Luminary Learning Gastrointestinal Disorder- Issue 1

Pharmacological and Clinical Treatment of Irritable Bowel Syndrome •  15 Pharmacological Targets Serotonin System in the Gastrointestinal Tract Serotonin, which is a derivative of the exogenous amino acid tryptophan is synthesized and stored in the enteric enterochromaffin (EC) cells located in the intestinal mucosa. In the human gastroin- testinal (GI) tract EC cells are the most abundant in the duodenum and rectum and the scarcest in the ileum. On the other hand activated mast cells may also contribute to the synthesis and secre- tion of serotonin. The concentration of serotonin is relatively low in the duodenum and ileum (1.4 and 0.6 nmol/mg protein, respectively) and gradually rises in the colon reaching 45 nmol/mg protein in the rectum [1]. The synthesis of serotonin in the gut requires tryptophan hydroxylase 1 (TPH1), which is a rate limiting enzyme in this process [2]. In neurons serotonin is synthesized by an isoform of tryptophan hydroxylase, TPH2 [3]. Additionally Moreover, the availability of sero- tonin in the GI tract is locally regulated by the serotonin-selective reuptake transporter (SERT) which removes it from the interstitial space following the release by EC cells. SERT is expressed by all epithelial cells of the intestinal mucosa [2]. Noteworthy, the expression of SERT is decreased in the gut of IBS patients [4]. Serotonin receptors are distributed on enteric neurons, extrinsic nerve fibers, smooth muscle cells, goblet cells and enterocytes [2]. They can exert excitatory and/or inhibitory activities Fig. 1: An overview on pharmacological targets for clinically validated anti-IBS drugs/interventions.  ClC-2  type 2 chloride ion channels;  CFTR  cystic fibrosis transmembrane conductance regulator;  CNS  central nervous system; GC-C Guanylate cyclase C Serotonin receptor ligands Agonists: • accelerated intestinal transit • altered visceral sensation Antagonists: • decreased intestinal transit • altered visceral sensation Antidepressants • altered visceral sensation • alleviation of mood- related symptoms • normalized gut motility CFTR channel antagonists • increased intest i nal secretion • accelerated intestinal transit Peripherally - restricted opioids Agonists: • inhibited intestinal motility • in c reased fluid absor p tion • analgesic effect • lack of CNS-related adverse effects Antibiotics • alterations in the intestinal flora that lead to the normalization of intestinal transit and alleviation of abdominal pain (exact mechanism of action unknown) GC- C activators • improved intestinal peristalsis • improved frequencyof defecation • reduced visceral pain ClC- 2 channel activators • in c reased intestinal secretion • improved stool consistency • improved frequency of defecation Hypnosis • improved intestinal transit and abdominal pain (exact mechanism of action unknown)