TPH1 is present mainly in peripheral organs such as the intestine and spleen, while TPH2 predominates in the brain stem [19,20]. Thus 5-HT seems to be synthesized independently in peripheral tissues and neurones by two different rate-limiting

TPH isoenzymes. The synthesis of 5-HT by EC cells begins by conversion of dietary tryptophan to 5-hyroxytryptophan (5-HTP) by the rate-limiting TPH1. 5-HTP is then converted to 5-HT by the enzyme l-amino acid decarboxylase. Newly produced 5-HT is packaged into granules/vesicles by the vesicular monoamine transporter 1. 5-HT is released mainly from the granules stored near the basal border of the EC cell, but studies have also identified granules near the apical membrane where release may also take place [21]. Once released, 5-HT is transported into surrounding epithelial cells by the serotonin reuptake transporter (SERT) find more and degraded to 5-hydroxyindoleacetic acid by monoamine oxidase A. 5-HT is released from EC cells into the blood, into the surrounding tissue and into the gut

lumen and participates in various gut functions [22]. Secretion of 5-HT by EC cells can be enhanced or attenuated by the action of signalling molecules released from surrounding cells, and alteration of 5-HT release may contribute to intestinal pathophysiology. Our recent work has shown an important immunoendocrine axis in the gut, where secretory products from CD4+ T cells interact with EC cells or their precursors Ivacaftor concentration to enhance 5-HT production in the gut via T helper type (Th2)-based mechanisms [23]. Recently we have observed that EC cell and 5-HT responses to the same enteric infectious agent are influenced by Th1 or Th2 cytokine predominance, suggesting the importance of the immunological profile of the inflammatory response in the regulation of EC cell biology [24]. The role of the host’s immune response underlying changes in EC cells and 5-HT has also been demonstrated RAS p21 protein activator 1 in a number of GI infection-induced

gut inflammations, which include infections with Salmonella typhimurium, rotavirus, Citrobacter rodentium, Trichuris muris, Nippostrongylus brasiliensis and Trichinella spiralis[10–12,23–26]. Thus the close proximity between EC cells and immune cells in the gut mucosa, and the recent knowledge showing that cytokines from immune cells can activate EC cell secretion, suggest that interaction between gut endocrine and immune systems may be responsible for aspects of pathophysiology in GI inflammation. 5-HT exerts a confounding range of effects in the gut, due largely to the presence of multiple receptor subtypes which are present on smooth muscle, enteric neurones and enterocytes [27,28]. Seven types of 5-HT receptors are now identified and among these, 5-HT3 and 5-HT4 receptors are shown to play important roles in GI physiology, including motor and secretory function.