Serotonin (5–hydroxytryptamine or 5–HT), widely known as the “good mood” hormone, is a monoamine, a derivative of the essential amino acid TRP obtained from food sources through the action of the tryptophan hydroxylase enzyme (TPH) ^[1][43]. It is a well-known neurotransmitter that acts at the level of the central nervous system (CNS) and it is a blood factor and a neurohormone that controls the function of several peripheral organs ^[2][44]. It also acts as a modulator of important physiological processes such as appetite, sleep, and mood, thus becoming a marker for the treatment of psychological disorders such as anxiety and depression ^[3][45]. The majority of the body’s serotonin (95%) is produced in the intestine, functioning as a hormone and autocrine, paracrine, and endocrine signaling.

It is of utmost importance that the intestine receives regulatory signals from the CNS for proper functioning. Recently, some studies have proved that the intestine is also capable of transmitting signals to the CNS which are then received by the brain. This two-way communication between the intestine and the brain is called “gut–brain axis” ^[4][46]. Dysfunctional intestinal microbiomes may be associated with behavioral disorders such as depression. Additionally, for this reason, serotonin, or its precursor TRP, seems to be an important molecule ^[5][47].

To further understand the physiologically relevant functions of 5-HT receptors, it is important to understand their distribution ^[6][48]. Several receptors are located in the CNS as well as the gut, so studying these receptors could lead to an increased understanding of brain–gut interactions ^[7][49]. Currently, there have been 14 different receptor subtypes belonging to the seven main receptor classes (5–HT1–7), which have been described in different parts of the brain, however their functions are still under investigation ^[8][50].

Many studies have investigated the different response of these receptors, but serotonin (5-HT) has a stimulatory effect on the hypothalamic–pituitary–adrenal (HPA) axis in both humans and rodents ^[9][51]. This interaction is mediated by the 5-HT1A receptor. However, only male rodents and not humans, respond to 5-HT1A antagonism to show increased corticosterone responses to stress ^[9][10][51,52].

The correlation between circulating levels of peripheral 5-HT and metabolic diseases has been discovered. This has been found to be attributable to the enzyme TPH, which in mammals catalyzed the 5-HT synthesis from TRP ^[11][12][53,54]. The enzyme has two isoforms: Tph 1, expressed mainly by enterochromaffin cells and adipocytes, and Tph2 expressed in neurons of the nuclei of the raphe, in the brain stem and in the enteric nervous system (ENS). Therefore, 5-HT has central and peripheral pools that operate separately.

Recently, Jones et al. discovered a modern function of 5-HT, highlighting an emerging pathway by which gut microbiota influences host health ^[13][55]. Since 5-HT cannot cross the blood–brain barrier, the central and peripheral pools of 5-HT are physically separate and act differently. In the brain, central 5-HT has an anorexigenic effect, whilst peripheral 5-HT acts on energy homeostasis. This action peripherally occurs in areas such as the liver and adipose tissue, in which the increase of 5-HT is associated with obesity and the development of metabolic diseases ^[14][56]. Enterochromaffin (EC) cells act as sensors within the intestinal lumen and are affected by the intestinal microbiome. In particular, the interactions between the intestinal microbiota and EC cells are important for glucose homeostasis. This mechanism may target the gut–brain axis signaling through gut microbiota and gut-derived 5-HT interaction.

The reduction of intestinal 5-HT levels has been shown to protect against diet-induced obesity, fatty liver disease, and glucose intolerance ^[15][16][57,58]. Except in cases where it is necessary to use drug therapy, the literature has provided evidence that suggests promoting the secretion of 5-HT could help counteract these psychological disorders.

The biochemical mechanism that can promote the synthesis of 5-HT after a period of physical activity has not yet been studied. Exercise represents one of the most common approaches for health and wellness, particularly forms of physical activity (PA) defined as mindful movement. Such exercises include yoga and Tai Chi and have been used increasingly as complementary health approaches. These are considered to be nonpharmacological and unconventional methods, validated for the treatment of anxiety and depression disorders ^[17][18][59,60]. For example, exercises such as meditation, yoga, breathing exercises, Tai Chi, or Qi Gong have provided statistically significant (but variable), results in terms of effectiveness, depending on style, duration over time, intensity, and if performed in combination ^[17][18][59,60].

Mindfulness-based stress reduction currently seems to be a widespread method which has yielded favorable results for well-being. Scientific evidence has shown that eight weeks of meditative practices are effective for improving emotional stability, the perception of well-being, and reducing the symptoms of stress, anxiety, and depression ^[19][61]. It also increases the immune response, improves blood pressure, and regulates the frequency of breathing, raising dopamine values and reducing GABA, adrenaline, and cortisol which are associated with anxious states. Unfortunately, the mechanisms that correlate physiological biomarkers and the effect of mindfulness remain poorly understood ^[20][21][62,63].

Despite this lack of understanding, several studies have investigated epigenetic changes as a result of mindfulness practices. For example, the methylation of the transporter gene of 5-HT, SLC6A4, which catalyzes the reuptake of 5-HT within the synaptic cleft ^[22][23][24][64,65,66] has been reported. In fact, researchers found that a significant decrease in methylation was observed at a genomic site of this gene after a period of 12 weeks with a mindfulness program, suggesting an effective practice in the treatment of stress-related disorders. Another study has shown that methylation in a CpG island (correlated with silencing of genes) in the 5′ region of the 5HTT gene, has been associated with a decrease in gene expression which, under stressful conditions, would induce changes in behavioral response ^[22][64]. Moreover, the postintervention mindfulness-program (MP) has shown that it can contribute to the reduction of gene methylation with a “preventive” effect on the onset of psychological stress ^[25][17].

Beneficial effects on mental health may also arise due to muscle pathways that are stimulated through exercise. In a recent study by Valente-Silva et al., the authors reported an interesting discovery of a biochemical pathway in skeletal muscle through which kynurenine (Kyn) ^[24][66] and TRP could have a positive impact on mental health. This has found to be controlled by the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1 α) involved in the cellular adaptive process ^[24][66]. The benefits of exercise in people with depression are recognized, although the underlying mechanisms remain unknown ^[26][27][67,68]. Exercise induces the production of PGC-1α1 in skeletal muscle and kynurenine aminotransferases (KATs) enzymes in turn convert kynurenine into kynurenic acid, which can act as a protective mechanism from depression ^[28][69].

Agudelo et al. described a mechanism by which the PGC-1α1 factor, produced in skeletal muscle, and whose synthesis is induced by training, changes the metabolism of kynurenine and protects against stress-induced depression. The activation of the pathway followed by PGC-1α1 increased the muscle expression of some KATs, thus improving the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood–brain barrier ^[29][30][70,71]. Reduction in plasma kynurenine levels has been shown to protect the brain from the stress-induced changes associated with depression ^[28][69].

In order for 5-HT synthesis to occur adequately throughout the body and the CNS, there must be sufficient intake of the essential amino acid TPH, through nutrition ^[31][72], which promotes psychological well-being ^[32][73]. Diet therefore plays an important role in enhancing 5-HT production and thus potentially protecting against the effects of conditions such as depression. For example, a direct association has been found between the consumption of processed foods (e.g., processed meats and refined cereals) and a greater risk of developing depression ^[33][74]. However, the MD and other more traditional dietary patterns, rich in fruits, vegetables, fish, and whole grains, have been correlated with a lower rate of depression ^[34][75].