The ever-changing roles of serotonin.

Serotonin (5-HT) has traditional roles as a key neurotransmitter in the central nervous system and as a regulatory hormone controlling a broad range of physiological functions. Perhaps the most classically-defined functions of 5-HT are centrally in the control of mood, sleep and anxiety and peripherally in the modulation of gastrointestinal motility. A more recently appreciated role for 5-HT has emerged, however, as an important metabolic hormone contributing to glucose homeostasis and adiposity, with a causal relationship existing between circulating 5-HT levels and metabolic diseases. Almost all peripheral 5-HT is derived from specialised enteroendocrine cells, called enterochromaffin (EC) cells, located throughout the length of the lining of the gastrointestinal tract. EC cells are important luminal sensory cells that can detect and respond to an array of ingested nutrients, as well as luminal gut microbiota and their associated metabolites. Intriguingly, the interaction between gut microbiota and EC cells is dynamic in nature and has strong implications for host physiology. In this review, we discuss the traditional and modern functions of 5-HT and highlight an emerging pathway by which gut microbiota influences host health. Serotonin, also known as 5-hydroxytryptamine (5-HT), is an important neurotransmitter, growth factor and hormone that mediates a range of physiological functions. In mammals, serotonin is synthesized from the essential amino acid tryptophan by the rate-limiting enzyme tryptophan hydroxylase (TPH), for which there are two isoforms expressed in distinct cell types throughout the body. Tph1 is mainly expressed by specialized gut endocrine cells known as enterochromaffin (EC) cells and by other non-neuronal cell types such as adipocytes (Walther et al., 2003). Tph2 is primarily expressed in neurons of the raphe nuclei of the brain stem and a subset of neurons in the enteric nervous system (ENS) (Yabut et al., 2019). As 5-HT cannot readily cross the blood-brain barrier, the central and peripheral pools of 5-HT are anatomically separated and as such, act in their own distinct manners (Martin et al., 2017c). In this review we discuss the peripheral roles of serotonin, with particular focus on the interaction of gut-derived serotonin with the gut microbiota, and address emerging evidence linking this relationship with host homeostasis.