Alterations in the brain-gut axis underlying visceral chemosensitivity in Nippostrongylus brasiliensis-infected mice
Alterations in the brain-gut axis underlying visceral chemosensitivity in Nippostrongylus brasiliensis-infected mice
复制标题
DOI：
10.1053/j.gastro.2007.02.019
复制
发表时间：
2007-04-01
期刊：
影响因子：
29.4
通讯作者：
Coulie, Bernard
中科院分区：
文献类型：
--
作者：
Aerssens, Jeroen;Hillsley, Kirk;Coulie, Bernard
背景和目标：内脏超敏反应是肠易激综合征的一个标志，通常认为本质上是机械敏感性的，并通过脊髓传入神经介导。应激和炎症都与内脏高敏感性有关，但内脏高敏感性的潜在分子机制尚不清楚。研究方法：用巴西日本圆线虫（Nb）幼虫感染小鼠，暴露于环境应激，并在3-4周后进行以下单独的研究。记录肠系膜传入神经活动对斜坡球囊扩张（60转Hg），或腔内灌注盐酸（50 mmol/L），或奥曲肽给药（2 μ mol/L）的反应。腹腔内注射霍乱毒素B-488可鉴定出投射到腹腔内脏的神经元。采用激光捕获显微切割技术分离背根和无剂量神经节中的荧光神经元。将RNA与Affyssin小鼠全基因组阵列杂交用于分析以评估应激和感染的影响。结果如下：在以前感染Nb的小鼠中，肠传入机械敏感性没有变化，但与对照动物相比，对管腔内盐酸的化学敏感性反应增加。在应激Nb感染小鼠中，迷走神经而非脊髓内脏感觉神经元的基因表达谱显著改变。减少传入反应生长抑素受体2刺激与低表达的迷走神经生长抑素受体2在强调Nb感染的小鼠，确认分子数据和功能后遗症之间的联系。结论：肠脑-肠轴的改变、化学敏感性的改变而非机械敏感性的改变以及通过迷走神经而非脊髓途径的改变与应激诱导的炎症后内脏高敏感性有关。
Background & Aims: Visceral hypersensitivity, a hallmark of irritable bowel syndrome, is generally considered to be mechanosensitive in nature and mediated via spinal afferents. Both stress and inflammation are implicated in visceral hypersensitivity, but the underlying molecular mechanisms of visceral hypersensitivity are unknown. Methods: Mice were infected with Nippostrongylus brasiliensis (Nb) larvae, exposed to environmental stress and the following separate studies performed 3-4 weeks later. Mesenteric afferent nerve activity was recorded in response to either ramp balloon distention (60 turn Hg), or to an intraluminal perfusion of hydrochloric acid (50 mmol/L), or to octreotide administration (2 mu mol/L). Intraperitoneal injection of cholera toxin B-488 identified neurons projecting to the abdominal viscera. Fluorescent neurons in dorsal root and no-dose ganglia were isolated using laser-capture microdissection. RNA was hybridized to Affymetrix Mouse whole genome arrays for analysis to evaluate the effects of stress and infection. Results: In mice previously infected with Nb, there was no change in intestinal afferent mechanosensitivity, but there was an increase in chemosensitive responses to intraluminal hydrochloric acid when compared with control animals. Gene expression profiles in vagal but not spinal visceral sensory neurons were significantly altered in stressed Nb-infected mice. Decreased afferent responses to somatostatin receptor 2 stimulation correlated with lower expression of vagal somatostatin receptor 2 in stressed Nb-infected mice, confirming a link between molecular data and functional sequelae. Conclusions: Alterations in the intestinal brain-gut axis, in chemosensitivity but not mechanosensitivity, and through vagal rather than spinal pathways, are implicated in stress-induced postinflammatory visceral hypersensitivity.