Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine

KG Margolis, K Stevanovic, Z Li, QM Yang, T Oravecz… - Gut, 2014 - gut.bmj.com
KG Margolis, K Stevanovic, Z Li, QM Yang, T Oravecz, B Zambrowicz, KG Jhaver, A Diacou…
Gut, 2014gut.bmj.com
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 …
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.
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