Chen Ling, Huang Zhipeng, Middelboe Mathias, Deng Deng, Ma Yingfei
State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
Marine Biological Section, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
NPJ Biofilms Microbiomes. 2025 Aug 16;11(1):163. doi: 10.1038/s41522-025-00802-x.
Colonization resistance is a fundamental mechanism by which microbiomes suppress pathogen invasion; however, the ecological and mechanistic determinants of its efficacy remain incompletely understood. Here, we constructed a defined microbial consortium and employed in vivo shrimp infection models to investigate the synergistic interaction between commensal microbes and a pathogen-specific phage in suppressing the pathogen Vibrio parahaemolyticus. Our in vitro experiment revealed that combining key taxa, particularly with phage integration, markedly enhanced pathogen exclusion. Furthermore, we demonstrated that establishing the consortium prior to pathogen exposure resulted in the irreversible suppression of pathogen proliferation, highlighting the critical importance of timing. Mechanistic analyses revealed that nutrient competition from commensals triggered prophage activation in the pathogen, thereby inhibiting its proliferation. Leveraging these insights, we rationally designed a minimalist, yet effective consortium that, when coupled with phage predation, consistently conferred robust colonization resistance in shrimp. This study delineates the core ecological principle underlying microbiota-mediated colonization resistance and establishes a tractable phage-commensal framework for pathogen control, with translational relevance in the context of rising antibiotic resistance in aquatic and potentially mammalian systems.
定殖抗性是微生物群抑制病原体入侵的一种基本机制；然而，其功效的生态和机制决定因素仍未完全了解。在这里，我们构建了一个特定的微生物群落，并采用体内对虾感染模型来研究共生微生物与病原体特异性噬菌体在抑制副溶血性弧菌病原体方面的协同相互作用。我们的体外实验表明，将关键分类群结合起来，特别是与噬菌体整合，可显著增强病原体的排除。此外，我们证明在病原体暴露之前建立群落会导致病原体增殖的不可逆抑制，突出了时间的关键重要性。机制分析表明，共生菌的营养竞争触发了病原体中的原噬菌体激活，从而抑制其增殖。利用这些见解，我们合理设计了一个简约但有效的群落，当与噬菌体捕食相结合时，能持续赋予对虾强大的定殖抗性。这项研究阐述了微生物群介导的定殖抗性背后的核心生态原理，并建立了一个易于处理的噬菌体 - 共生菌框架用于病原体控制，在水生系统以及可能的哺乳动物系统中抗生素耐药性不断上升的背景下具有转化意义。
