What is (not) known about the dynamics of the human gut virome in health and disease
Graphical abstract
Introduction
In recent years, the relevance of the human gut microbiota in health as in disease has become increasingly apparent, resulting in an increased interest in this ecosystem. It includes a prokaryotic, eukaryotic and viral component, and the former has by far received the most attention. Population-wide studies have resulted in a better understanding of this prokaryotic component, its beneficial functions in healthy individuals, and the factors that influence their composition, such as diet, age, disease states, medication and geography [1, 2, 3]. Research focusing on the viral component in the gut microbiome, or simply the gut virome, is lagging behind and its relevance in health and disease has yet to be shown.
Current methods to investigate the gut virome composition, mostly start with a purification of viral particles and an elimination of all cells and free-floating nucleic acids [4]. This step often involves filtration, centrifugation and enzymatic reactions and neglects intracellular and very large viruses. Next, nucleic acids are extracted and amplified, but the lack of conserved regions in viral genomes (like the 16S rRNA gene in prokaryotes) for targeted amplification, as well as the difficulty to simultaneously amplify multiple types of viral genomes (circular or linear, RNA or DNA, single stranded or double stranded) make this step challenging. In addition, incomplete viral databases and bioinformatics challenges are just a few more factors explaining the limited research of the human gut virome [5].
The first paper ever mentioning the ‘virome’ was published in 2003 [6], recognizing the presence of a viral component in the human microbiome, and in the same year the first bacteriophages were sequenced from human feces and their huge novelty and diversity was recognized [7]. The observation that gut viruses can be found in all individuals led to the realization that, in contrast to pathogenic effects, there might actually be an important role of the gut virome in normal homeostasis. The gut virome refers to both eukaryotic viruses and bacteriophages. The former can infect the human host, the eukaryotic component of the gut microbiota, including fungi and parasites, or just pass through the gastrointestinal tract as part of our diet (e.g. plant viruses) [8]. The pathogenic effect of eukaryotic gut viruses, resulting in transient or latent infection and disease, is well established; however, evidence for a beneficial role of eukaryotic gut viruses in health is scarce. One study showed that a persistent norovirus infection can restore intestinal morphology and functions in a germ-free or antibiotic-treated mice suggesting that this eukaryotic virus can act as a commensal bacterium with beneficial functions in the gut [9]. Also, the frequent observation of members from the Anelloviridae and Circoviridae in human stool, without any clear pathology, indicates they may be commensals [10,11]. In contrast to the infant gut virome, in healthy human adults, low abundances of eukaryotic viruses are reported.
Bacteriophages are the most abundant entities on earth and, unsurprisingly, this observation also extends to the gut, where bacteriophages constitute the most abundant inhabitants. Most bacteriophage genomes sequenced from human gut or feces samples belong to the dsDNA families Siphoviridae, Podoviridae, and Myoviridae (order Caudovirales) and ssDNA family Microviridae [12, 13, 14]. Only few studies report archaeal viruses of the family Lipothrixviridae, probably because of the low abundances of their hosts [15]. Gut bacteriophages can influence the prokaryotic communities in terms of composition and function, by direct lysis of their hosts (lytic phages) or by genome integration, which can change the fitness and phenotype of the host. Such gene transfers can result in antibiotic resistance, production of toxins or increased energy harvest [16]. Moreover, some phages can change the surface structures of prokaryotes, such as lipopolysaccharides, and influence the interactions of the prokaryote with the human host [17]. Therefore, phages in the gut are more than only predators, in some cases helping their host by providing genes conferring a competitive advantage in the ecosystem they both reside in.
Unfortunately, the dynamics in the human gut virome remain poorly understood. The scope of this work is to highlight recent advances regarding these human gut virome dynamics by specifically focusing on longitudinal studies. These studies aid in understanding the composition of the gut virome and its changes over time in healthy conditions, disease states and following antibiotics treatment. Furthermore, studies focusing on both the gut prokaryotic and virome composition reveal the interaction between those two populations.
Section snippets
Interpersonal variation in the human gut virome and the responsible factors
Almost a decade ago, Reyes et al. were the first to recognize the high interpersonal variation of the gut virome in adults: every individual had a unique virome composition. Monozygotic (MZ) adult twins and their mothers shared similar bacterial communities, whereas their viral gut communities were not shared [14]. In contrast, Lim et al. found that infant twins harboured a more similar virome compared to unrelated children [15], which might be explained by their shared environment and diet. A
Dynamic development of the infant gut virome towards a more stable adult-like gut virome
Directly after birth, the human gut is exposed to and colonized by an enormous number of viruses, prokaryotes and eukaryotes. In the following weeks and months, a stable community of these organisms is formed. Multiple environmental factors influence the development of the infant gut microbiota and are suggested to be confounding factors in virome studies. Whether or not the gut of newborns is completely sterile, is still a matter of debate. Viral-like particles (VLPs) could not be detected via
No kill-the-winner dynamics in the healthy human gut
Microscopic investigation of fecal samples measured an abundance of the order 108 to 109 VLPs per gram of stool compared to a bacterial abundance of around 109 cells per gram, resulting in a phage-to-bacteria ratio of approximately 1:1 or even as low as 0.1:1 [34,35]. This number is much lower than the 10:1 ratio estimated in, for example, marine samples, even taken into account the recent discovery that this ratio can vary from 2.6:1 to 160:1 [36,37]. The cyclic change in abundance, where an
Changes in the virome after antibiotic treatment
The gut phageome in healthy adults consists mostly of temperate phages. However, under stressful conditions such as antibiotic treatment, prophages are induced with potential effects on the bacterial gut community and the activation of kill-the-winner dynamics, as is seen in the gut viromes of swine [42]. In 2015, Abeles et al. investigated the influence of antibiotic therapy on different virome samples, longitudinally selected from four adults. Their main results showed that broad-spectrum
Conclusion
In contrast to the increasing knowledge towards the bacterial microbiome and its role in health and disease, research focusing on the virome is only an emerging field of interest. For both, bacteriophages and eukaryotic viruses, potential beneficial roles have been suggested. Unfortunately, the dynamics in the human gut virome remain poorly understood. Longitudinal studies investigating the gut virome in healthy individuals showed a high interindividual diversity, meaning that everyone’s viral
Funding
This work was supported by the ‘Fonds Wetenschappelijk Onderzoek’ (Research foundation Flanders) to Leen Beller [1S61618N].
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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