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.NEW & NOTEWORTHY
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.