title: 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.
authors.affiliation: Department of Pathology and Molecular Medicine, Farncombe Family Digestive Health Research Institute, Health Sciences Centre, McMaster University, Hamilton, Ontario, Canada; and.
authors.forename: Janice J
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Pathology and Molecular Medicine, Farncombe Family Digestive Health Research Institute, Health Sciences Centre, McMaster University, Hamilton, Ontario, Canada; and.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology and Molecular Medicine, Farncombe Family Digestive Health Research Institute, Health Sciences Centre, McMaster University, Hamilton, Ontario, Canada; and.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Terc
authors.affiliation: Lexicon Pharmaceuticals Inc., The Woodlands, Texas.
authors.forename: Brian
authors.initials: B
authors.lastname: Zambrowicz
authors.affiliation: Lexicon Pharmaceuticals Inc., The Woodlands, Texas.
authors.forename: Qi M
authors.initials: QM
authors.lastname: Yang
authors.affiliation: Department of Pathology and Molecular Medicine, Farncombe Family Digestive Health Research Institute, Health Sciences Centre, McMaster University, Hamilton, Ontario, Canada; and khanwal@mcmaster.ca.
authors.forename: Waliul I
authors.initials: WI
authors.lastname: Khan
mesh_terms: D000818:Animals; D003106:Colon / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004759:Enterochromaffin Cells / Q000187:drug effects; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D012701:Serotonin / Q000096:biosynthesis*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014257:Trichuriasis / Q000150:complications* / Q000469:parasitology; D014258:Trichuris; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors
chemical_list: D016207:Cytokines; D011743:Pyrimidines; D012702:Serotonin Antagonists; D012701:Serotonin; C000592493:telotristat; D010649:Phenylalanine; D016264:Dextran Sulfate; D009195:Peroxidase; D014365:Tryptophan Hydroxylase
keywords: enterochromaffin cells; experimental colitis; inflammatory bowel disease; tryptophan hydroxylase