Serotonin is a key-signaling regulator that modulates a wide range of effects on host physiology, including the control of gut motility, secretory reflexes, platelet aggregation, regulation of immune responses, and regulation of mood and behavior [
67]. Once tryptophan is absorbed in the gut, it crosses the blood–brain barrier to be partially metabolized into serotonin in the raphe nuclei within the brain stem [
34]. However, the majority (~95%) of serotonin in the body is synthesized, stored, and released in the gut, mainly from a subset of enteroendocrine cells called enterochromaffin cells in the intestinal mucosa [
19]. The small amount of serotonin that is not in enterochromaffin cells is in the enteric nervous system, in particular, the myenteric plexus, which contains descending serotonergic interneurons [
68] (
Figure 1B).
Enterochromaffin cells, also known as epithelial sensory transducers, secrete serotonin in response to mucosal stimuli, such as microbiota metabolites as discussed below. Once synthesized, serotonin is secreted in the lamina propria, where it has access to the nerve fibers. This implies a large amount of serotonin is secreted in the extracellular space. Thus, to avoid receptors’ desensitization by their contact with excessive amounts of serotonin, which is toxic [
69], serotonin overflow must be efficiently controlled. One important player in serotonin uptake by gut epithelial cells, thus serotonergic termination, is the Na
+/Cl
− dependent, serotonin transporter (SERT). SERT, is a recently crystallized protein [
70] comprised of 12 transmembrane domains, and is a member of a large superfamily of sodium/chloride dependent transporters, which also contain transporters for other neurotransmitters, such as dopamine and norepinephrine [
71].
Secreted serotonin mediates its actions via several receptor subtypes [
72], where it has been observed to affect epithelial cells’ proliferation and secretion [
73], but mainly acts as a regulator of the gut motility. Secretion of serotonin by enterochromaffin cells activates intrinsic primary afferent neurons (IPANs) in the submucosal plexus via its action on 5-HT
1P receptor. These cells initiate peristaltic and secretory reflexes, which influences gut motility (
Figure 1C). Moreover, intestinal serotonin activates extrinsic sensory nerves via its action on 5-HT
3, which are postsynaptic receptors found on the terminals of extrinsic sensory neurons terminal in the gut and transmit noxious signals to the brain [
74] (
Figure 1B). Though it does not initiate peristaltic movement, 5-HT
3 conveys any kind of change in gut motility to the brain via its presence on myenteric IPANs and in the myenteric plexus, where they mediate fast excitatory neurotransmission [
75]. Similarly, 5-HT
4 receptors themselves do not initiate peristaltic reflexes, but because of their location at the terminals of submucosal IPANs, at synapses within the myenteric plexus, and at the neuromuscular junction, stimulation of 5-HT
4 receptors is critical for these reflexes [
76]. 5-HT
4 receptors work through stimulating the production of the neurotransmitters acetylcholine and calcitonin gene-related peptide, which enhances the spread of stimuli around and through the gut wall, to ultimately enhance and maintain a normal gut motility [
77,
78].
The strong link between inflammation, and disruptions of serotonin metabolism has been well established. Immune cells including lymphocytes, mast cells, dendritic cells and monocytes have all been reported to express SERT, serotonin receptors and enzymes involved in the production and metabolism of serotonin [
79,
80] (
Figure 1C). T lymphocytes express the main components of serotonin metabolism, i.e., tryptophan hydroxylase (TPH), the first rate limiting enzyme involved in serotonin production, SERT, monoamine oxidase (MAO) [
80], which breaks down serotonin into its metabolite 5-HIAA, and 5-HT receptors [
80]. While resting, naïve T cells express very little TPH1, the TPH isoform present in the intestinal enterochromaffin cells, where intestinal serotonin is synthesized, activated T cells show approximately 30-fold higher expression of TPH1, suggesting increased levels of serotonin in activated T cells [
81], and 5-HT receptors, including 5-HT
1B, 5-HT
2A, and 5-HT
7 receptors [
81]. However, expression of SERT in T cells is still questionable; León-Ponte et al. shows that neither naïve nor activated T cells express high-affinity SERT [
81], however another study claims that SERT is present in T cells membranes [
82] (
Figure 1C). Thus, these contradictory conclusions warrant further investigation. B lymphocytes are also known to express 5-HT receptors, including 5-HT
1A, 5-HT
2A, 5-HT
3A and 5-HT
7 [
80], and activated B cells exhibit a significant increase in SERT expression [
83] (
Figure 1C). Whether B cells express other components of serotonin machinery and thus influencing serotonin signaling, it is still unknown. Like T cells, monocytes, the immature leukocytes that eventually differentiate into macrophages or dendritic cells, express the complete set of components needed for serotonin production [
80]. Dendritic cells, have also been found to mediate the release of proinflammatory cytokines, IL-1β and IL-8 via 5-HT
3, 5-HT
4, and 5-HT
7 receptor subtypes [
84]. In fact, serotonin has been demonstrated as an important regulator of the immune system. For example, serotonin has been described to modulate proinflammatory cytokines production in human monocytes via stimulation of different 5-HT receptor subtypes, particularly 5-HT
3, 5-HT
4, and 5-HT
7 receptors [
85] (
Figure 1C). Interestingly, deletion of 5-HT
4 receptors in mice results in inflammatory response, slowed colonic motility, and behavioral abnormalities [
86,
87]. Similarly, reduced expression of SERT and subsequent altered serotonin levels, have been associated with different inflammatory and diarrheal disorders [
15,
16,
88]. Targeted deletion of the SERT in mice led to increased colonic motility and increased water in stools [
89] in a similar manner to that observed in inflammatory bowel disorders, where SERT expression is also reduced [
18,
90]. That the altered structure or expression of SERT leads to disrupted serotonin transmission [
91], the current data point to a strong link between intestinal inflammation, disruption of serotonin signaling and the consequent alteration in gut motility, and development of depression. Whether the altered gut motility [
14,
16,
88,
89,
92,
93] is the driving factor in inducting depression in this cascade is unclear. One plausible mechanism is via the gut motility-mediated changes in the microbial population complexity, which might exert detrimental effects on enteric and central neurons leading to a state of depression.