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

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 host and the microbiome in different GIT sections. 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.