迷走神经调节绵羊胎儿近期免疫代谢稳态：对回肠末端的影响
The vagus nerve regulates immunometabolic homeostasis in the ovine fetus near term: impact on terminal ileum
摘要：
迷走神经对胎儿炎症和葡萄糖敏感的作用尚不清楚。我们假设迷走神经切断术（Vx）将引发全身葡萄糖水平升高，并且这将在全身和器官特异性炎症期间增强。传出迷走神经刺激（VNS）应扭转这种表型。选用57只足月绵羊胎羊，分别以脂多糖（LPS）、VX+LPS、VX+LPS+选择性传出VNS作为对照组和治疗组。抽取胎儿动脉血样本7天，以分析炎症（IL-6）、胰岛素、血气和代谢（葡萄糖）。在54 h时，进行尸检;末端回肠巨噬细胞;定量CD 11 c（M1表型）免疫荧光以检测炎症。在各治疗组中，血气和心血管变化表明轻度败血症。LPS组IL-6在3 h达高峰，VX+ LPS 400组IL-6峰值下降，VX+ LPS 800组IL-6峰值增加一倍，传出VNS在54 h内加速炎症反应的减轻。M1巨噬细胞活性仅在LPS和Vx+ LPS 800组中增加。VX+LPS组的葡萄糖和胰岛素水平在3 h时分别是对照组的1.3倍和2.3倍，传出VNS使葡萄糖水平正常化。迷走神经支配的完全撤销导致葡萄糖水平持续增加至少54小时和间歇性高胰岛素血症的72小时延迟发作。在中度胎儿炎症的条件下，这与较高水平的肠道炎症有关;传出VNS降低全身炎症反应，并恢复葡萄糖和末端回肠炎症的水平，但不恢复胰岛素水平。我们的研究结果揭示了一种新的监管，激素，迷走神经的作用，在免疫代谢反应，内毒素在近期胎儿。
英文摘要：
The contribution of the vagus nerve to inflammation and glucosensing in the fetus is not understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype. Near-term fetal sheep (n=57) were surgically prepared with vascular catheters and ECG electrodes as control and treatment groups (lipopolysaccharide (LPS), Vx+LPS, Vx+LPS+selective efferent VNS). Fetal arterial blood samples were drawn for 7 days to profile inflammation (IL-6), insulin, blood gas and metabolism (glucose). At 54 h, a necropsy was performed; terminal ileum macrophages; CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h, in the LPS group IL-6 peaked; that peak was decreased in Vx+LPS400 and doubled in Vx+LPS800 group; the efferent VNS sped up the reduction of the inflammatory response profile over 54 h. M1 macrophage activity was increased in the LPS and Vx+LPS800 groups only. Glucose and insulin levels in the Vx+LPS group were respectively 1.3-fold and 2.3-fold higher vs. control at 3 h, and the efferent VNS normalized glucose levels. Complete withdrawal of vagal innervation results in a 72h delayed onset of sustained increase in glucose levels for at least 54h and intermittent hyperinsulinemia. Under conditions of moderate fetal inflammation, this is related to higher levels of gut inflammation; the efferent VNS reduces the systemic inflammatory response as well as restores both the levels of glucose and terminal ileum inflammation, but not the insulin levels. Our findings reveal a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses.
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