Abstract
Background: Chorioamnionitis, inflammation of the fetal membranes during pregnancy, is often caused by intra-amniotic (IA) infection with single or multiple microbes. Chorioamnionitis can be either acute or chronic and is associated with adverse postnatal outcomes of the intestine, including necrotizing enterocolitis (NEC). Neonates with NEC have structural and functional damage to the intestinal mucosa and the enteric nervous system (ENS), with loss of enteric neurons and glial cells. Yet, the impact of acute, chronic, or repetitive antenatal inflammatory stimuli on the development of the intestinal mucosa and ENS has not been studied. The aim of this study was therefore to investigate the effect of acute, chronic, and repetitive microbial exposure on the intestinal mucosa, submucosa and ENS in premature lambs.Materials and Methods: A sheep model of pregnancy was used in which the ileal mucosa, submucosa, and ENS were assessed following IA exposure to lipopolysaccharide (LPS) for 2 or 7 days (acute), Ureaplasma parvum (UP) for 42 days (chronic), or repetitive microbial exposure (42 days UP with 2 or 7 days LPS).Results: IA LPS exposure for 7 days or IA UP exposure for 42 days caused intestinal injury and inflammation in the mucosal and submucosal layers of the gut. Repetitive microbial exposure did not further aggravate injury of the terminal ileum. Chronic IA UP exposure caused significant structural ENS alterations characterized by loss of PGP9.5 and S100β immunoreactivity, whereas these changes were not found after re-exposure of chronic UP-exposed fetuses to LPS for 2 or 7 days.Conclusion: The in utero loss of PGP9.5 and S100β immunoreactivity following chronic UP exposure corresponds with intestinal changes in neonates with NEC and may therefore form a novel mechanistic explanation for the association of chorioamnionitis and NEC.
Highlights
Preterm birth is a common and major worldwide health issue, contributing to significant neonatal morbidity and mortality [1]
There was a higher intestinal damage score for all experimental groups compared to the control (p < 0.005 for the 7 days LPS group, p < 0.05 for the 42 days Ureaplasma parvum (UP) group and 42 days UP + 7 days LPS group, and p = 0.06 for the 42 days UP + 2 days LPS group all compared to the control; Figure 2), except for the animals exposed to 2 days of LPS
Combining these two inflammatory insults resulted in an increased mucosal MPO-positive cell count compared to the control (p < 0.005; Figure 3), and this experimental group tended to be increased when compared to the UP + 2 days LPS-exposed group (p = 0.07; Figure 3)
Summary
Preterm birth is a common and major worldwide health issue, contributing to significant neonatal morbidity and mortality [1]. Chorioamnionitis, defined as inflammatory cell infiltration of fetal membranes, is frequently associated with preterm birth and typically occurs due to an ascending bacterial infection [5,6,7] that can be acute or chronic [8]. Intrauterine exposure of preterm infants to chorioamnionitis is associated with an increased risk of adverse neonatal outcomes [9, 10], including necrotizing enterocolitis (NEC) [9, 11, 12]. Ureaplasma spp. can cause chronic chorioamnionitis that does not evoke a maternal response, but is still associated with adverse fetal outcomes [16]. Chorioamnionitis can be either acute or chronic and is associated with adverse postnatal outcomes of the intestine, including necrotizing enterocolitis (NEC). The aim of this study was to investigate the effect of acute, chronic, and repetitive microbial exposure on the intestinal mucosa, submucosa and ENS in premature lambs
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