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Page 4 of 19 Misera et al. Microbiome Res Rep 2024;3:48 https://dx.doi.org/10.20517/mrr.2023.81

Physiological responses to stress
A stressful stimulus triggers an immediate sympathetic nervous system response that releases adrenaline
and noradrenaline from the adrenal glands. The HPA axis is activated with prolonged stress, resulting in the
adrenal glands secreting cortisol. This stress hormone affects lipid, carbohydrate and protein metabolism
and immune function. These biochemical and physiological changes manifest as heart palpitations,
accelerated breathing, trembling hands, dry mouth, sweating, and/or intestinal reactions such as abdominal
cramps, pain, and diarrhea [22,23] . Consequently, the body, with the help of the CNS and hormones, not only
minimizes intestinal blood supply and mucus production but also purges food by inducing diarrhea and
vomiting. The blood, along with the energy supply, is redirected to the muscles and brain, coordinating the
cascade of the “fight or flight response”. These processes allowed humans to survive throughout evolution
and continue to impact the body even though stress stimuli have changed. In stress-sensitive people, public
speaking or financial troubles activate the “catastrophic program” in the brain in the same way that the
threat of a wild animal attack or a flood previously did. It is well established that chronic stress affects
[24]
gastrointestinal, physical, and mental health . Examples of these manifestations are disorders of gut-brain
[31]
interactions (DGBIs) [25-27] , including irritable bowel syndrome [28-30] or functional dyspepsia . However, the
majority of chronic gastrointestinal disorders are also frequently associated with high comorbidity of
[32]
psychological disorders .
Chronic stress is one of the factors that play a role in the onset of psychiatric disorders . This relationship
[33]
is illustrated by the stress susceptibility model [Figure 1] .
[34]
This model illustrates the psychological theory that there is a link between internal and external factors and
stress susceptibility, which can impact the risk of various diseases, including mental disorders. In this
theory, internal factors include genetics, biological and cellular factors, and gut microbiota composition .
[35]
External factors or buffering factors are psychosocial factors such as financial stability, a regulated lifestyle, a
sense of security, or education that can impact the ability to respond to stress. These factors collectively
determine how much stress an individual can endure before decompensation occurs. Decompensation
manifests as atypical behavior when a person cannot regulate their emotions. It is a natural defense
mechanism but can lead to mental and physical illness if persistent [36,37] . Standard therapies often overlook
internal factors, like the gut microbiota, which are crucial for stress management. Stimuli affecting the brain
are interpreted based on past experiences. If a stimulus is perceived as stressful, the brain triggers
biochemical reactions, including cortisol release, impacting organs like the gut. The gut microbiota then
signals the brain about the body’s state. Favorable internal factors help manage stress and prevent
decompensation. Modulating these factors can break the vicious cycle and improve therapeutic outcomes .
[35]

MICROBIOTA AND STRESS
Microbiota and neuromodulation
The fact that various microorganisms inhabit the gut has been known for years. However, it is recent
scientific research that has begun to elucidate the functions and significance of the intestinal “microbiota”,
which refers to the collection of microorganisms populating the gut. It is known that the gut microbiota is a
critical element in the functioning of the brain-gut axis and that it has an impact not only on physical
processes but also on mental processes. The gut microbiota plays an essential role in the human body, such
that some scientists call it a separate organ . The composition of the gut microbiota is individual to each
[38]
person and is constantly changing. The number and type of microorganisms in the different levels of the
gastrointestinal tract vary. Environmental conditions such as the availability of oxygen and nutrients, the
pH value, the intestinal transit time, and even the structure and immunological properties of the intestinal
epithelium determine the number and type of microorganisms that populate them. In addition, gender and
epigenetic factors such as diet, medications, stimulants, past medical history, latitude, and age influence the