The contribution of bacteriophages to host-microbe interactions in the intestine

描述（由申请人提供）：哺乳动物肠道是对宿主健康不可或缺的密集细菌群落的家园。这种细菌群的改变会引起肠道窘迫，甚至在某些情况下引起炎症性疾病。除了细菌，肠道中也有大量的病毒。真核病毒和原核病毒都构成了肠道“病毒群”，然而，感染细菌的病毒，即噬菌体（噬菌体）占主导地位。大多数肠道噬菌体以溶原性噬菌体的形式存在，稳定地整合到细菌染色体中。当细菌细胞受到压力或受到营养物质刺激时，噬菌体通常会进行裂解诱导以产生感染性噬菌体颗粒。初步研究表明，共生细菌粪肠球菌V583在小鼠肠道中生长时可诱导原噬菌体。体外，噬菌体的诱导依赖于氨基酸浓度的升高；然而，营养介导的噬菌体诱导的确切机制尚不清楚。此外，体内研究表明，裂解噬菌体颗粒的释放使粪肠球菌能够与遗传相关的肠球菌竞争类似的肠道资源。综上所述，这些初步发现表明噬菌体可以影响哺乳动物肠道生态系统中细菌定植的动态，并建立了粪芽孢杆菌作为研究噬菌体-宿主相互作用的肠道噬菌体模型。这项研究的长期目标是了解肠道噬菌体如何影响人体生理和健康。在K01奖励机制下提出的具体研究将通过定义肠道中诱导噬菌体产生的机制，通过确定噬菌体如何影响宿主免疫，以及通过探索噬菌体捕食如何影响细菌与宿主的相互作用来推进这一目标。这些研究将为肠道噬菌体如何影响宿主健康和生理提供新的见解，并将为未来探索噬菌体作为操纵微生物群以改善健康的治疗工具奠定基础。

DESCRIPTION (provided by applicant): The mammalian intestine is home to a dense community of bacteria that are integral to host health. Alterations in this bacterial population ca cause intestinal distress and even in some cases inflammatory disease. Aside from bacteria, viruses are also abundant in the intestinal tract. Both eukaryotic and prokaryotic viruses make up the intestinal "virome", however, viruses that infect bacteria, known as bacteriophages (phages), dominate. The majority of intestinal phages exist as lysogenic prophages that are stably integrated into bacterial chromosomes. Prophages typically undergo lytic induction to produce infectious phage particles when bacterial cells are stressed or when they are stimulated by nutrients. Preliminary studies have revealed that the commensal bacterium Enterococcus faecalis V583 induces the prophages when growing in the mouse intestine. In vitro, prophage induction depends on elevated amino acid concentrations; however, the exact mechanisms underlying nutrient-mediated induction of prophages are unknown. Further, in vivo studies indicate that the release of lytic phage particles allows E. faecalis to compete with genetically related enterococci vying for similar intestinal resources. Together, these initial findings indicae that phages can impact the dynamics of bacterial colonization in the mammalian intestinal ecosystem and have established E. faecalis prophages as model intestinal phages for the study of phage-host interactions. The long-term goal of this research is to understand how intestinal bacteriophages impact human physiology and health. The specific research proposed under this K01 award mechanism will advance this goal by defining the mechanisms that elicit phage production in the intestine, by determining how bacteriophage impact host immunity, and by exploring how phage predation impacts bacterial interactions with the host. These studies will provide novel insights into how intestinal phages influence host health and physiology, and will set the stage for future exploration of phage as therapeutic tools for manipulating the microbiota to improve health.