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

抗生素对治疗感染是必不可少的。然而，它们也会对宿主产生长期影响。因此，研究抗生素的副作用非常重要。在BioIMPACT中，我们将测试以下假设：由于抗生素治疗，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，在菌株水平上研究人类粪便群落中由厌氧诱导的变化。这项工作依赖于我们在高端培养方法，（Meta）基因组学和gnotobiology方面的综合专业知识，并在四个主要领域组织：（i）在人源化小鼠中进行抗生素干预，以研究受控条件下基于代谢组学和测序的生态系统动力学;（ii）建立培养细菌及其菌株水平基因组景观的个性化收藏;（iii）在细胞培养中进行基因组学研究。㈢深入分析药物-细菌相互作用的表型和合成群落的功能设计; ㈣在无菌小鼠中进行概念验证功能研究，以测试菌株变异性对抗生素引起的代谢组和生态系统挑战的影响。除了这一主要目标外，该项目还将提供有关培养细菌多样性和功能的大量数据，考虑到肠道微生物组研究因许多微生物及其功能仍然未知而受到阻碍，这一点至关重要。此外，已知肠道微生物群具有个体特异性，但实验模型并不能概括这些特征，这也将在BioIMPACT中得到解决。总之，该项目将为肠道微生物组的生态和培养部分提供新的见解，并使用分离物测试基于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.