**5. Dynamics of FVT-based modulation of the microbiome**

The mechanisms through which FVT modifies the recipient's gut microbiome is the subject of ongoing investigation and is likely the result of complex community interactions between donor phages and recipient bacteria, all of which is likely heavily influenced by the host gut environment. Temperate and lytic phages exhibit different population dynamics within microbial communities, and administration of individual strains of exogenous phages into the gastrointestinal tract of mice has been used to study these dynamics [5, 6, 62]. In a gnotobiotic mouse model where the gut is colonized by a defined community of resident gut bacteria, the administration of monocultures of lytic phages exhibiting a narrow host range can reduce populations of their host bacteria through predation [5]. It was also observed that reducing targeted host bacteria subsequently leads to a cascading effect in which populations of non-host bacteria in the microbiome are affected through interbacterial interactions. This effect propagated throughout the gut the microbiota with far-reaching consequences for the composition, structure, and function of the microbiota. Additionally, there is some evidence that a phage therapy approach has the potential to control or eliminate bacterial pathogens, such as *Enterococcus faecalis*, in the gut [63]. These studies provide models for studying basic phage-bacterial dynamics in the gut, particularly 'kill-the-winner' population dynamics where lytic phages act as predators leading to a suppression of their bacterial hosts and opening of new ecological niches for non-host bacteria.

Since both temperate and lytic phages are transferred to the recipient during FMT and sustained in the recipient's virome afterwards [17], it is likely that multiple population dynamics are at play in the setting of FVT. In a study using gnotobiotic mice with a defined microbiota, administration of a FVT from human feces resulted in a cascade of changing abundance of different gut bacteria that modeled primarily that of temperate phage-bacteria dynamics [62]. In another study by Bao and colleagues, the investigators found that administration of lytic or temperate phage monocultures into the gut of healthy mice modulated the microbiome by changing relative abundances of host and non-host bacterial populations at both phylum and genus level [6]. Of note, in this particular study, lytic phages promoted a beneficial gut environment while temperate phages promoted conditions that would enable disease to occur. Other co-evolutionary phage-bacteria dynamics that have been observed in microbial communities include 'piggyback-the-winner,' 'arms-race,' and 'kill-the-relative' dynamics, which are reviewed in detail elsewhere [2, 64]. Collectively, these dynamics are thought to contribute to the onset and maintenance of states of dysbiosis in the microbiome and are therefore also likely to have a role in recovery from dysbiosis in the setting of FVT. In the setting of rCDI, it is unclear whether exogenous phages with a broad host range down-regulate *C. difficile* populations or whether they promote a healthier microbiome with less ideal conditions for *C. difficile* colonization.
