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Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine
  1. Kara Gross Margolis1,
  2. Korey Stevanovic1,
  3. Zhishan Li2,
  4. Qi Melissa Yang3,
  5. Tamas Oravecz3,
  6. Brian Zambrowicz3,
  7. Kanchan G Jhaver3,
  8. Alexander Diacou2,
  9. Michael D Gershon2
  1. 1Department of Pediatrics, Columbia University, College of P&S, New York, New York, USA
  2. 2Department of Pathology and Cell Biology, Columbia University, College of P&S, New York, New York, USA
  3. 3Lexicon Pharmaceuticals Inc., The Woodlands, Texas, USA
  1. Correspondence to Professor Michael D Gershon, Department of Pathology and Cell Biology, Columbia University, P&S, 630 West 168th Street, New York, NY 10032, USA; mdg4{at}columbia.edu

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.

Design 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.

  • Enteric Nervous System
  • Experimental Colitis
  • Gastrointestinal Transit
  • Neurogastroenterology
  • Serotonin

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