to alteration in
expression of brain-derived neurotrophic factor - an important player in brain regulation and
cognitive function. Most importantly, colonization with normal gut flora leads to resolution of
all these alterations in function2.
One proposed mechanism of how the microbiome influences the CNS is through the
vagus nerve. Researchers showed chronic treatment with Lactobacillus rhamnosus could
influence the expression of γ-aminobutyric acid (GABA) receptors in different regions of the
brain. GABA dysfunction has, along with other neurotransmitters, been implicated in the
development of anxiety and depression. Most importantly from this study, researchers found
vagotomized mice did not have the same alterations in GABA receptor expression, suggesting
the effect of Lactobacillus rhamnosus was absent in those mice7.
Another potential mechanism of the microbiome’s influence over the GBA is through
bacterial secretion of local neurotransmitters, including GABA, serotonin, histamine,
acetylcholine, catecholamines, and nitric oxide among others. There are additional bacterial
metabolites, such as short-chain fatty acids, which influence the ENS through mucosal
serotonin release and sympathetic nervous system stimulation 2.
The commensal bacteria of the gut are also thought to influence inflammation in the
gut. One study found enteric non-absorbable antibiotics administered to mice led to an
increase in myeloperoxidase and substance P, indicating increased inflammation and pain
respectively. These mice also showed increased visceral hypersensitivity to colonic distention
consistent with the proposed mechanism of IBS. Furthermore, these changes were then
attenuated by the colonization with Lactobacillus paracasei. Thus, it is now known that
perturbations in gut microbiota lead to increased intestinal inflammation and the expression of
substance P and myeloperoxidase8.
Inflammation also plays an important role in depression. The blood-brain barrier (BBB) is
a critically important barrier to pathogen entry into the CNS, also preventing the entry of
antibodies and other small molecules as well as cells. While the peripheral immune system is
normally separated from the central immune system by the BBB, peripheral cells and
inflammatory mediators can enter through “gaps” in the tight epithelial junctions or during
times of illness and infection. Excess or prolonged cytokine activity leads to disruption of
synthesis, release, and reuptake of neurotransmitters9.
This link is has been further reinforced by a study done on learned helplessness in mice.
After induction of learned helplessness, the mice were then separated into those that
recovered after four weeks and those that did not. The mice who did not recover
spontaneously showed higher levels of tumor necrosis factor (TNF), interleukin-17A, and
interleukin-23 in addition to increased BBB permeability. Mice that did not spontaneously
recover were given the TNF-inhibitor etanercept. They were able to recover from their learned
helplessness and even showed repaired BBB10. In summary, altered gut microbiota is associated
with increased inflammation, and peripheral inflammation has been shown alter the activity of
CNS neurotransmitters8,10.
The gut microbiome not only is involved in inflammation and direct cognitive effects,
but it also changes how oral drugs are metabolized. Olanzapine is shown to alter the gut
microbiome, leading to significant weight gain by shifting the balance towards “obesogenic”
bacteria13. Coadministration of antibiotics and olanzapine was shown to attenuate weight gain
in rats14. Selective serotonin reuptake inhibitors (SSRIs) likewise impact the gut microbiome,
acting as antibiotics. Sertraline, fluoxetine, and paroxetine have the strongest antimicrobial
activity, where as fluvoxamine, escitalopram, and citalopram have the least12. There is limited
evidence showing fluoxetine directly impacts the gut microbiome, which may be responsible for
the weight gain commonly seen as a side effect15. It is possible that patients with different
compositions of gut microbiome are more prone to certain side effects, and the future of
treatment-resistant depression may involve restoring an appropriate gut microbiome or
selection of therapy based upon the exact composition of a patient’s microbiome12.
Among the numerous neuropsychiatric conditions with links to the human microbiome,
perhaps the most interesting is autism. The etiology of ASD is currently unknown, and
treatment focuses on symptom management17. Germ-free mice and rats are shown to have
decreased social functioning, preferring interaction with a non-social object over novel mice
and preferring interacting with familiar rather than unfamiliar mice. Interestingly, colonization
of the gut or administration of probiotics have been shown to reduce these symptoms of social
inhibition in germ-free mice18. Additionally, colonization with the human gut bacteria,
Bacteroides fragilis, reduced stereotyped behaviors such as vocalizations and burying behavior
in mice18. While this is preliminary data, the previously established link between the
microbiome and the bidirectional GBA provides a plausible mechanism for how gut bacteria
could contribute to autism and its symptoms.
Humans have existed alongside microbes for the entirety of their existence. The
relationship between pathogenic and commensal microbes and human physiology is complex.
While research on the impact of the microbiome is still in its infancy, data suggests a strong link
between neuropsychiatric illness and GI tract dysbiosis2. Conditions such as depression, anxiety,
autism spectrum disorder, schizophrenia, epilepsy, and Parkinson’s disease have all been
shown to have links to microbiome dysfunction16. Gut microbes have been shown to alter the
metabolism of and even create neurotransmitters2. They also influence inflammation in the
body, which has been shown to impact the CNS and even contribute to or cause psychiatric
disorders2,9. There is even some evidence to indicate the gut microbiome may directly affect
CNS neurotransmitters through action on the vagus nerve7. While these direct effects are
further studied, there is solid evidence that the gut microbiome influences the ENS, and the
ENS influences the CNS2,5,16. While further research is needed, the future of treating psychiatric
illness may involve tailored therapy based on a patient’s unique gut microbiota2,16.
Bibliography
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