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Borrego-Ruiz et al. Microbiome Res Rep. 2025;4:20 https://dx.doi.org/10.20517/mrr.2024.78 Page 11 of 22

[158]
domain associated with lower α- and β-microbial diversity . Table 2 shows several studies examining
changes in the GM composition of patients with depression.

Retrospective studies have shown a consistent association between ELS and cognitive decline in adulthood,
linked to systemic inflammation [159,160] . ELS has also been related to neurological deficits in executive
function, memory capacity, and processing speed [161-163] , which are associated with significant changes in the
[164]
hippocampus and the prefrontal cortex , thereby affecting the hypothalamic-pituitary-adrenal (HPA) axis
and the neuroendocrine system, both implicated in stress regulation due to the release of cortisol .
[165]
Cortisol influences a range of cognitive and physiological processes, including immunity, inflammation, and
neuroplasticity . Additionally, individuals subjected to ELS frequently present psychiatric comorbidity
[166]
with multiple behavioral consequences [167-169] . Moreover, individuals who have experienced childhood and
adolescent psychological trauma possess significant difficulties in regulating their emotions, limitations
regarding their social interactions, reduced capacity to concentrate, and persistent psychological distress
have demonstrated that, upon crossing the BBB, SCFAs modulate neurotransmitter levels within the
that persists into adulthood .
[170]
Chronic stress, in combination with GM dysbiosis, has been shown to disrupt SCFA metabolism and
exacerbate dysfunction in the microbiota-gut-brain axis in individuals with depression. SCFAs exhibit
neuroprotective effects and are involved in pathological processes linked to the onset and progression of
depression, such as neuroinflammation, neuroendocrine fluctuations, chronic cerebral hypoperfusion, and
epigenetic modifications .
[171]

SCFAs present in the systemic circulation are capable of crossing the blood-brain barrier (BBB), thereby
modulating the transfer of nutrients and molecules that are instrumental in preserving the integrity of the
BBB. This process exerts a direct influence on brain development and the maintenance of central nervous
[172]
system (CNS) homeostasis . Furthermore, SCFAs have been shown to regulate a multitude of
fundamental behavioral and neurological processes by modulating the HPA axis, the immune system, and
tryptophan metabolism, as well as by contributing to the synthesis of various metabolites, including
neurotransmitters with neuroactive properties .
[173]

Within the microbiota-gut-brain axis, SCFAs play a pivotal role in the synthesis and release of peripheral
neurotransmitters, such as acetylcholine and serotonin (5-HT) . However, the permeability of the BBB
[174]
can limit the access of these neurotransmitters into the brain, potentially hindering their ability to directly
affect CNS function. Although peripheral blood 5-HT has been shown to regulate gastrointestinal motility
and excretion, it may also constitute a potential indirect mechanism by which cognitive, emotional, and
behavioral responses are influenced via neuroendocrine pathways or vagal afferents . In addition, studies
[175]
[176]
CNS .

DISCUSSION AND FINAL REMARKS
The present review aimed to summarize the impact of early-life GM development and dysbiosis on long-
term health, focusing on its role in physiological and mental health. Reinforcing key findings, a large body
of recent studies have explored this topic, primarily focusing on psychosocial factors [177,178] , acute
stress [179-182] , mental disorders , as well as physiological, metabolic, and immune processes . However,
[184]
[183]
much still remains to be elucidated regarding the underlying mechanisms and long-term effects of early-life
GM alterations.