The Gut Virome: the ‘Missing Link’ Between 2019, Vol
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TAG0010.1177/1756284819836620Therapeutic Advances in GastroenterologyI Mukhopadhya, JP Segal 836620review-article20192019 Therapeutic Advances in Gastroenterology Review Ther Adv Gastroenterol The gut virome: the ‘missing link’ between 2019, Vol. 12: 1–17 DOI:https://doi.org/10.1177/1756284819836620 10.1177/ gut bacteria and host immunity? 1756284819836620https://doi.org/10.1177/1756284819836620 © The Author(s), 2019. Article reuse guidelines: Indrani Mukhopadhya, Jonathan P. Segal, Simon R. Carding, Ailsa L. Hart sagepub.com/journals- and Georgina L. Hold permissions Abstract: The human gut virome includes a diverse collection of viruses that infect our own cells as well as other commensal organisms, directly impacting on our well-being. Despite its predominance, the virome remains one of the least understood components of the gut microbiota, with appropriate analysis toolkits still in development. Based on its interconnectivity with all living cells, it is clear that the virome cannot be studied in isolation. Here we review the current understanding of the human gut virome, specifically in relation to other constituents of the microbiome, its evolution and life-long association with its host, and our current understanding in the context of inflammatory bowel disease and associated therapies. We propose that the gut virome and the gut bacterial microbiome share similar trajectories and interact in both health and disease and that future microbiota studies should in parallel characterize the gut virome to uncover its role in health and disease. Keywords: gut virome, gut microbiota, inflammatory bowel disease, host:microbiota interactions, microbial therapeutics, microbial dynamics Received: 5 January 2019; revised manuscript accepted: 14 February 2019. Correspondence to: Georgina L. Hold Microbiome Research Centre, St George & Key points • Further research into the interconnectivity Sutherland Clinical School, • The human intestinal microbiome repre- of the virome with other elements of the University of New South Wales, Sydney, NSW 2217, sents one of the most complex ecosystems microbiome is essential to fully define the Australia on Earth and has taken millions of years to role of the gut virome in human health. georgina.hold@unsw. coevolve. edu.au Indrani Mukhopadhya • DNA and RNA viruses that collectively Gastrointestinal Research make up the intestinal virome outnumber Introduction Group, Division of Applied Medicine, University of bacterial cells by as much as 10:1, and The human intestinal microbiota comprising bac- Aberdeen, Foresterhill, include eukaryotic viruses which infect teria, viruses, fungi, multicellular parasites and Aberdeen, UK Gut Health Group, The eukaryotic cells, endogenous retroviruses, archaea represents one of the most complex eco- Rowett Institute, University bacterial viruses (i.e. bacteriophages) and systems on Earth. It has coevolved over millions of Aberdeen, Foresterhill, archaeal viruses that infect archaea. of years to help shape and influence human devel- Aberdeen, UK Jonathan P. Segal 1 • Diet is an important and constant environ- opment, and in particular immune defences. Ailsa L. Hart mental and lifestyle factor that can influ- The DNA and RNA viruses that collectively make St. Mark’s Hospital, Watford Road, Harrow, UK ence the gut microbiome, including its viral up the intestinal virome are at least equivalent in Imperial College London, component. number to bacterial cells,2 although on gut South Kensington Campus, Department of Surgery • Transkingdom interactions between virome mucosal surfaces and within the mucus layers and Cancer, London, UK components and bacteria highlights that they may outnumber bacterial cells by 20:1.3 Simon R. Carding there are additional layers of complexity Each gram of human gut content is estimated to Gut Microbes and Health Research Programme, to consider in terms of host–microbial contain at least 108–109 virus-like particles The Quadram Institute, homeostasis. (VLPs), the vast majority of which are crAssphage Norwich Research Park, Norwich, Norfolk, UK • Current microbial therapeutics including (cross-assembly phage), which are DNA phages Norwich Medical School, faecal microbial transplantation need to belonging to the family Podoviridae (Box 1).4,5 University of East Anglia, Norwich Research Park, consider the contribution of the virome. Viruses have cross-kingdom interactions with Norwich, Norfolk, UK journals.sagepub.com/home/tag 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Gastroenterology 