Metabolomics analysis identifies intestinal microbiota-derived biomarkers of colonization resistance in clindamycin-treated mice.
Metabolomics analysis identifies intestinal microbiota-derived biomarkers of colonization resistance in clindamycin-treated mice.
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DOI：
10.1371/journal.pone.0101267
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Donskey CJ
中科院分区：
文献类型：
--
作者：
Jump RL;Polinkovsky A;Hurless K;Sitzlar B;Eckart K;Tomas M;Deshpande A;Nerandzic MM;Donskey CJ
肠道微生物群通过一种称为定植抗性的防御机制保护宿主免受肠道病原体的侵害。排泄到肠道的抗生素可能会破坏定植抵抗并改变微生物群的正常代谢功能。我们使用小鼠模型来验证假设，即粪便标本中细菌代谢物水平的改变可以提供有用的生物标志物，表明抗生素治疗后细菌定植耐药性的破坏或完整。为了评估小鼠体内定植耐药性，在使用林可沙胺类抗生素克林霉素治疗后的不同时间点，用口服万古霉素耐药肠球菌或艰难梭菌孢子刺激小鼠。对于同时使用抗生素治疗的小鼠组，使用定量实时聚合酶链反应分析粪便样本，以评估微生物群的变化并使用非靶向代谢谱。为了评估这些发现是否适用于另一类抑制肠道厌氧菌的抗生素，对哌拉西林/他唑巴坦进行了类似的实验。定植耐药性在5天内开始恢复，在克林霉素治疗后12天恢复完整，与厚壁菌门的毛螺杆菌科和瘤胃球菌科的恢复菌一致。克林霉素治疗引起粪便标本中代谢物的显著变化。在分析的484种化合物中，146种（30%）在克林霉素治疗期间浓度显著增加或减少，随后恢复到基线，与体内定植抗性的恢复一致。这些化合物被认为是定植抗性的潜在生物标志物，包括碳水化合物或蛋白质代谢的中间产物，这些中间产物在克林霉素处理下增加（戊糖、γ -谷氨酰氨基酸和肌醇代谢物）或减少（戊糖、二肽）。哌拉西林/他唑巴坦治疗引起了肠道微生物群和粪便代谢物的类似改变。抗生素治疗后定植耐药性的恢复与几种粪便细菌代谢物的恢复一致。这些代谢物可以提供有用的生物标志物，表明在抗生素治疗期间和之后完整或破坏的定植抗性。
The intestinal microbiota protect the host against enteric pathogens through a defense mechanism termed colonization resistance. Antibiotics excreted into the intestinal tract may disrupt colonization resistance and alter normal metabolic functions of the microbiota. We used a mouse model to test the hypothesis that alterations in levels of bacterial metabolites in fecal specimens could provide useful biomarkers indicating disrupted or intact colonization resistance after antibiotic treatment. To assess in vivo colonization resistance, mice were challenged with oral vancomycin-resistant Enterococcus or Clostridium difficile spores at varying time points after treatment with the lincosamide antibiotic clindamycin. For concurrent groups of antibiotic-treated mice, stool samples were analyzed using quantitative real-time polymerase chain reaction to assess changes in the microbiota and using non-targeted metabolic profiling. To assess whether the findings were applicable to another antibiotic class that suppresses intestinal anaerobes, similar experiments were conducted with piperacillin/tazobactam. Colonization resistance began to recover within 5 days and was intact by 12 days after clindamycin treatment, coinciding with the recovery bacteria from the families Lachnospiraceae and Ruminococcaceae, both part of the phylum Firmicutes. Clindamycin treatment caused marked changes in metabolites present in fecal specimens. Of 484 compounds analyzed, 146 (30%) exhibited a significant increase or decrease in concentration during clindamycin treatment followed by recovery to baseline that coincided with restoration of in vivo colonization resistance. Identified as potential biomarkers of colonization resistance, these compounds included intermediates in carbohydrate or protein metabolism that increased (pentitols, gamma-glutamyl amino acids and inositol metabolites) or decreased (pentoses, dipeptides) with clindamycin treatment. Piperacillin/tazobactam treatment caused similar alterations in the intestinal microbiota and fecal metabolites. Recovery of colonization resistance after antibiotic treatment coincided with restoration of several fecal bacterial metabolites. These metabolites could provide useful biomarkers indicating intact or disrupted colonization resistance during and after antibiotic treatment.
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