Antibiotic-Induced Dysbiosis Predicts Mortality in an Animal Model of Clostridium difficile Infection
Antibiotic-Induced Dysbiosis Predicts Mortality in an Animal Model of Clostridium difficile Infection
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DOI：
10.1128/aac.00925-18
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发表时间：
2018-10-01
影响因子：
4.9
通讯作者：
de Gunzburg, Jean
中科院分区：
文献类型：
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作者：
Burdet, Charles;Sayah-Jeanne, Sakina;de Gunzburg, Jean
抗生素对肠道微生物群的破坏有利于艰难梭菌的定殖。我们使用木炭吸附剂来降低肠道抗生素浓度，研究了粪便中抗生素浓度与生态失调强度之间的关系，并量化了这种强度与死亡率之间的联系。我们从第 1 天 (D-1) 到第 5 天通过皮下注射向仓鼠施用莫西沙星 (n = 70) 或克林霉素 (n = 60)，并在第 3 天用艰难梭菌产毒菌株攻击它们。仓鼠接受不同剂量的木炭吸附剂 DAV131A，以调节肠道抗生素浓度。使用从 16S rRNA 基因分析确定的多样性指数在 D-0 和 D-3 评估肠道生态失调。监测存活率直至 D-16。我们分析了艰难梭菌攻击时粪便抗生素浓度与生态失调之间的关系，并研究了它们预测动物随后死亡的能力。增加 DAV131A 剂量可降低粪便中两种抗生素的浓度，降低生态失调，并将存活率从 0% 提高至 100%。死亡率与生态失调水平相关（莫西沙星治疗动物香农指数变化P < 10(-5)，克林霉素治疗动物P < 10(-9)）。 Shannon 多样性指数和未加权 UniFrac 距离最能预测死亡，受试者工作曲线 (ROC) 下面积分别为 0.89（95% 置信区间 [CI]，0.82，0.95）和 0.95（0.90，0.98）。总而言之，莫西沙星和克林霉素破坏了肠道微生物群的多样性，并且依赖于 DAV131A 剂量；艰难梭菌攻击后的死亡率与生态失调的强度有关，与两种抗生素的情况类似。
Antibiotic disruption of the intestinal microbiota favors colonization by Clostridium difficile. Using a charcoal-based adsorbent to decrease intestinal antibiotic concentrations, we studied the relationship between antibiotic concentrations in feces and the intensity of dysbiosis and quantified the link between this intensity and mortality. We administered either moxifloxacin (n = 70) or clindamycin (n = 60) to hamsters by subcutaneous injection from day 1 (D-1) to D-5 and challenged them with a C. difficile toxigenic strain at D-3. Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D-0 and D-3 using diversity indices determined from 16S rRNA gene profiling. Survival was monitored until D-16. We analyzed the relationship between fecal antibiotic concentrations and dysbiosis at the time of C. difficile challenge and studied their capacity to predict subsequent death of the animals. Increasing doses of DAV131A reduced fecal concentrations of both antibiotics, lowered dysbiosis, and increased survival from 0% to 100%. Mortality was related to the level of dysbiosis (P < 10(-5) for the change of Shannon index in moxifloxacin-treated animals and P < 10(-9) in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the receiver operating curve (ROC) of 0.89 (95% confidence interval [CI], 0.82, 0.95) and 0.95 (0.90, 0.98), respectively. Altogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency on the DAV131A dose; mortality after C. difficile challenge was related to the intensity of dysbiosis in similar manners with the two antibiotics.