The Human Gut Phageome: Origins and Roles in the Human Gut Microbiome

Abstract

The investigation of the microbial populations of the human body, known as the microbiome, has led to a revolutionary field of science, and understanding of its impacts on human development and health. The majority of microbiome research to date has focussed on bacteria and other kingdoms of life, such as fungi. Trailing behind these is the interrogation of the gut viruses, specifically the phageome. Bacteriophages, viruses that infect bacterial hosts, are known to dictate the dynamics and diversity of bacterial populations in a number of ecosystems. However, the phageome of the human gut, while of apparent importance, remains an area of many unknowns. In this paper we discuss the role of bacteriophages within the human gut microbiome. We examine the methods used to study bacteriophage populations, how this evolved over time and what we now understand about the phageome. We review the phageome development in infancy, and factors that may influence phage populations in adult life. The role and action of the phageome is then discussed at both a biological-level, and in the broader context of human health and disease.

Keywords: bacteriophages; biofilm; diet; disease; gut microbiome; isolation; metagenomics; phage.

Figure 1

Timeline of methodological discoveries. A summarised timeline including the invention of key tools for the study of phages, from their discovery in 1921 to recent modern metagenomic sequencing technologies. Adapted from Mokili et al. (2012).

Figure 2

Schematic of the human gut, indicating unknown inputs to the gut phageome from diet and the environment, highlighting the largely unknown phage composition of the ileum and colon and indicating the relative proportions of phages in the best understood samples: faeces. Circle size provides a rough guide to the relative abundance of phage particles observed in different gut compartments (Zoetendal et al., 2012; Hoyles et al., 2014; Shkoporov and Hill, 2019), but current understanding is still lacking. Most research activity has focused on faecal samples, represented in the lowest pie chart, depicting the relative proportions of different phage groups identified through metagenome analysis, based on Shkoporov and Hill (2019).

Figure 3

Changes in the gut phageome over the human lifetime. Pie charts represent the observed ratios of different phage groups at discrete sampling times, from birth where no endemic phages were observed to adults, while the humped line describes changes in phage diversity and abundance over time, which both peak in the weeks after birth (Breitbart et al., 2008; Reyes et al., 2010; Kim et al., 2011; Lim et al., 2015; McCann et al., 2018).

Figure 4

Diagram of the gut and bacterial and phage concentrations in the lumen, mucosa and epithelial cells. In the human gut, multiple different host-prey dynamics are theorised to occur dependent on the proximity to the gut mucosa. At the top of the mucosa, viruses take a lysogenic strategy or “piggyback-the-winner” as hosts are abundant here. Deeper within the mucosa, the viruses switch to a lytic or “kill-the-winner” strategy as at this point the bacteria are less abundant (Silveira and Rohwer, 2016). (Right) Some phages encode Ig-like domains that allow them to bind to the mucosa and evade the immune system, (Left) Phages can undergo transcytosis and be engulfed and transported through epithelial cells.