Deciphering the mechanisms underlying phage-bacterial coexistence in the gut

Objective

Bacteriophages (phages) are major drivers of microbial diversity and ecosystem function in many habitats. In the human gut, they play a crucial role in shaping bacterial populations, influencing host health and microbiome stability. While several studies have revealed that phages and their bacterial hosts can coexist for extended periods, the mechanisms underlying this long-term coexistence remain largely unknown. Understanding how such stability is maintained is essential for both fundamental microbiome research and the development of phage-based therapies. This project aims to dissect some of the molecular and ecological mechanisms that sustain stable phage-bacterial coexistence in the gut. Using Escherichia coli and Enterococcus faecalis (two commensal species commonly found in the intestinal microbiota) and their corresponding phages, I will establish controlled in vitro systems to study how factors such as nutrient composition, community complexity, and culture conditions influence coexistence dynamics. Combining these assays with deep sequencing, metabolomics and proteomics, genomic changes and molecular pathways involved in resistance and phage persistence will be decoded. The functional role will be validated through the knockdown of the identified pathways and, ultimately, tested in gnotobiotic mice colonized with the OMM12 synthetic microbial community. The expected outcome is a detailed mechanistic understanding of how phages and their hosts coexist over time in the gut environment. By uncovering the key genetic and ecological factors involved, this project will provide fundamental insights into microbiome resilience and control. This knowledge will also help inform the rational design of microbiome-targeted interventions and improve the predictability and safety of phage therapy in clinical settings.