Reactivation of Inflammatory Bowel Disease in a Mouse Model of Depression
Reactivation of Inflammatory Bowel Disease in a Mouse Model of Depression
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DOI：
10.1053/j.gastro.2009.02.069
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发表时间：
2009-06-01
期刊：
影响因子：
29.4
通讯作者：
Collins, Stephen M.
中科院分区：
文献类型：
--
作者：
Ghia, Jean-Eric;Blennerhassett, Patricia;Collins, Stephen M.
背景与目的：炎症性肠病（IBD）患者经常伴有抑郁症，但其在IBD发病机制中的作用尚不清楚。我们在小鼠模型中研究了慢性炎症建立后抑郁的发展是否会重新激活IBD的急性复发及其潜在的药理学机制。方法：用葡聚糖硫酸钠（DSS）或二硝基苯磺酸诱导C57BL/6小鼠结肠炎。采用嗅球切除或慢性脑室注射利血平诱导抑郁。结肠炎在随后暴露于DSS或二硝基苯磺酸后再次激活。一些小鼠被给予抗抑郁药去甲基咪嗪。在缺乏烟碱乙酰胆碱受体α 7亚基（α 7nAchR）的小鼠中诱导急性dss -结肠炎，并进行迷走神经切断术。评估疾病严重程度、结肠组织组织学和炎症。通过结肠样品和巨噬细胞培养的酶联免疫吸附分析来测定c反应蛋白和促炎细胞因子的水平。结果：在结肠炎已建立并处于静止状态的小鼠中诱导抑郁再激活炎症。诱导与巨噬细胞胆碱能抑制促炎细胞因子分泌受损有关，并由α - 7nAchR介导；从抑郁小鼠中分离的巨噬细胞显示促炎细胞因子分泌增加。去甲基咪帕明可以预防抑郁症引起的结肠炎再激活，并伴有促炎细胞因子分泌的正常化。结论：抑郁症通过α 7nAchR重新激活休眠的慢性结肠炎。这些发现鼓励对IBD患者抑郁症状的行为进行更密切的监测，因为治疗可能会预防炎症。此外，α - 7nAchR激动剂可能不需要精神药物就能达到这种效果。
Background & Aims: Patients with inflammatory bowel disease (IBD) frequently also have depression, yet little is known of its role in IBD pathogenesis. We investigated whether the development of depression after the establishment of chronic inflammation reactivates an acute relapse of IBD and underlying pharmacologic mechanisms in mouse models. Methods: Colitis was induced by administration of dextran sulfate sodium (DSS) or dinitrobenzenesulfonic acid to C57BL/6 mice. Depression was induced by olfactory bulbectomy or chronic intracerebroventricular injection of reserpine. Colitis was reactivated by subsequent exposure to DSS or dinitrobenzenesulfonic acid. Some mice were given the antidepressant desmethylimipramine. Acute DSS-colitis was induced in mice lacking the alpha 7 subunit of the nicotinic acetylcholine receptor (alpha 7nAchR), and vagotomy was perfomed. Disease severity and colon tissue histology and inflammation were evaluated. Levels of C-reactive protein and proinflammatory cytokines were determined by enzyme-linked immunosorbent assay analysis of colon samples and macrophage culture. Results: Induction of depression reactivated inflammation in mice in which colitis had been established and become quiescent. The induction was associated with impaired cholinergic inhibition of proinflammatory cytokine secretion by macrophages and mediated by alpha 7nAchR on these cells; macrophages isolated from depressed mice showed increased proinflammatory cytokine secretion. Depression-induced reactivation of colitis was prevented by desmethylimipramine and accompanied by a normalization of proinflammatory cytokine secretion. Conclusions: Depression reactivates dormant chronic colitis via the alpha 7nAchR These findings encourage closer monitoring of behavior for signs of depression in IBD patients because treatment might prevent inflammatory conditions. Furthermore, alpha 7nAchR agonists might achieve this effect without the need for psychotropic medication.