Page 35 - JCBP-3-3

Journal of Clinical and
Basic Psychosomatics Microbiota in psychosomatic disorders

inflammatory effects by inhibiting histone deacetylases, in both depression and anxiety. In addition to serotonin
thereby promoting the expression of anti-inflammatory depletion, pro-inflammatory cytokines can disrupt the
genes and reducing the release of pro-inflammatory dopamine system. Inflammation-induced oxidative stress
cytokines such as interleukin (IL)-6 and tumor necrosis and cytokine signaling reduce dopamine synthesis by
factor-alpha (TNF-α). 35,36 Through this mechanism, altering the availability of its pre-cursor, tyrosine, and
SCFAs help maintain systemic and neuroimmune interfering with the function of enzymes such as tyrosine
homeostasis, reducing the risk of neuroinflammation hydroxylase. Dopamine dysregulation is associated with
that is often associated with depressive and anxiety symptoms of anhedonia, a core feature of depression,
disorders. Gut microbiota also plays a pivotal role in as well as motivational deficits seen in both depression
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immune system development and regulation. Under and anxiety. Glutamate, the primary excitatory
healthy conditions, beneficial gut bacteria promote neurotransmitter in the brain, is also affected by cytokine-
immune tolerance by maintaining a balance between induced neuroinflammation. Elevated levels of cytokines,
pro-inflammatory and anti-inflammatory responses. particularly IL-6 and TNF-α, can lead to excessive
Gut-associated lymphoid tissue continuously interacts glutamate release and impaired reuptake by astrocytes,
with microbial antigens, promoting immune tolerance resulting in glutamate excitotoxicity. This overactivation
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to non-pathogenic organisms and preventing excessive of glutamatergic signaling damages neurons and impairs
immune responses. For example, B. fragilis produces synaptic plasticity, processes that are critical for learning,
polysaccharide A, which regulates T-cell responses memory, and emotional regulation. The disruption of
and promotes anti-inflammatory signaling (Table 1). these systems contributes to cognitive and emotional
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In addition, Bifidobacteria supports gut health by dysfunction commonly observed in mood disorders.
preventing pathogen colonization and aiding immune Cytokine-induced inflammation also affects neurogenesis,
function, particularly in infants (Table 1). particularly in the hippocampus, a brain region involved
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in mood regulation and cognitive function. Chronic
SCFA, particularly butyrate, promote the production of
tight junction proteins that seal the gut lining, preventing a inflammation can inhibit the production of brain-derived
neurotrophic factor (BDNF), a protein essential for
“leaky gut”. 36-39 When this barrier is compromised, bacterial neurogenesis and synaptic plasticity. Reduced BDNF
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endotoxins, such as lipopolysaccharide (LPS), can enter the levels have been observed in individuals with depression
bloodstream, triggering the release of pro-inflammatory and anxiety, and inflammation-mediated suppression
cytokines such as IL-6, TNF-α, and IL-1β by immune of BDNF further contributes to neuronal atrophy and
cells. Once released, these cytokines exert systemic effects impaired hippocampal function. In addition, cytokine
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that extend to the brain, disrupting normal neuronal signaling can lead to HPA axis dysregulation. Abnormal
function and contributing to neuroinflammation. The cortisol levels, in turn, exacerbate mood disorders by
transport of pro-inflammatory cytokines across the BBB increasing stress sensitivity and further promoting gut
can activate microglia, the brain’s resident immune cells. permeability and systemic inflammation, perpetuating a
Activated microglia produce additional pro-inflammatory vicious cycle. 56
mediators, which can further amplify the inflammatory
response within the brain. 43-45 Pro-inflammatory cytokines 2.2. Bile acids
interfere with key neurotransmitter systems involved in Bile acids, traditionally known for their role in fat
mood regulation, particularly serotonin, dopamine, and digestion, have recently been recognized as important
glutamate. 46,47 In the case of serotonin, pro-inflammatory signaling molecules affecting metabolic and neurological
cytokines can increase the expression of the enzyme processes. Gut bacteria modify primary bile acids
indoleamine 2,3-dioxygenase, which diverts the produced by the liver into secondary bile acids, which then
metabolism of tryptophan (the pre-cursor of serotonin) interact with various receptors in the body, including the
away from serotonin synthesis and toward the production farnesoid X receptor (FXR) and the G-protein-coupled
of kynurenine. 49,50 As a result, serotonin levels in the bile acid receptor (TGR5). These receptors are expressed
brain are reduced, contributing to depressive symptoms. not only in the liver and intestines but also in the brain,
Moreover, the kynurenine pathway can generate neurotoxic where they influence neurochemical pathways. 41,42 For
metabolites, such as quinolinic acid, which overstimulates instance, activation of TGR5 can modulate energy
N-methyl-D-aspartate receptors, leading to excitotoxicity homeostasis and mitochondrial function in neurons,
and further neuronal damage. 50,51
while FXR activation has been linked to the regulation of
This imbalance between neuroprotective and neuroinflammation. Bile acids can also indirectly influence
neurotoxic kynurenine metabolites has been implicated brain function by modulating gut microbial composition

Volume 3 Issue 3 (2025) 29 doi: 10.36922/JCBP025040008