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Illuminating the human virome in health and disease

  • Massachusetts General Hospital, Harvard Medical School, Boston USA


Abstract Although the microbiome is established as an important regulator of health and disease, the role of viruses that inhabit asymptomatic humans (collectively, the virome) is less defined. While we are still characterizing what constitutes a healthy or diseased virome, an exciting next step is to move beyond correlations and toward identification of specific viruses and their precise mechanisms of beneficial or harmful immunomodulation. Illuminating this will represent a first step toward developing virome-focused therapies.
C O M M E N T Open Access
Illuminating the human virome in health
and disease
Fatemeh Adiliaghdam
and Kate L. Jeffrey
Although the microbiome is established as an important regulator of health and disease, the role of viruses that
inhabit asymptomatic humans (collectively, the virome) is less defined. While we are still characterizing what
constitutes a healthy or diseased virome, an exciting next step is to move beyond correlations and toward
identification of specific viruses and their precise mechanisms of beneficial or harmful immunomodulation.
Illuminating this will represent a first step toward developing virome-focused therapies.
Late to the party
In the study of microorganisms, bacteria frequently steal
the limelight. During an influenza outbreak in late 1800,
it was the bacterium Haemophilus influenzae isolated
from sputum that was first presumed to cause disease.
During the 1918 influenza pandemic, urgent efforts to
isolate this causative bacterium failed and it was not
until the 1930s that a filterable agent, a virus, Influenza
H1N1, was identified as the culprit [1]. Similarly, in the
pursuit of understanding human commensal microor-
ganisms, the last 20 years of research has focused almost
exclusively on bacteria and their regulation of our im-
mune and nervous systems. In comparison, very little is
known about eukaryotic and prokaryotic viruses that
also inhabit asymptomatic humans. Given that the name
virus was coined from the Latin word meaning slimy li-
quid or poison and that viruses are considered obligate
pathogens, a possibly beneficial viromeis surprising to
The late start for viruses in the commensal micro-
organism field is in large part due to our inability to
readily culture or detect them, as was the case during
the discovery of the influenza virus. We do not yet know
the eukaryotic cell or bacterial host of most viruses, and
there is no universal 16S ribosomal RNA equivalent, as
in bacteria, allowing for rapid taxonomic
characterization. Technologies such as metagenomics
have only recently enabled identification of viruses in
healthy human tissues. This initially involved sequencing
all DNA or RNA in a sample (human, bacterial, and
viral), and computationally aligning the massive number
of sequences to identify those that resemble known viral
genes. An improvement on this approach now involves
filtering samples to purge eukaryotic cells and bacteria
so that only virus-like particles (VLPs) remain for se-
quencing. However, since the virome consists of both
temperate bacteriophages within bacterial genomes and
free VLPs, both total and VLP sequencing will likely pro-
vide greater representation of all viruses. Nonetheless,
with the approaches taken thus far, studies have revealed
viruses are abundant in human feces, blood, skin, lung,
oral cavity, and an array of other tissues of healthy and
diseased individuals [25].
A moving target
The human intestinal virome established at birth is
dominated by bacteria-infecting viruses, while eukaryotic
viruses gradually emerge after birth [6]. One gram of hu-
man feces contains around 10
VLPs, and explora-
tory sequencing has shown that the identifiable fraction
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* Correspondence:
Department of Medicine, Division of Gastroenterology and the Center for
the Study of Inflammatory Bowel Disease, Massachusetts General Hospital,
Harvard Medical School, Boston, MA 02114, USA
Center for Microbiome Informatics and Therapeutics, Massachusetts Institute
of Technology, Cambridge, MA 02139, USA
Adiliaghdam and Jeffrey Genome Medicine (2020) 12:66
of this virome is primarily bacteriophages, including
dsDNA Caudovirales, ssDNA Microviridae [2], and the
recently identified predominant CrAssphage [7]. Viruses
that infect eukaryotic cells within the human fecal vir-
ome have been identified to belong to families Astroviri-
dae,Anelloviridae,Picornaviridae,Caliciviridae, and
Herpesviridae, among others [2,3].
However, many hurdles in our ability to catalog the
human virome remain, making this data far from final.
(1) The vast majority of viruses share little to no hom-
ology with annotated viruses in reference databases. Vi-
ruses infecting animals, plants, fungi, and protozoans
(collectively eukaryotic viruses) number around 100 mil-
lion species while those infecting bacteria are estimated
at 10 trillion, yet a large proportion remain unannotated.
While the NCBI Virus Portal (https://www.ncbi.nlm.nih.
gov/labs/virus/vssi/#/) is reporting new annotations at
an exponential rate, virologists have struggled to distin-
guish clear classes and kingdoms for most of the viro-
sphere, with the exception of a recently published
taxonomic hierarchy [8]. Thus, reanalysis of relatively re-
cent human virome publications may already be war-
ranted. (2) Computational analysis methods vary
considerably across virome studies, as this is a nascent
field, making direct comparisons difficult. (3) Viruses
rely on the host organism for successful replication;
therefore, the discovery of viruses that specifically infect
human cells may be better achieved by analysis of less
accessible tissue and cells, rather than feces or bodily
fluids, where they are likely scarce. (4) False positives in
sequencing data remain an issue as many sequencing re-
agents, or DNA spike-ins during sequencing, are derived
from bacteriophages or bacteria carrying bacteriophages.
