Gut phages and their interactions with bacterial and mammalian hosts

Abstract

The mammalian gut microbiome is a dense and diverse community of microorganisms that reside in the distal gastrointestinal tract. In recent decades, the bacterial members of the gut microbiome have been the subject of intense research. Less well studied is the large community of bacteriophages that reside in the gut, which number in the billions of viral particles per gram of feces, and consist of considerable unknown viral "dark matter." This community of gut-residing bacteriophages, called the gut "phageome," plays a central role in the gut microbiome through predation and transformation of native gut bacteria, and through interactions with their mammalian hosts. In this review, we will summarize what is known about the composition and origins of the gut phageome, as well as its role in microbiome homeostasis and host health. Furthermore, we will outline the interactions of gut phages with their bacterial and mammalian hosts, and plot a course for the mechanistic study of these systems.

Keywords: microbiome; phages.

Fig 1

Phage lifestyles. Depicted are various forms of phage replication. Phages initially adsorb to surface structures on their bacterial hosts, triggering injection of their genome as a linear molecule into the host cell cytosol. After genome circularization, diverse phages pursue different lifestyles. Under certain conditions, some phages are maintained episomally in various carrier states that do not result in cell lysis. Both virulent and temperate phages participate in lytic replication, wherein phage genomes replicate and are packaged into newly synthesized viral particles, which are released by cell lysis. Temperate phages participate in lysogeny, where the phage genome recombines with the bacterial genome, resulting in prophage integration. Integrated prophages largely silence their lytic genes but can influence bacterial physiology by expressing other phage-encoded factors or re-wiring host transcription.

Fig 2

Interactions of phage, bacteria, and human hosts. Depicted are the pairwise interactions of gut phages, their host bacteria, and humans. Gut phages modulate bacterial abundance but can also generate and maintain bacterial diversity through genetic transfer and predatory selection. By acting as a permissive or restrictive growth substrate for phages, gut bacteria affect phage abundance, and in resisting phage infection, bacteria select for diverse phage populations. Following endocytosis, gut phages interact with the mammalian immune system via Toll-like receptor 3 (TLR3) pathways and antagonize anti-bacterial tumor necrosis factor (TNF) signaling via the type I interferon response (IFN). Gut bacteria interface directly with the mammalian immune system through metabolites and signaling molecules including short-chain fatty acids (SCFAs), lipopolysaccharides (LPS), nucleotide oligomerization domain (NOD) ligands, and various other pathways reviewed elsewhere. The mammalian immune system controls gut bacterial populations through antimicrobial peptides (AMPs), soluble immunoglobulin (IgA), and other mechanisms reviewed elsewhere.

Fig 3

Frameworks for phage–host interactions. (A) In the kill-the-winner ecological framework, phages prey on the fastest-growing clones. Following a lytic epidemic, phage populations decay until the next clonal takeover. This results in offset oscillations of phage and host abundance. (B) In the piggyback-the-winner ecological framework, phage populations grow steadily as bacterial populations grow, potentially avoiding lytic epidemics through lysogeny, pseudolysogeny, or other low-VMR-type replicative strategies. In the absence of temperate representatives, how crAssphages and other virulent gut phages maintain low levels of stable replication remains a mystery. (C) One model to explain low VMR during crAssphage infection is that crAssphages remain in an episomal state until reactivating stimuli induce lytic replication. (D) Another model is that crAssphages have an extended and highly regulated lytic cycle.

Fig 4

In vivo experiments to examine causal roles for phage in bacterial and host phenotypes. (A–C) The effects of phage on their bacterial targets can be examined in gnotobiotic animals colonized with single isolates (A), communities with “defined” inocula (B), or complex and undefined “intact” communities via fecal microbiota transplants (FMTs) and fecal virome transplants (FVTs) (C). (D) The sufficiency of a phage isolate for a host phenotype can be assessed by using a monocolonized arm of animals (top left experimental group) compared to uncolonized controls (bottom left group). The necessity of the isolate for a host phenotype can be examined by comparing a complete cocktail of phages (top right experimental group) compared to one in which it is excluded from the cocktail (bottom right group).