Personalized effects of antibiotics on the human gut microbiome via high-throughput cultivation

抗生素对于治愈感染是必不可少的。然而，它们也会影响共生微生物，对宿主产生长期影响。因此，研究抗生素的副作用是很重要的。在BioIMPACT中，我们将测试这一假设，即由于抗生素治疗而导致人类肠道细菌的进化漂移以个性化的方式影响生态系统功能。因此，我们将使用厌氧培养和测序技术相结合的方法，在菌株水平上研究抗生素诱导的人类粪便群落的变化。这项工作依赖于我们在高端培养方法、(Meta)基因组学和生理学方面的专业知识，并在四个主要领域进行安排：(I)对人源化小鼠进行抗生素干预，以研究受控条件下基于代谢和测序的生态系统动态；(Ii)在菌株水平上建立个性化的培养细菌集合及其基因组图谱；(Iii)对药物-细菌相互作用和合成群落的功能设计进行深入的表型分析；(Iv)对GnoBiotic小鼠进行概念验证功能研究，以测试菌株变异性对代谢组的影响和抗生素对生态系统的挑战。除了这一主要目标外，该项目还将提供有关培养细菌的多样性和功能的大量数据，这是至关重要的，因为许多微生物及其功能仍不清楚，这一事实阻碍了肠道微生物组的研究。此外，肠道微生物区系是已知的个体特有的，但实验模型不能概括这些特征，这也将在BioIMPACT中讨论。总而言之，该项目将为肠道微生物群的生态学和培养部分提供新的见解，并测试使用分离物的个性化微生物组应用的新概念。

Antibiotics are essential for curing infections. However, they also affect commensal microbes with long term-consequences for the host. It is thus important to study collateral effects of antibiotics. In BioIMPACT, we will test the hypothesis that evolutionary drifts in human gut bacteria due to antibiotic treatment influence ecosystem functions in a personalized manner. Therefore, we will investigate antibiotic-induced changes within human fecal communities at the strain-level using a combination of anaerobic cultivation and sequencing techniques. The work relies on our combined expertise in high-end cultivation approaches, (meta)genomics, and gnotobiology, and is organized in four main areas: (i) antibiotic intervention in humanized mice to study metabolomic- and sequencing-based ecosystem dynamics under controlled conditions; (ii) establishment of personalized collections of cultured bacteria and their genomic landscape at the strain-level; (iii) in-depth phenotyping of drug-bacteria interactions and functional design of synthetic communities; (iv) proof-of-concept functional studies in gnotobiotic mice to test the effect of strain variability on the metabolome and ecosystem challenge by antibiotics. Besides this main objective, the project will also deliver a large amount of data on the diversity and functions of cultured bacteria, which is essential considering that gut microbiome research is hampered by the fact that many microbes and their functions are still unknown. Moreover, the gut microbiota is known to be individual-specific but experimental models do not recapitulate these features, which will also be addressed in BioIMPACT. In summary, this project will deliver novel insights into the ecology and cultured fraction of gut microbiomes and test new concepts for personalized microbiome-based applications using isolates.