Serotonin is an Endogenous Regulator of the Aryl Hydrocarbon Receptor in the Intestine

Serotonin (5-hydroxytryptamine, 5-HT) is a tryptophan-derived neurotransmitter and hormone that plays an important role in regulating diverse physiological processes in both the brain and the gut. In the GI tract, 5-HT modulates electrolyte secretion and absorption, blood flow, perception of nausea or pain, and intestinal motility. The GI tract is a major source of 5-HT, with 95% of the whole body 5-HT being synthesized by specialized epithelial cells called enterochromaffin (EC) cells. EC cells release 5-HT into the intestinal lumen and the lamina propria where it can bind to 5-HT receptors (5-HTRs) to elicit its various physiological actions. Extracellular 5-HT is internalized by the serotonin transporter (SLC6A4, SERT), which transports 5-HT into the cell with high affinity. Decreased SERT expression and altered extracellular 5-HT levels have been implicated in several GI disorders such as Crohn’s disease (CD), ulcerative colitis (UC) and irritable bowel syndrome (IBS). With an overall goal to understand the impact of SERT deficiency on intestinal physiology, we performed a microarray analysis to compare gene expression in the ileal mucosa between wild-type (WT) mice and SERT knockout (KO) mice. Interestingly, the most down-regulated gene in the SERT KO mice was cytochrome P450 family 1, member A1 (Cyp1a1) which is the primary gene target of the aryl hydrocarbon receptor (AhR) signaling pathway. Aryl hydrocarbon receptor (AhR) is a ligand-activated nuclear receptor that plays critical roles in immune regulation and detoxification of environmental contaminants such as polycyclic aromatic hydrocarbons (PAHs). Over recent years, a new role for AhR has been established in the recognition of bacterial products and modulation of microbial pathogen defenses. While tryptophan metabolites have been shown to activate AhR, the involvement of 5-HT and serotonergic machinery in AhR signaling has not been previously established. Thus, the purpose of this study was to investigate the link between the AhR and serotonergic pathways to establish a new role of intestinal 5-HT. Learning more about this link will enhance our understanding of how 5-HT contributes to intestinal homeostasis under basal conditions, while also providing a novel perspective of how 5-HT can play a role in the pathophysiology of intestinal disorders.