Serotonin Has a Critical Role in the Pathogenesis of Experimental Colitis

In the enterochromaffin (EC) cell, tryptophan (T) is converted to 5-hydroxytryptophan (5-OH-T) by 5-HT's rate limiting biosynthetic enzyme TPH1. 5-OH-T is then converted to 5-HT with the assistance of L-aromatic acid decarboxylase (L-AAAD) and biogenic amine synthesis. Once secreted from the EC cell, some 5-HT is taken up by the 5-HT reuptake transporters, located mainly in mucosal enterocytes. The remainder goes into the blood where it is captured and concentrated by the platelets which release it upon stimulation. Once in the enterocyte, 5-HT is metabolized by monamine oxidases and UDP-glucuronosyltransferase to its inactive metabolites, 5-hydroxyindoleacetic acid and 5-hydroxytryptamine glucuronide. These inactive metabolites are ultimately excreted by the kidneys. In conditions where excessive 5-HT is produced, and the 5-HT reuptake transporters and platelets cannot hold more 5-HT, excess 5-HT flows into the gut lumen and blood in its active form.

5-HT and Mechanisms of Intestinal Inflammation: Luminal inflammatory stimuli cause EC cell hyperplasia and possible activation of EC cells resulting in increased 5-HT release. While some 5-HT is taken up by SERT in epithelial cells as well as platelets in the blood, excess 5-HT circulates acts locally on epithelial cells as well as on lamina propria cells, such as macrophages, dendritic cells, lymphocytes and enteric nerves via binding on specific 5-HT receptors. This binding triggers activation of the NF-κB system and possible other proinflammatory signaling pathways resulting in transcription of proinflammatory cytokines and chemokines, such as IL-1β and IL-6. Proinflammatory mediators further amplify the intestinal inflammatory response by stimulating enteric nerves to release 5-HT and other neurotransmitters that perpetuate inflammation. 5-HT, cytokines and other neurotransmitters also act on the intestinal epithelium altering tight junctional permeability and stimulating fluid secretion, as well as on smooth muscle cells causing motility changes associated with intestinal inflammatory conditions.