Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands.
Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands.
Front Immunol. 2020 Mar 17;11:189. doi: 10.3389/fimmu.2020.00189. eCollection 2020.
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. 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), (UP) for 42 days (chronic), or repetitive microbial exposure (42 days UP with 2 or 7 days LPS). 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. The 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.
绒毛膜羊膜炎，即妊娠期间胎儿膜的炎症，通常由单一或多种微生物引起的羊膜内（IA）感染引起。绒毛膜羊膜炎可以是急性的或慢性的，并与肠道的不良产后结局相关，包括坏死性小肠结肠炎（NEC）。患有 NEC 的新生儿的肠黏膜和肠神经系统（ENS）结构和功能受损，肠神经元和神经胶质细胞丢失。然而，急性、慢性或反复的产前炎症刺激对肠黏膜和 ENS 的发育的影响尚未被研究。因此，本研究旨在研究急性、慢性和反复微生物暴露对早产羔羊肠黏膜、黏膜下层和 ENS 的影响。使用绵羊妊娠模型，在 IA 暴露于脂多糖（LPS）2 或 7 天后（急性）、42 天后（慢性）或反复微生物暴露（42 天 UP 加 2 或 7 天 LPS）后评估回肠黏膜、黏膜下层和 ENS。IA LPS 暴露 7 天或 IA UP 暴露 42 天导致肠道黏膜和黏膜下层的肠损伤和炎症。反复微生物暴露并没有进一步加重末端回肠的损伤。慢性 IA UP 暴露导致 ENS 结构的显著改变，其特征是 PGP9.5 和 S100β免疫反应性丧失，而在慢性 UP 暴露的胎儿重新暴露于 LPS 2 或 7 天后没有发现这些变化。慢性 UP 暴露后 PGP9.5 和 S100β免疫反应性的丧失与 NEC 新生儿的肠道变化相对应，因此可能为绒毛膜羊膜炎和 NEC 之间的关联提供了一种新的机制解释。
