title: Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine.
abstract: OBJECTIVE
  Enterochromaffin cell-derived serotonin (5-HT) promotes intestinal inflammation. We tested hypotheses that peripheral tryptophan hydroxylase (TPH) inhibitors, administered orally, block 5-HT biosynthesis and deplete 5-HT from enterochromaffin cells sufficiently to ameliorate intestinal inflammation; moreover, peripheral TPH inhibitors fail to enter the murine enteric nervous system (ENS) or central nervous systems and thus do not affect constitutive gastrointestinal motility.
  
  
  METHODS
  Two peripheral TPH inhibitors, LP-920540 and telotristat etiprate (LX1032; LX1606) were given orally to mice. Effects were measured on 5-HT levels in the gut, blood and brain, 5-HT immunoreactivity in the ENS, gastrointestinal motility and severity of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Quantitation of clinical scores, histological damage and intestinal expression of inflammation-associated cytokines and chemokines with focused microarrays and real-time reverse transcriptase PCR were employed to evaluate the severity of intestinal inflammation.
  
  
  RESULTS
  LP-920540 and LX1032 reduced 5-HT significantly in the gut and blood but not in the brain. Neither LP-920540 nor LX1032 decreased 5-HT immunoreactive neurons or fibres in the myenteric plexus and neither altered total gastrointestinal transit time, colonic motility or gastric emptying in mice. In contrast, oral LP-920540 and LX1032 reduced the severity of TNBS-induced colitis; the expression of 24% of 84 genes encoding inflammation-related cytokines and chemokines was lowered at least fourfold and the reduced expression of 17% was statistically significant.
  
  
  CONCLUSIONS
  Observations suggest that that peripheral TPH inhibitors uncouple the positive linkage of enterochromaffin cell-derived 5-HT to intestinal inflammation. Because peripheral TPH inhibitors evidently do not enter the murine ENS, they lack deleterious effects on constitutive intestinal motility in mice.
authors.affiliation: Department of Pediatrics, Columbia University, College of P&S, , New York, New York, USA.
authors.forename: Kara Gross
authors.initials: KG
authors.lastname: Margolis
authors.forename: Korey
authors.initials: K
authors.lastname: Stevanovic
authors.forename: Zhishan
authors.initials: Z
authors.lastname: Li
authors.forename: Qi Melissa
authors.initials: QM
authors.lastname: Yang
authors.forename: Tamas
authors.initials: T
authors.lastname: Oravecz
authors.forename: Brian
authors.initials: B
authors.lastname: Zambrowicz
authors.forename: Kanchan G
authors.initials: KG
authors.lastname: Jhaver
authors.forename: Alexander
authors.initials: A
authors.lastname: Diacou
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gershon
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009197:Myenteric Plexus / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012701:Serotonin / Q000096:biosynthesis* / Q000097:blood; D012720:Severity of Illness Index; D014302:Trinitrobenzenesulfonic Acid; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D011743:Pyrimidines; C000592492:ethyl 2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3'-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; D012701:Serotonin; C000592493:telotristat; D010649:Phenylalanine; D014302:Trinitrobenzenesulfonic Acid; D014365:Tryptophan Hydroxylase
keywords: Enteric Nervous System; Experimental Colitis; Gastrointestinal Transit; Neurogastroenterology; Serotonin