Shifts in the Gut Metabolome and Clostridium difficile Transcriptome throughout Colonization and Infection in a Mouse Model.
Shifts in the Gut Metabolome and Clostridium difficile Transcriptome throughout Colonization and Infection in a Mouse Model.
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DOI：
10.1128/msphere.00089-18
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发表时间：
2018-03
期刊：
影响因子：
4.8
通讯作者：
Theriot CM
中科院分区：
文献类型：
--
作者：
Fletcher JR;Erwin S;Lanzas C;Theriot CM
艰难梭菌是一种具有全球意义的细菌病原体，是腹泻相关性腹泻的主要原因。抗生素耗尽了固有的肠道微生物群，并将肠道中的代谢环境改变为有利于艰难梭菌生长的环境。在这里，我们使用代谢组学和转录组学来定义抗生素后以及艰难梭菌定植和感染的初始阶段的肠道环境。我们表明，氨基酸，特别是脯氨酸和支链氨基酸，以及碳水化合物的丰度随着时间的推移而减少，艰难梭菌基因表达与细菌在体内对其的利用是一致的。我们采用了一种综合的方法来分析代谢物组和转录物组，以确定代谢物和转录物之间的关联。这突出了关键营养素在定植早期阶段的重要性，这些数据为开发基于使用细菌的疗法提供了理论基础，这些细菌专门竞争艰难梭菌定植和疾病所必需的营养素。抗生素改变肠道微生物群并降低对艰难梭菌定植的抗性;然而，驱动定植抗性的机制尚不清楚。由于抗生素治疗导致的对艰难梭菌定殖的抗性丧失与肠道代谢组的改变相关，具体地，与艰难梭菌可用于体外生长的营养素水平的增加相关。为了确定艰难梭菌在体内定植和发病所需的营养素，我们使用质谱和RNA测序（RNA Seq）的组合来模拟小鼠模型中急性感染期间的肠道代谢组和艰难梭菌转录组，时间点如下：0、12、24和30 h。我们还对组学数据进行了基于多变量的整合，以定义在整个定殖和感染过程中最重要的特征。在这里，我们表明，氨基酸，特别是脯氨酸和支链氨基酸，和碳水化合物的丰度随着时间的推移在小鼠盲肠和艰难梭菌基因表达是一致的，它们在体内的利用。这也通过组学数据的基于多变量的整合得到了加强，其中我们能够在整个定殖和感染的不同时间点之间区分支持艰难梭菌生理学的代谢物和转录物。本报告说明了氨基酸和其他营养素的可用性对于艰难梭菌定植和疾病进展的初始阶段是多么重要。未来的研究确定营养物质的来源和能够在肠道中击败艰难梭菌的工程细菌对于开发新的靶向细菌治疗方法将是重要的。重要性艰难梭菌是一种具有全球意义的细菌病原体，是腹泻相关性腹泻的主要原因。抗生素耗尽了固有的肠道微生物群，并将肠道中的代谢环境改变为有利于艰难梭菌生长的环境。在这里，我们使用代谢组学和转录组学来定义抗生素后以及艰难梭菌定植和感染的初始阶段的肠道环境。我们表明，氨基酸，特别是脯氨酸和支链氨基酸，以及碳水化合物的丰度随着时间的推移而减少，艰难梭菌基因表达与细菌在体内对其的利用是一致的。我们采用了一种综合的方法来分析代谢物组和转录物组，以确定代谢物和转录物之间的关联。这突出了关键营养素在定植早期阶段的重要性，这些数据为开发基于使用细菌的疗法提供了理论基础，这些细菌专门竞争艰难梭菌定植和疾病所必需的营养素。
Clostridium difficile is a bacterial pathogen of global significance that is a major cause of antibiotic-associated diarrhea. Antibiotics deplete the indigenous gut microbiota and change the metabolic environment in the gut to one favoring C. difficile growth. Here we used metabolomics and transcriptomics to define the gut environment after antibiotics and during the initial stages of C. difficile colonization and infection. We show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time and that C. difficile gene expression is consistent with their utilization by the bacterium in vivo. We employed an integrated approach to analyze the metabolome and transcriptome to identify associations between metabolites and transcripts. This highlighted the importance of key nutrients in the early stages of colonization, and the data provide a rationale for the development of therapies based on the use of bacteria that specifically compete for nutrients that are essential for C. difficile colonization and disease. Antibiotics alter the gut microbiota and decrease resistance to Clostridium difficile colonization; however, the mechanisms driving colonization resistance are not well understood. Loss of resistance to C. difficile colonization due to antibiotic treatment is associated with alterations in the gut metabolome, specifically, with increases in levels of nutrients that C. difficile can utilize for growth in vitro. To define the nutrients that C. difficile requires for colonization and pathogenesis in vivo, we used a combination of mass spectrometry and RNA sequencing (RNA Seq) to model the gut metabolome and C. difficile transcriptome throughout an acute infection in a mouse model at the following time points: 0, 12, 24, and 30 h. We also performed multivariate-based integration of the omics data to define the signatures that were most important throughout colonization and infection. Here we show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time in the mouse cecum and that C. difficile gene expression is consistent with their utilization in vivo. This was also reinforced by the multivariate-based integration of the omics data where we were able to discriminate the metabolites and transcripts that support C. difficile physiology between the different time points throughout colonization and infection. This report illustrates how important the availability of amino acids and other nutrients is for the initial stages of C. difficile colonization and progression of disease. Future studies identifying the source of the nutrients and engineering bacteria capable of outcompeting C. difficile in the gut will be important for developing new targeted bacterial therapeutics. IMPORTANCE Clostridium difficile is a bacterial pathogen of global significance that is a major cause of antibiotic-associated diarrhea. Antibiotics deplete the indigenous gut microbiota and change the metabolic environment in the gut to one favoring C. difficile growth. Here we used metabolomics and transcriptomics to define the gut environment after antibiotics and during the initial stages of C. difficile colonization and infection. We show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time and that C. difficile gene expression is consistent with their utilization by the bacterium in vivo. We employed an integrated approach to analyze the metabolome and transcriptome to identify associations between metabolites and transcripts. This highlighted the importance of key nutrients in the early stages of colonization, and the data provide a rationale for the development of therapies based on the use of bacteria that specifically compete for nutrients that are essential for C. difficile colonization and disease.