Enteric serotonin and oxytocin: endogenous regulation of severity in a murine model of necrotizing enterocolitis

Abstract

Necrotizing enterocolitis (NEC), a gastrointestinal inflammatory disease of unknown etiology that may also affect the liver, causes a great deal of morbidity and mortality in premature infants. We tested the hypothesis that signaling molecules, which are endogenous to the bowel, regulate the severity of intestinal and hepatic damage in an established murine NEC model. Specifically, we postulated that mucosal serotonin (5-HT), which is proinflammatory, would exacerbate experimental NEC and that oxytocin (OT), which is present in enteric neurons and is anti-inflammatory, would oppose it. Genetic deletion of the 5-HT transporter (SERT), which increases and prolongs effects of 5-HT, was found to increase the severity of systemic manifestations, intestinal inflammation, and associated hepatotoxicity of experimental NEC. In contrast, genetic deletion of tryptophan hydroxylase 1 (TPH1), which is responsible for 5-HT biosynthesis in enterochromaffin (EC) cells of the intestinal mucosa, and TPH inhibition with LP-920540 both decrease the severity of experimental NEC in the small intestine and liver. These observations suggest that 5-HT from EC cells helps to drive the inflammatory damage to the gut and liver that occurs in the murine NEC model. Administration of OT decreased, while the OT receptor antagonist atosiban exacerbated, the intestinal inflammation of experimental NEC. Data from the current investigation are consistent with the tested hypotheses-that the enteric signaling molecules, 5-HT (positively) and OT (negatively) regulate severity of inflammation in a mouse model of NEC. Moreover, we suggest that mucosally restricted inhibition of 5-HT biosynthesis and/or administration of OT may be useful in the treatment of NEC. Serotonin (5-HT) and oxytocin reciprocally regulate the severity of intestinal inflammation and hepatotoxicity in a murine model of necrotizing enterocolitis (NEC). Selective depletion of mucosal 5-HT through genetic deletion or inhibition of tryptophan hydroxylase-1 ameliorates, while deletion of the 5-HT uptake transporter, which increases 5-HT availability, exacerbates the severity of NEC. In contrast, oxytocin reduces, while the oxytocin receptor antagonist atosiban enhances, NEC severity. Peripheral tryptophan hydroxylase inhibition may be useful in treatment of NEC.

Potentiation of serotonin signaling protects against intestinal ischemia and reperfusion injury in mice

“…However, the severity of these peaks is different; again, it is unclear whether the lesser injury peak seen in the SERTKO is due to protection from injury or have actually been the subject of recent studies. 20,21 Interestingly, when compared to the results of the current study, it initially appears counterintuitive that knockout of the SERT would result in worsening inflammation in a colitis model and increased severity of disease in a model of necrotizing enterocolitis. An important difference between the current study and the above-mentioned work relates to the end points studied.…”

“…Likewise, could a patient with inflammatory bowel disease be treated with 5‐HT manipulation along with other surgical and medical therapy to decrease the length of resected intestine and aid in post‐operative adaptation? The above questions have actually been the subject of recent studies . Interestingly, when compared to the results of the current study, it initially appears counterintuitive that knockout of the SERT would result in worsening inflammation in a colitis model and increased severity of disease in a model of necrotizing enterocolitis.…”

Necrotizing enterocolitis

“…Although neuronal‐derived 5‐HT may have anti‐inflammatory effects, decreased mucosal 5‐HT, produced by either knockout of tryptophan hydroxylase I (TPH1), the rate‐limiting enzyme in the biosynthesis of EC cell 5‐HT, or use of a chemical inhibitor of TPH activation, leads to an amelioration of inflammation . Conversely, knockout of SERT, which increases 5‐HT effects by decreasing its reuptake and metabolism, leads to increased NEC inflammation . Although SERT inhibitors (SSRI) are commonly used during pregnancy and lactation, and various behavioral and pulmonary effects on the neonate have been described, only very limited data suggest a link between maternal SSRI use and NEC …”

“…22,56,57 Recently, it has been demonstrated that 5-HT regulates inflammation in an experimental murine NEC model. 58 Although neuronal-derived 5-HT may have anti-inflammatory effects, decreased mucosal 5-HT, produced by either knockout of tryptophan hydroxylase I (TPH1), the rate-limiting enzyme in the biosynthesis of EC cell 5-HT, or use of a chemical inhibitor of TPH activation, leads to an amelioration of inflammation. 58 Conversely, knockout of SERT, which increases 5-HT effects by decreasing its reuptake and metabolism, leads to increased NEC inflammation.…”

“…58 Conversely, knockout of SERT, which increases 5-HT effects by decreasing its reuptake and metabolism, leads to increased NEC inflammation. 58 Although SERT inhibitors (SSRI) are commonly used during pregnancy and lactation, and various behavioral and pulmonary effects on the neonate have been described, only very limited data suggest a link between maternal SSRI use and NEC. 59,60 The poor neurodevelopmental outcomes in infants with NEC may be secondary to a systemic inflammatory response and/or alterations in the gut-brain axis.…”