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Blocking peripheral serotonin synthesis by telotristat etiprate (LX1032/LX1606) reduces severity of both chemical- and infection-induced intestinal inflammation.

Abstract
Mucosal inflammation is accompanied by an alteration in 5-HT. Intestinal 5-HT synthesis is catalyzed by tryptophan hydroxylase 1 (Tph1) and we have shown that mice deficient in this rate-limiting enzyme have reduced severity of intestinal inflammation in models of chemical-induced experimental colitis. Here, we investigated the effect of blocking peripheral 5-HT synthesis in generation of intestinal inflammation by a using peripheral Tph inhibitor, telotristat etiprate (LX1606), in models of intestinal inflammation. LX1606 was given orally either prophylactically or therapeutically to mice with dextran sulfate sodium (DSS)-induced colitis or with infection with Trichuris muris. Severity of intestinal inflammation was measured by assessment of disease activity scores, histological damage, and MPO and inflammatory cytokine levels. LX1606 significantly reduced intestinal 5-HT levels and delayed onset and severity of DSS-induced acute and chronic colitis. This was associated with decreased MPO and proinflammatory cytokine levels compared with vehicle-treated controls. In the infection-induced inflammation model, treatment with LX1606 enhanced worm expulsion as well as increased IL-10 production and goblet cell numbers. LX1606-treated mice had significantly lower MPO and IL-1β levels compared with controls postinfection. Our results demonstrate that peripheral 5-HT plays an important role in intestinal inflammation and in the generation of immune responses. Pharmacological reduction of peripheral 5-HT may serve as a potential strategy for modulating various intestinal inflammatory disorders.
AuthorsJanice J Kim, Huaqing Wang, Joshua D Terc, Brian Zambrowicz, Qi M Yang, Waliul I Khan
JournalAmerican journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 309 Issue 6 Pg. G455-65 (Sep 15 2015) ISSN: 1522-1547 [Electronic] United States
PMID26206858 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 the American Physiological Society.
Chemical References
  • Cytokines
  • Pyrimidines
  • Serotonin Antagonists
  • Serotonin
  • telotristat
  • Phenylalanine
  • Dextran Sulfate
  • Peroxidase
  • Tryptophan Hydroxylase
Topics
  • Animals
  • Colon (metabolism)
  • Cytokines (metabolism)
  • Dextran Sulfate
  • Enterochromaffin Cells (drug effects)
  • Inflammatory Bowel Diseases (chemically induced, drug therapy, etiology)
  • Mice
  • Mice, Inbred C57BL
  • Peroxidase (metabolism)
  • Phenylalanine (analogs & derivatives, pharmacology)
  • Pyrimidines (pharmacology)
  • Serotonin (biosynthesis)
  • Serotonin Antagonists (pharmacology)
  • Trichuriasis (complications, parasitology)
  • Trichuris
  • Tryptophan Hydroxylase (antagonists & inhibitors)

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