Mechanisms underlying bacteriophages and bacteria stable coexistence and its consequences on gut microbiome function.

越来越多的人类疾病与肠道微生物区系(IM)改变有关。IM由包括病毒在内的数万亿种微生物组成，其中以细菌为原型的噬菌体(噬菌体)最为丰富。噬菌体通过管理特定的细菌种群结构和与粘膜免疫系统相互作用，是人类健康和疾病的重要效应者和指示器。尽管基于超基因组的研究已经研究了它们在肠道中的丰度、多样性和随时间的稳定性，但对噬菌体在IM动态平衡中的作用及其对全球微生物组功能的影响知之甚少。此外，关于噬菌体和它们的细菌宿主随时间动态相互作用的机制存在知识空白。人类拥有个性化的病毒，表现出高度的时间稳定性。健康人的病毒体组成与细菌群落相关，并在炎症性疾病期间发生变化。有趣的是，噬菌体可以推动肠道内的促炎免疫反应，并加剧结肠炎症状。目前我们对噬菌体在IM中的作用的理解的一个限制是缺乏合适的模型系统来探索噬菌体的功能和剖析噬菌体-细菌相互作用的机制。为了克服这一限制，我们使用了一个定义的合成细菌群落，寡鼠微生物群(OMM)和菌株特定的噬菌体在稳定定植的灵芝小鼠中。在PhaStGut中，我们将对噬菌体生态进行深入的表征，并研究它们对肠道微生物群和相关功能的影响。此外，我们还将研究噬菌体及其宿主细菌在肠道中稳定共存的机制。最终目标是为基于噬菌体的IM工程改进策略。我们由四个合作伙伴组成的高度跨学科的团队将使用一种综合方法，将元转录组学、元代谢组学和3D DNA捕获结合在一起。因此，我们将揭示控制噬菌体和它们的宿主细菌之间动态相互作用的机制，这些机制塑造了哺乳动物IM。PhaStGut将为以噬菌体为导向的微生物组工程战略的发展开辟道路，以维持人类健康

An increasing number of human diseases is associated with an altered intestinal microbiota (IM). The IM consists of trillions of microbes including viruses amongst which bacteriophages (phages) that predate on bacteria are the most abundant. Phages are important effectors and indicators of human health and disease by managing specific bacterial population structures and by interacting with the mucosal immune system. Despite metagenome-based studies have addressed their abundance, diversity and stability over time in the gut, little in known on the role of phages in IM homeostasis and its impact on global microbiome functions. Furthermore, there is a gap in knowledge pertaining to the mechanisms by which phages and their bacterial hosts dynamically interact over time.Humans harbor personalized viromes exhibiting high temporal stability. Virome composition of healthy individuals correlates with bacterial communities and is altered during inflammatory disease. Interestingly, phages can drive proinflammatory immune responses in the gut and aggravate colitis symptoms. A current limitation to our understanding of the role of phages in the IM is the lack of suitable model systems to probe phage functions and dissect the mechanisms of phage-bacteria interactions. To overcome this limitation, we employ a defined synthetic bacterial community, the Oligo-Mouse-Microbiota (OMM) and strain-specific phages in stably colonized gnotobiotic mice. In PhaStGut, we will conduct an in-depth characterization of phage ecology and study their influence on the microbiome and related functions in the gut. In addition, we will study the mechanisms underlying stable coexistence of phages and their host bacteria in the gut. The final goal is to refine strategies for phage-based IM engineering. Our highly interdisciplinary team, consisting of four partners, will use an integrated approach, combining meta-transcriptomics, meta-metabolomics and 3D DNA capture in gnotobiotic mice. Thereby, we will uncover mechanisms governing the dynamic interplay between phages and their host bacteria that shape the mammalian IM. PhaStGut will open avenues for the development of phage-guided strategies for microbiome engineering to sustain human health