Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Gastroenterology. 2010 Dec;139(6):2102-2112.e1. doi: 10.1053/j.gastro.2010.06.063. Epub 2010 Jun 27.
BACKGROUND & AIMS: Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms.
AKR mice were infected with the noninvasive parasite Trichuris muris and given etanercept, budesonide, or specific probiotics. Subdiaphragmatic vagotomy was performed in a subgroup of mice before infection. Gastrointestinal inflammation was assessed by histology and quantification of myeloperoxidase activity. Serum proteins were measured by proteomic analysis, circulating cytokines were measured by fluorescence activated cell sorting array, and serum tryptophan and kynurenine were measured by liquid chromatography. Behavior was assessed using light/dark preference and step-down tests. In situ hybridization was used to assess brain-derived neurotrophic factor (BDNF) expression in the brain.
T muris caused mild to moderate colonic inflammation and anxiety-like behavior that was associated with decreased hippocampal BDNF messenger RNA (mRNA). Circulating tumor necrosis factor-α and interferon-γ, as well as the kynurenine and kynurenine/tryptophan ratio, were increased. Proteomic analysis showed altered levels of several proteins related to inflammation and neural function. Administration of etanercept, and to a lesser degree of budesonide, normalized behavior, reduced cytokine and kynurenine levels, but did not influence BDNF expression. The probiotic Bifidobacterium longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels. Anxiety-like behavior was present in infected mice after vagotomy.
Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry, which can be normalized by inflammation-dependent and -independent mechanisms, neither of which requires the integrity of the vagus nerve.
临床和临床前研究表明胃肠道炎症和感染与行为改变有关。我们研究了慢性肠道炎症是否会改变行为和大脑生物化学，并探讨了潜在的机制。
AKR 小鼠感染非侵袭性寄生虫旋毛虫，并给予依那西普、布地奈德或特定益生菌。在感染前，对一小部分小鼠进行膈下迷走神经切断术。通过组织学和髓过氧化物酶活性定量评估胃肠道炎症。通过蛋白质组学分析测量血清蛋白，通过荧光激活细胞分选阵列测量循环细胞因子，通过液相色谱测量血清色氨酸和犬尿氨酸。通过光/暗偏好和下台阶测试评估行为。通过原位杂交评估大脑源性神经营养因子（BDNF）在大脑中的表达。
T muris 引起轻度至中度结肠炎症和焦虑样行为，与海马 BDNF 信使 RNA（mRNA）减少有关。循环肿瘤坏死因子-α和干扰素-γ以及犬尿氨酸和犬尿氨酸/色氨酸比值升高。蛋白质组学分析显示与炎症和神经功能相关的几种蛋白质水平发生改变。依那西普给药，程度较轻的布地奈德给药，可使行为正常化，降低细胞因子和犬尿氨酸水平，但不影响 BDNF 表达。益生菌长双歧杆菌使行为和 BDNF mRNA 正常化，但不影响细胞因子或犬尿氨酸水平。迷走神经切断术后，感染小鼠出现焦虑样行为。
慢性胃肠道炎症引起焦虑样行为，并改变中枢神经系统生物化学，这可以通过炎症依赖和非依赖机制正常化，其中任何一种机制都不需要迷走神经的完整性。
