CHU Sainte Justine Research Center, Montreal QC, Canada ; Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montreal QC, Canada.
Front Integr Neurosci. 2013 Aug 8;7:57. doi: 10.3389/fnint.2013.00057. eCollection 2013.
Necrotizing enterocolitis (NEC) is an acute neonatal inflammatory disease that affects the intestine and may result in necrosis, systemic sepsis and multisystem organ failure. NEC affects 5-10% of all infants with birth weight ≤ 1500 g or gestational age less than 30 weeks. Chorioamnionitis (CA) is the main manifestation of pathological inflammation in the fetus and is strong associated with NEC. CA affects 20% of full-term pregnancies and upto 60% of preterm pregnancies and, notably, is often an occult finding. Intrauterine exposure to inflammatory stimuli may switch innate immunity cells such as macrophages to a reactive phenotype ("priming"). Confronted with renewed inflammatory stimuli during labour or postnatally, such sensitized cells can sustain a chronic or exaggerated production of proinflammatory cytokines associated with NEC (two-hit hypothesis). Via the cholinergic anti-inflammatory pathway, a neurally mediated innate anti-inflammatory mechanism, higher levels of vagal activity are associated with lower systemic levels of proinflammatory cytokines. This effect is mediated by the α7 subunit nicotinic acetylcholine receptor (α7nAChR) on macrophages. The gut is the most extensive organ innervated by the vagus nerve; it is also the primary site of innate immunity in the newborn. Here we review the mechanisms of possible neuroimmunological brain-gut interactions involved in the induction and control of antenatal intestinal inflammatory response and priming. We propose a neuroimmunological framework to (1) study the long-term effects of perinatal intestinal response to infection and (2) to uncover new targets for preventive and therapeutic intervention.
坏死性小肠结肠炎（NEC）是一种影响肠道的急性新生儿炎症性疾病，可能导致坏死、全身败血症和多器官衰竭。NEC 影响所有出生体重≤1500 克或胎龄小于 30 周的婴儿的 5-10%。绒毛膜羊膜炎（CA）是胎儿病理炎症的主要表现，与 NEC 密切相关。CA 影响 20%的足月妊娠和高达 60%的早产妊娠，值得注意的是，它通常是隐匿性的。宫内暴露于炎症刺激物可能会使先天免疫细胞（如巨噬细胞）转变为反应性表型（“致敏”）。在分娩或产后再次遇到炎症刺激时，这些致敏细胞可以持续产生与 NEC 相关的促炎细胞因子（二次打击假说）。通过胆碱能抗炎途径，一种神经介导的先天抗炎机制，较高水平的迷走神经活动与较低的全身促炎细胞因子水平相关。这种效应是通过巨噬细胞上的α7 亚单位烟碱型乙酰胆碱受体（α7nAChR）介导的。肠道是受迷走神经支配的最大器官；它也是新生儿先天免疫的主要部位。在这里，我们综述了可能的神经免疫脑-肠相互作用的机制，这些机制涉及到产前肠道炎症反应和致敏的诱导和控制。我们提出了一个神经免疫框架，用于（1）研究围产期肠道对感染反应的长期影响，以及（2）揭示预防和治疗干预的新靶点。
