The PHAGENET project seeks to elucidate the role of bacteriophages (phages) and phage-mediated horizontal gene transfer (HGT) in the functioning of the human gut microbiome. Complex microbial communities such as the human gut microbiome are believed to evolve and adapt primarily through HGT. HGT circumvents the barriers imposed by vertical evolution and allows individual strains to access the common distributed gene pool (the pangenome). The pangenome of any given microbial species, as well as the collective pangenome of the microbiome, act as “public libraries” of genetic material that can be re-shuffled and subjected to natural selection in the different genetic backgrounds of individual microbiome members.
The resulting dissemination of fitness-increasing “beneficial” traits is thought to be essential for the maintenance of functional diversity, resistance to adverse events and resilience in the microbiome. Likewise, “undesirable” (from a human perspective) traits such as antibiotic resistance genes (ARGs), toxins and virulence factors get a chance to be “sampled”, shared, and positively selected. Therefore, it should be expected that HGT plays a central role in the emergence and evolution of antibiotic-resistant pathogens, so called “superbugs”. These antibiotic resistant pathogens are one of the key unsolved problems faced by European and global healthcare systems, estimated to cause 25,000 deaths and economic losses of €1.5 billion annually in the EU alone.
The overarching aim of PHAGENET is to find out whether or not that phage-mediated HGT operates at high rate in the human gut microbiome, and whether or not it plays a major role in maintaining genetic diversity, resistance, and resilience. The central hypothesis underpinning this research project is that phages are the most abundant, the most sophisticated and most efficient gene-transfer pathway within the microbiome, acting to (a) increase the connectivity and accessibility of bacterial pangenomes in the microbiome; (b) create a repository or “filing” system of non-essential genes; (c) provide a channel for communication (genetic exchange, HGT) between individual human microbiome and the broader environment; and (d) help to rapidly spread specific fitness-promoting genes (including ARGs and virulence genes) and alleles required by bacterial populations.
