A Mouse Model of Clostridium difficile-Associated Disease
A Mouse Model of Clostridium difficile-Associated Disease
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DOI：
10.1053/j.gastro.2008.09.002
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发表时间：
2008-12-01
期刊：
影响因子：
29.4
通讯作者：
Kelly, Ciaran P.
中科院分区：
文献类型：
--
作者：
Chen, Xinhua;Katchar, Kianoosh;Kelly, Ciaran P.
背景与目的：艰难梭菌感染可引起院内抗生素相关性腹泻和结肠炎。仓鼠历来被用来研究疾病的发病机制和治疗方法，但由于缺乏仓鼠特异性试剂和转基因动物，而且它们会患上暴发性疾病，因此不是理想的模型。本研究的目的是建立一种更接近人类疾病的抗生素诱导的艰难梭菌相关疾病（CDAD）小鼠模型。方法：将C57BL/6小鼠分别给予卡那霉素、庆大霉素、粘菌素、甲硝唑和万古霉素混合抗生素治疗3 d。2 d后注射克林霉素，1 d后注射不同剂量的艰难梭菌。结果：小鼠暴露于抗生素，然后用艰难梭菌攻击出现腹泻和体重减轻。疾病严重程度根据激发剂量从暴发性到轻度不等。典型的CDAD组织学特征明显。口服万古霉素在所有小鼠中都能预防CDAD，但68%的小鼠在停止治疗后死于结肠炎。所有在CDAD初始发作后存活的动物在随后的艰难梭菌再次感染后没有出现腹泻或结肠炎的证据。模型中不同菌株的艰难梭菌对小鼠的毒力不同。结论：我们建立了一种与人类疾病密切相关的CDAD小鼠模型。鉴于最近CDAD发病率和严重程度的大幅增加，该模型将在测试新的治疗方法、检查疾病发病机制和阐明保护性免疫机制方面具有价值。
Background & Aims: Infection with Clostridium difficile causes nosocomial antibiotic-associated diarrhea and colitis. Hamsters historically have been used to investigate disease pathogenesis and treatment, but are not ideal models because of the lack of hamster-specific reagents and genetically modified animals, and because they develop fulminant disease. The aim of this study was to establish a mouse model of antibiotic-induced C difficile-associated disease (CDAD) that more closely resembles human disease. Methods: C57BL/6 mice were exposed to a mixture of antibiotics (kanamycin, gentamicin, colistin, metronidazole, and vancomycin) for 3 days. Two days later, they were given injections of clindamycin and then challenged 1 day later with different doses of C difficile. Results: Mice that were exposed to antibiotics and then challenged with C difficile developed diarrhea and lost weight. Disease severity varied from fulminant to minimal in accordance with the challenge dose. Typical histologic features of CDAD were evident. Oral vancomycin prevented CDAD in all mice, but 68% died from colitis after treatment was discontinued. All animals that survived an initial episode of CDAD showed no evidence of diarrhea or colitis after subsequent rechallenge with C difficile. Different strains of C difficile tested in the model showed different levels of virulence in mice. Conclusions: We have developed a mouse model of CDAD that closely represents the human disease. in light of the recent substantial increases in CDAD incidence and severity, this model will be valuable in testing new treatments, examining disease pathogenesis, and elucidating mechanisms of protective immunity.