The interplay between microbiome dynamics and pathogen dynamics in a murine model of Clostridium difficile infection
The interplay between microbiome dynamics and pathogen dynamics in a murine model of Clostridium difficile infection
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DOI：
10.4161/gmic.2.3.16333
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发表时间：
2011-01-01
期刊：
影响因子：
12.2
通讯作者：
Young, Vincent B.
中科院分区：
文献类型：
--
作者：
Reeves, Angela E.;Theriot, Casey M.;Young, Vincent B.
艰难梭菌感染（CDI）是在抗生素给药的情况下发生的，其中正常土著肠道微生物群会导致对艰难梭菌定植和结肠炎的敏感性。使用CDI的鼠模型，我们证明了土著肠道微生物群的社区结构的变化与对艰难梭菌的定殖耐药性丧失有关。 Several antibiotic regimens were tested in combination for the ability to overcome colonization resistance, including a five antibiotic cocktail consisting of kanamycin, gentamicin, colistin, metronidazole and vancomycin administered in drinking water for three days, a single intraperitoneal dose of clindamycin or 10 days of cefoperazone in drinking water.在抗生素处理后，通过口服饲料的10（5）个菌落形成VPI 10463的菌落形成单位挑战动物。在艰难梭菌挑战之前接受了抗生素鸡尾酒和克林霉素的动物遵循了两种临床课程之一，在挑战后2-4天内在临床上生病和垂死，或者在临床上保持良好。临床上病变的动物组织学严重的结肠炎。在临床上保持良好的动物中，这些组织病理学的发现明显不那么严重。对从尸检中肠道组织检测到的16S rRNA基因序列的分析表明，蛋白质细菌在临床疾病动物中占主导地位。相比之下，临床上良好动物的肠道微生物群落更像是未经治疗的动物，这些动物由公司成员主导。在艰难梭菌挑战之前接受头孢曲松治疗的所有动物均在临床上生病和垂死，以剂量依赖于挑战后2-5天。这些动物中的肠道群落以艰难梭菌为主，这表明头孢曲松治疗导致定殖耐药性损失更大。因此，该系统中出现的结肠炎的严重程度反映了肠道社区中艰难梭菌的扩张与土著微生物群落的生态动力学之间的相互作用，因为它从抗生素扰动中恢复过来。我们证明，改变这两个相对过程的平衡改变了临床结果，因此可能导致CDI的新型预防和治疗方法。
Clostridium difficile infection (CDI) arises in the setting of antibiotic administration where disruption of the normal indigenous gut microbiota leads to susceptibility to C. difficile colonization and colitis. Using a murine model of CDI, we demonstrate that changes in the community structure of the indigenous gut microbiota are associated with the loss of colonization resistance against C. difficile. Several antibiotic regimens were tested in combination for the ability to overcome colonization resistance, including a five antibiotic cocktail consisting of kanamycin, gentamicin, colistin, metronidazole and vancomycin administered in drinking water for three days, a single intraperitoneal dose of clindamycin or 10 days of cefoperazone in drinking water. Following antibiotic treatment animals were challenged with 10(5) colony forming units of C. difficile strain VPI 10463 via oral gavage. Animals that received the antibiotic cocktail and clindamycin prior to C. difficile challenge followed one of two clinical courses, either becoming clinically ill and moribund within 2-4 days post challenge, or remaining clinically well. Animals that became clinically ill developed histologically severe colitis. These histopathologic findings were significantly less severe in animals that remained clinically well. Analysis of 16S rRNA gene sequences retrieved from gut tissue at necropsy demonstrated that Proteobacteria dominated the gut microbiota in clinically ill animals. In contrast, the gut microbial community of clinically well animals more closely resembled untreated animals, which were dominated by members of the Firmicutes. All animals that received cefoperazone treatment prior to C. difficile challenge were clinically ill and moribund by 2-5 days post challenge in a dose dependent manner. The gut communities in these animals were dominated by C. difficile suggesting that cefoperazone treatment resulted in a greater loss in colonization resistance. Thus, the severity of colitis that arises in this system reflects the interplay between the expansion of C. difficile in the gut community and the ecologic dynamics of the indigenous microbial community as it recovers from antibiotic perturbation. We demonstrate that altering the balance of these two opposing processes alters clinical outcome and thus may lead to novel preventative and therapeutic approaches for CDI.