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群（IM）的改变有关。IM由包括病毒在内的数万亿微生物组成，其中以细菌为食的噬菌体（噬菌体）最多。噬菌体通过控制特定的细菌群体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器和指示器。尽管基于宏基因组的研究已经解决了它们在肠道中的丰度、多样性和稳定性，但对噬菌体在肠道内稳态中的作用及其对全球微生物组功能的影响知之甚少。此外，关于噬菌体及其细菌宿主随时间动态相互作用的机制的知识还存在空白。人类拥有个性化的病毒群，表现出高度的时间稳定性。健康个体的病毒组组成与细菌群落相关，并在炎症性疾病期间发生改变。有趣的是，噬菌体可以驱动肠道的促炎免疫反应，加重结肠炎症状。目前我们对噬菌体在IM中的作用的理解的限制是缺乏合适的模型系统来探测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，我们在稳定定植的非生物小鼠中使用了一个确定的合成细菌群落，寡聚小鼠微生物群（OMM）和菌株特异性噬菌体。在PhaStGut中，我们将深入表征噬菌体生态学，研究其对肠道微生物组的影响及相关功能。此外，我们将研究噬菌体及其宿主细菌在肠道中稳定共存的机制。最终目标是完善基于噬菌体的IM工程策略。我们高度跨学科的团队，由四个合作伙伴组成，将使用综合方法，结合meta转录组学，meta代谢组学和3D DNA捕获在非生物小鼠中。因此，我们将揭示控制噬菌体及其宿主细菌之间形成哺乳动物IM的动态相互作用的机制。PhaStGut将为噬菌体导向的微生物组工程策略的发展开辟道路，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