Abstract
BackgroundChorioamnionitis, inflammation of the chorion and amnion, which often results from intrauterine infection, is associated with premature birth and contributes to significant neonatal morbidity and mortality, including necrotizing enterocolitis (NEC). Recently, we have shown that chronic chorioamnionitis is associated with significant structural enteric nervous system (ENS) abnormalities that may predispose to later NEC development. Understanding time point specific effects of an intra-amniotic (IA) infection on the ENS is important for further understanding the pathophysiological processes and for finding a window for optimal therapeutic strategies for an individual patient. The aim of this study was therefore to gain insight in the longitudinal effects of intrauterine LPS exposure (ranging from 5 h to 15 days before premature delivery) on the intestinal mucosa, submucosa, and ENS in fetal lambs by use of a well-established translational ovine chorioamnionitis model.MethodsWe used an ovine chorioamnionitis model to assess outcomes of the fetal ileal mucosa, submucosa and ENS following IA exposure to one dose of 10 mg LPS for 5, 12 or 24 h or 2, 4, 8 or 15 days.ResultsFour days of IA LPS exposure causes a decreased PGP9.5- and S100β-positive surface area in the myenteric plexus along with submucosal and mucosal intestinal inflammation that coincided with systemic inflammation. These changes were preceded by a glial cell reaction with early systemic and local gut inflammation. ENS changes and inflammation recovered 15 days after the IA LPS exposure.ConclusionsThe pattern of mucosal and submucosal inflammation, and ENS alterations in the fetus changed over time following IA LPS exposure. Although ENS damage seemed to recover after prolonged IA LPS exposure, additional postnatal inflammatory exposure, which a premature is likely to encounter, may further harm the ENS and influence functional outcome. In this context, 4 to 8 days of IA LPS exposure may form a period of increased ENS vulnerability and a potential window for optimal therapeutic strategies.
Highlights
Chorioamnionitis, inflammation of the chorion and amnion, which often results from intrauterine infection, is associated with premature birth and contributes to significant neonatal morbidity and mortality, including necrotizing enterocolitis (NEC)
Chorioamnionitis induced intestinal inflammation A statistically significant increase in MPO-positive cells was seen in the mucosa 4 and 8 days after IA LPS exposure, compared to control (p < 0.05; Table 2)
There was an increase of MPOpositive cells in animals exposed to 4 days of IA LPS, and submucosal MPO-positive cells still tended to be increased after 8 days of IA LPS exposure, compared to control (p < 0.05 and p = 0.08; Fig. 2)
Summary
Chorioamnionitis, inflammation of the chorion and amnion, which often results from intrauterine infection, is associated with premature birth and contributes to significant neonatal morbidity and mortality, including necrotizing enterocolitis (NEC). Chorioamnionitis, inflammation of the chorion and amnion during pregnancy, is associated with premature birth and contributes to significant neonatal morbidity and mortality (Galinsky et al 2013; Goldenberg et al 2000; Kim et al 2015). Chorioamnionitis typically results from a bacterial infection ascending through the birth canal (Goldenberg et al 2000). It is often clinically silent and difficult to diagnose, but can affect the developing fetus (Gantert et al 2010). ENS development continues in the early postnatal period (Hao et al 2016; Burns et al 2009) during which it is shaped by amongst others immune cells, microbiota and enteral nutrition (Hao et al 2016)
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