Finally, a central role in the MGBA is played by metabolic mediators, including tryptophan metabolites such as serotonin (5-hydroxytryptamine, 5-HT), melatonin, SCFAs, and other neurotransmitters. 5-HT is involved in most branches of the MGBA; for instance, it acts as a neurotransmitter both in the CNS and ENS, and 5-HT receptors have a critical function in the HPA
[49][77]. The production of host 5-HT in the gut is regulated by microbiota, as indigenous spore-forming bacteria, derived from mouse and human microbiota, have been shown to promote 5-HT biosynthesis from enterochromaffin cells in the colon, thus impacting GI motility and homeostasis
[50][78]. SCFAs (acetate, propionate, and butyrate) are thought to influence gut–brain communication through different potential pathways, either directly or indirectly. Once produced by colonic fermentation, SCFAs can exert a direct effect on the intestinal mucosal immunity and can modulate the integrity and function of the gut barrier. Furthermore, by interacting with the EECs, SCFAs promote a direct gut–brain signaling through the secretion of gut hormones, such as GLP-1 and PYY, and other metabolic mediators such as γ-aminobutyric acid and 5-HT. In addition, they can induce systemic inflammation through differentiation of T regulatory cells and secretion of interleukins and can probably also act centrally in the CNS by modulating neuroinflammation
[51][79].
There are several factors which could have a specific impact on the MGBA development in early life; one of the most relevant might be prematurity, as preterm birth interrupts the physiological growth and development of both the GI tract and the nervous system and leads to a certain degree of microbial dysbiosis. Despite that, at present there are no studies specifically designed to describe the unique features of the MGBA in preterm infants
[52][80]. In addition, nutrition during sensitive developmental time windows is thought to have a major impact on the microbiota-gut–brain crosstalk
[53][54][81,82], either through an effect of single nutrients (
for e
xample.g., milk fat globule membranes
[55][83], human milk oligosaccharides
[56][84], or through the well-known benefits of exclusive human milk feeding compared to other feeding sources
[57][85].