One hundred years after their discovery [1,2], the interest towards the therapeutic use of bacteriophages (briefly: phages) has resurged due to the escalating rise of multi-drug–resistant bacteria [3,4]. However, besides regulatory hurdles, realization of this treatment concept is hampered by efficiency and safety concerns [5]. Conversely, metagenome studies have shown that phages are consistent and dominant members of the human microbiome, suggesting an unknown role of phages in human health and disease [6]. Therefore, the recognition and understanding of phages as common members of the human microbiome may provide the required confidence and pave the way for their targeted medical application, which will go beyond the classical form of phage therapy. Here we provide a holistic perspective regarding the impact of human-associated phages and possible consequences for our well-being. The influence of phages is rather complex, because the consequence of infection is not restricted to the immediate host. Any drop-out or altered physiology of the bacterial host can have profound effects on other members within the microbiome as well. Phages are best known for their ability to “arm” bacteria with virulence genes, which converts a benign bacterial strain into a highly pathogenic strain, causing an acute and severe infection [7,8]. Hence, phages are broadly regarded as notorious “providers” of virulence genes, which has conferred upon them a largely negative reputation. However, considering that phages are our permanent companions along with bacteria, the emergence of novel pathogenic bacterial strains is actually a comparably rare event. We believe that from a global perspective, the impacts of phages are rather subtle and mostly in a regulatory and positive way. A stable, healthy microbiome can probably only evolve and be maintained through phage activity. Nonetheless, metagenomic studies have also indicated altered phages populations in dysbiosis. This means that human diseases, characterized by distorted bacterial communities, may ultimately also have phage-driven origins. From this it follows that phages are critical mediators of human health but also of disease, lending them somewhat the character of a “Janus-Face” (Fig 1). It will be one of the greatest challenges of future research to disentangle the dynamic and complex interplays between phages and bacteria. This endeavor is worthwhile, because understanding phage activity in humans (good or bad) can be considered a golden chance for developing strategies that aim at the directed use of phages in favor of human health [9]. Fig 1 The Janus-Face of phages. The human microbiome is biogeographically structured across the four major habitats: the oral cavity, the gastrointestinal tract, the vagina, and the skin [10,11]. Each habitat is characterized by numerous sub-niches and surfaces harboring a myriad of bacteria, archaea, eukaryotes, and viruses, most of which are phages [9,12–14]. Given the distinctiveness of each body site, phage–bacterial interactions may be quite distinctive as well. However, some general principles may apply, such as the “kill the winner” hypothesis, which argues that the chances of superior (thus growing) bacterial populations encountering phages increases with increasing cell density [15]. This, in turn, initiates the decline of the “winner.” As a consequence, phages aid in sustaining bacterial diversity as they prevent overgrowth of certain bacterial species or strains over others. Clearly, more complex interactions may exist, and a number of models of how bacteria and phages may influence each other have been described recently [6].
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