The gut virome: A new microbiome component in health and disease

Abstract

The human gastrointestinal tract harbours an abundance of viruses, collectively known as the gut virome. The gut virome is highly heterogeneous across populations and is linked to geography, ethnicity, diet, lifestyle, and urbanisation. The currently known function of the gut virome varies greatly across human populations, and much remains unknown. We review current literature on the human gut virome, and the intricate trans-kingdom interplay among gut viruses, bacteria, and the mammalian host underlying health and diseases. We summarise evidence on the use of the gut virome as diagnostic markers and a therapeutic target. We shed light on novel avenues of microbiome-inspired diagnosis and therapies. We also review pre-clinical and clinical studies on gut virome-rectification-based therapies, including faecal microbiota transplantation, faecal virome transplantation, and refined phage therapy. Our review suggests that future research effort should focus on unravelling the mechanisms exerted by gut viruses/phages in human pathophysiology, and on developing phage-prompted precision therapies.

Keywords: Faecal virome transplantation; Gut virome; Microbiome; Phage; Phage therapy; Virus.

Figure 1

The composition of the human gut virome. a) The composition, richness, and diversity of the gut virome change as a function of age. b) The ratio of bacteriophage to bacteria abundance changes as a function of age.

Figure 2

Interactions between gut viruses and bacteria. a) Four primary life cycles of phages. b) Infection of phages facilitates phenotypic alterations of the bacterial host. Phages are a natural predator of bacteria, and how their predatory behaviour shapes the bacterial community composition largely depends on their replication cycles. In the lytic replication cycle, phages inject their genome into the host bacterium and end with the release of viral offspring and lysis of the host bacteria cell. The lysogenic replication cycle is a life cycle led by temperate phages under favourable conditions in the human gut. The integration of prophages facilitates alterations in bacterial phenotypes via transfer of phage-coding factors and horizontal transfer of genes encoding for antibiotic-resistance or toxins between bacterial communities, and thus enhance metabolism capacity, environmental adaptation, and pathogenicity of gut bacteria. c) The inducing factors of prophages. Temperate phages remain at a prophage state unless encountering stimulating factors, such as antibiotics, ultraviolet radiation, alterations in temperature or pH, chemical/diet inducers as well as oxidative/inflammatory stress.

Figure 3

Gut virome and host immunity. a) The interaction between phages and the human immune system. b) Eukaryotic viruses play a key role in maintaining the homeostasis of the human gut and host immunity. In the human GI tract, phages adhere to mucosal surfaces to prevent luminal bacterial pathogens from adhesion. Numerous phages can be transported across the intestinal epithelial cells towards the systemic circulation and directly influence the human immune system. Innate immune cells recognise these viruses and regulate release of cytokines (such as IFN-γ) and enhance opsonization and recognition of bacteria. Antigen presenting cells (APC) cells present phage-derived peptides to naive T cells and activate the humoral and cellular immunity. Activated B cells differentiate into plasmacytes, to release phage-specific antibodies to clear phages from the body circulation. Colonisation of eukaryotic viruses is also crucial for maintaining the homeostasis of gut and host immunity. In the steady state, RNA virus can be recognised by the RIG-I receptor of dendritic cells (DCs) to maintain the homeostasis of IELs. In the inflammation state, murine Rotavirus (MRVs) activates IFN-I/IL-22-dependent pathways to prevent mice from intestinal injury. The bulk eukaryotic viruses trigger surface TLR3/TLR7-dependent production of IFN-β to protect the host from inflammation. In an immunodeficient state, the supplementation of astrovirus can protect mice from viral (MNVs/MRVs) infection via production of IFN-γ. Abbreviations: LC, lymphoid cell; IEL, intestinal intraepithelial lymphocyte; TLR, Toll-like receptor; IL, interleukin; IFN, interferon.

Figure 4

The gut virome in human diseases.