Dataset Information


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

ABSTRACT: 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.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.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.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.


PROVIDER: S-EPMC4034681 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

Similar Datasets

2020-01-01 | S-EPMC7584960 | BioStudies
2019-01-01 | S-EPMC6619411 | BioStudies
2011-01-01 | S-EPMC4442094 | BioStudies
2019-01-01 | S-EPMC6650329 | BioStudies
2013-01-01 | S-EPMC3547480 | BioStudies
2014-01-01 | S-EPMC4778708 | BioStudies
1000-01-01 | S-EPMC5352190 | BioStudies
2019-01-01 | S-EPMC6362283 | BioStudies
2008-01-01 | S-EPMC2439511 | BioStudies
1000-01-01 | S-EPMC6016808 | BioStudies