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.

Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

“…Children exposed to SSRIs or tricyclic antidepressants in utero were found to be 10-fold more likely to require laxatives for constipation, which is consistent with the idea that antenatal SERT inhibition disturbs ENS development and leads to persistent defects in GI motility (54). The ENS contributes to many GI disorders in adults, including irritable bowel syndrome (55) and inflammatory bowel disease (23,56). Given the importance of 5-HT signaling to ENS development and the long-lasting effects of fluoxetine treatment on sympathetic output, further investigation is probably warranted of the administration to pregnant or lactating women of antidepressants that affect SERT or 5-HT function.…”

“…Methods used to extract RNA, reversetranscribe it to DNA, and quantify transcript abundance with real-time PCR have been described previously (22,23) and are detailed in Supplemental Methods. Transcript expression was normalized to that of glyceraldehyde-3-phosphate dehydrogenase (Gapdh).…”

“…Two 5-HT depots exist in the gut, each with its own biosynthetic enzyme (22,23). A large tryptophan hydroxylase 1-dependent (TPH1-dependent) 5-HT pool exists in mucosal enterochromaffin (EC) cells and, in rats and mice, mast cells, whereas a smaller TPH2-dependent pool exists in the serotonergic neurons of the enteric nervous system (ENS).…”

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“…Consequently, it does not diminish central serotonin levels, thus avoiding the side effects that it would entail otherwise [27,28,[52][53][54][55].…”

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“…The expression of TPH is restricted to the intestinal and pancreatic enterochromaffin cells, b cells of the islets of Langerhans, mononuclear leukocytes, mast cells, pinealocytes and raphe neurons. Different genes encode the two different TPH isoforms, TPH1 and TPH2, located in enterochromaffin cells and CNS respectively (58).…”