12 Box 1. Getting access to the virome. To study the virome, VLPs are separated from cellular components, usually using a combination of filtration, density centrifugation and enzymatic treatments to eliminate free nucleic acids.9 The nucleic acids are then sequenced and analysed. Compared to the bacterial component of the intestinal microbiome, the intestinal virome has been under-investigated and largely ignored, in large part due to the limited tools available for their identification and classification. Recent advances in high-throughput, next-generation sequencing has allowed detailed and in-depth analysis of microbial communities (metagenomics), leading to the identification of new microbial species, which has only recently been applied to the characterization of the virome.10 There are, however, too few reference viromes, and those that do exist are dominated by unknown sequences with 60–90% of the reads often lacking functional or taxonomic annotations (the ‘viral dark matter’).2,11 Currently, it is estimated that roughly 1% of the virome has been sequenced, leaving the bulk yet to be characterized.8 other organisms within the microbiota that are therefore important in influencing the course together with host genetic variation can change and outcome of virus infections.15 the host (human) phenotype. These virus-driven phenotypic changes can be beneficial to the host or increase the risk of disease.6,7 Currently, it is Bacteriophages estimated that less than 1% of the virome has Microbial viruses modulate their bacterial hosts been sequenced, leaving the bulk of the virome directly through affecting their mortality and yet to be characterized.8 through horizontal gene transfer, and indirectly by reprogramming host metabolism. The human GI tract contains an estimated 1015 bacterio- Human gut virome: main players phages (phages; the phageome) which may repre- sent the richest concentration of biological entities Eukaryotic viruses on Earth.16 Phages can be functionally catego- Sequencing of eukaryotic viral communities in rized based on the lifecycle they adopt after infect- faecal samples from children has identified ing host cells.17 Lytic (virulent) phages lyse the Picobirnaviridae, Adenoviridae, Anelloviridae and cells they infect by hijacking the host cell’s repli- Astroviridae family members, and species such as cation mechanism to package and produce more bocaviruses, enteroviruses, rotaviruses and sapovi- phages and lytic enzymes that cause cell lysis and ruses.12 In addition, disease-associated viruses the release of newly formed phages from the cell. such as herpesviruses, polyomaviruses, anellovi- By contrast, temperate phages incorporate their ruses, adenoviruses, papillomaviruses, polyomavi- genetic material into the host cell chromosome as ruses, hepatitis B virus, hepatitis C virus and prophages and replicate alongside the host cell. In human immunodeficiency virus (HIV) are also some instances, temperate phages do not inte- present in the intestinal viromes of some individu- grate and exist as circular or linear plasmids als, indicating that the gastrointestinal (GI) tract within the host bacterial cell.18 A third category contains viruses capable of infecting host cells. As are pseudolysogenic phages, which upon infect- the majority of humans remain asymptomatic it ing a cell neither integrate stably into the host has been proposed that these pathogenic viruses genome nor co-opt cell replication machinery, or (pathobionts) have become part of the metagen- kill the host cell.17 Recently, analysis of the viral ome of normal individuals, with the majority fraction of existing metagenomic studies identi- rarely causing disease and remaining dormant fied a DNA phage called crAssphage which, due within the host.6,13 Experiments in germ-free and to limitations in our ability to identify phage antibiotic-treated mice have shown that the bacte- sequences, had been overlooked in previous stud- rial microbiome can promote the replication and ies.5 CrAssphages are highly abundant in the gut in some cases persistence of enteric viruses13 with microbiome, it has been predicted, based on host the efficient transmission of mouse mammary co-occurrence profiling that crAssphage infect tumour virus requiring intestinal bacteria.14 Bacteroides species. However, our understanding Interactions between viruses and bacteria, and of crAssphage is limited as they have only recently other constituents of the intestinal microbiome, been isolated in culture.5 2 journals.sagepub.com/home/tag I Mukhopadhya, JP Segal et al. Acquisition of gut