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.

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.

• Authors: Kara Gross Margolis, Korey Stevanovic, Zhishan Li, Qi Melissa Yang, Tamas Oravecz, Brian Zambrowicz, Kanchan G Jhaver, Alexander Diacou, Michael D Gershon
• Journal: Gut (Gut) Vol. 63 Issue 6 Pg. 928-37 (Jun 2014) ISSN: 1468-3288 [Electronic] England
• PMID: 23749550 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Enzyme Inhibitors
• Pyrimidines
• ethyl 2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3'-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid
• Serotonin
• telotristat
• Phenylalanine
• Trinitrobenzenesulfonic Acid
• Tryptophan Hydroxylase

Topics

• Animals
• Brain (metabolism)
• Colitis (chemically induced, metabolism, pathology)
• Cytokines (genetics)
• Down-Regulation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Gastrointestinal Motility (drug effects)
• Gene Expression (drug effects)
• Intestinal Mucosa (metabolism)
• Male
• Mice, Inbred C57BL
• Myenteric Plexus (metabolism)
• Neurons (metabolism)
• Phenylalanine (analogs & derivatives, pharmacology)
• Pyrimidines (pharmacology)
• Serotonin (biosynthesis, blood)
• Severity of Illness Index
• Trinitrobenzenesulfonic Acid
• Tryptophan Hydroxylase (antagonists & inhibitors)