**1. Introduction**

While the role of the bacterial community during fecal microbiota transplantation (FMT) has been the focus of extensive investigation, there has been substantially less examination of the viral community. The growing body of research on the viruses of the gut microbiome, referred to, herein, as the gut virome, points to their role as an important regulator of gut homeostasis [1–4]. This occurs through the modification of microbiome structure, composition, and function by gut bacteriophages [5–9], as well as through direct interaction between the enteric virome and the human immune system [4, 10–14]. In line with the gut virome's regulatory role, several recent studies have shown that fecal virome transplantation (FVT), a procedure similar to FMT albeit filtered to exclude intact fecal bacteria, has potential for resolving gut microbiome dysbiosis and restoring a healthy microbiota [15–18]. The full breadth of possibilities for FVT are only now beginning to unfold, but this emerging field of study has produced exciting findings that suggest FVT may be a versatile therapeutic treatment for multiple forms of dysbiosis. Not only has FVT been used effectively for clinical treatment of *Clostridium difficile* infection (CDI), but promising preliminary results suggest FVT has potential for resolving other dysbiosis such as those associated with diabetes and small intestinal bacterial overgrowth. In this chapter we will be reviewing the current state of gut virome research and discussing the clinical potential for FVT.

### **2. The gut virome**

The gut virome consists of a robust and diverse community of eukaryotic and bacterial viruses, with bacterial viruses (herein referred to as bacteriophages,

or phages) estimated to make up between 90% [19] and 97.7% [20] of the membership of the gut virome. Approximately 1014 viruses, comprised of ~1200 virotypes, reside in the gastrointestinal tract at any given time [21], a population that is roughly 10 times that of gut bacteria but comparable in diversity [22, 23]. However, the ratio of phages to bacteria is approximately 1:1 in the infant gut suggesting the population changes over the course of development [24]. Like microbiome composition, virome composition is highly responsive to diet and when individuals are placed on the same diet, their viromes have been found to converge [25]. However, once established, the human gut virome has been shown to have high inter-individual variation [26], sufficient enough for viromes to be distinguishable between related individuals, such as between infants and mothers [27]. Individual viromes are also stable over time and approximately 80% of gut viruses have been shown to persist over a 2.5 year period [28]. At the population level, metagenomic analysis of viromes has demonstrated that there is a core of shared viruses among viromes within a population that can be used to distinguish between other geographically distinct groups [29, 30]. Recent findings by Manrique and colleagues have suggested that there is also a globally distributed set of core phages that are considered to constitute a "healthy gut phageome;" in part, because the prevalence of these phages is significantly decreased in the setting of inflammatory bowel disease (IBD; [31]. Specific phage community compositions and structures are associated with specific gastrointestinal and extraintestinal diseases including colon cancer [32], IBD [14, 33–36], rCDI [16, 37], and diabetes [15, 38].