A consensus on laboratory techniques and computa-
tional analysis pipelines is a much-needed advance in
the virome field. (5) We still have a very limited perspec-
tive on the healthy human tissue-specific virome. We
know little about the virome in individuals from differ-
ent geographic locations, in those consuming different
diets, and in old or young individuals, and thus, it is dif-
ficult to discern cases of vertical and horizontal trans-
mission or composition changes before, during, and
after disease onset. A tighter grasp on what a healthy vir-
ome looks likean equivalent to the Human Micro-
biome Projectwould allow clearer inferences about
how the virome influences disease.
Making the leap from correlation to causation
Despite the present limitations in characterizing the hu-
man virome in health, robust fluctuations in the virome
in multiple diseases have been reported. In inflammatory
bowel disease (IBD), it was found that enteric Caudovir-
ales temperate phage expanded, although the degree that
this was due to alterations in bacteria remains
unresolved [2,3]. In colorectal cancer, virome signatures
were shown to differentiate individuals at the early ver-
sus late stages of disease. In type I diabetes, expanded
enteric bacteriophage diversity was found to precede dis-
ease and Circoviridae eukaryotic viruses were enriched
in controls. In cystic fibrosis, sputum phage communi-
ties were highly similar and eukaryotic viral communities
were found to be dominated by herpesviruses and retro-
viruses. In graft-versus-host disease (GVHD), a progres-
sive expansion of eukaryotic gut viruses was shown to
follow hematopoietic stem cell transplant, and picobir-
naviruses were associated with early post-transplant
GVHD. In HIV patients, low peripheral CD4 T cell
counts were associated with an expansion of enteric ade-
noviruses [5]. However, this cataloging of diseased vir-
omes is vastly outpacing our mechanistic understanding
as we still do not know whether these altered viromes
actually contribute to disease.
A lesson from the microbiome field, at this juncture
in virome research, would be to move beyond correla-
tions and toward a detailed analysis of how certain vi-
ruses autonomously or cooperatively educate our
physiology. Functional studies in mice have found
that enteric viruses inhabiting a healthy host provide
immune and gut homeostasis. Depletion of viruses or
virus receptors in healthy mice exacerbates intestinal
inflammation while treatment with viral ligands pro-
tects from disease [5]. However, precise mechanisms
by which individual viruses provide protection are
limited. Furthermore, how human virome composition
impacts health or disease remains ambiguous as direct
functional studies are currently lacking. However,
both prokaryotic and eukaryotic viromes possess the
ability to directly immunomodulate their human hosts
based on reports of trans-kingdom interactions of
bacteriophage and human immune cells [9]. Further-
more, given that viruses exist in complex communi-
ties comprising bacteria, fungi, and protozoans,
indirect outcomes of virome changes will almost def-
initely occur through alteration of surrounding micro-
organism communities. Another question and
appealing avenue of investigation is whether com-
mensal viruses impact the hostsabilitytofight
pathogenic viruses through tonic stimulation of anti-
viral immunity or if conversely, acute virus infection
impacts the resident virome. Finally, since complex
disease phenotypes are the result of environmental
triggers in the context of genetic susceptibility, vari-
able impact of the virome will depend on host genet-
ics and should be considered. For instance, a loss-of-
function variant of host virus receptor MDA-5
(encoded by gene IFIH1) associates with incidence of
IBD but protects from type I diabetes [5]suggesting
divergent roles for viruses in different contexts.
Adiliaghdam and Jeffrey Genome Medicine (2020) 12:66 Page 2 of 3
Translating to diagnosis and therapy
The ultimate goal of virome research is to translate find-
ings into diagnostic and therapeutic opportunities. With
accurate mapping of the virome in different human tis-
sues in healthy and disease states, we can begin to use
certain viruses as biomarkers or attempt to manipulate
virome signatures. Moving from association to causation
will confidently enable us to harness the healthy virome
or disrupt the disease-associated one. Uncoupling the
roles of eukaryotic and prokaryotic viruses on immune
state and improvements on propagation of individual
candidate viruses for functional studies will advance
these goals. Therapeutic avenues could also focus on the
beneficial or detrimental host immune responses to vi-
ruses, rather than the viruses themselves to mitigate
virome-related diseases. Viruses may also serve an im-
portant role in fecal microbiota transplants (FMTs) since
filtered feces (removing the bacterial component) have
the same efficacy in treating the Clostridium difficile pa-
tients [10]. However, there is still no knowledge of the
virome composition of FMTs and no consensus on if
this is something we should be measuring in donor and
recipient patients. Finally, benign viruses within the
healthy virome could conceivably be used for safe gene
delivery into humans.
We have just begun to reveal the complexities and
promise of the virome using computational genomics,
but application of the virome remains relatively underex-
plored. Many challenges in the virome field remain, but
let us not repeat history and let bacteria steal the lime-
light. Viruses, fungi, and other commensals within the
human microorganism ecosystem are likely equally im-
portant; we just need to overcome a few more hurdles to
realize their full potential.
DNA: Deoxyribonucleic acid; RNA: Ribonucleic acid; dsDNA: Double-stranded
DNA; ssDNA: Single-stranded DNA; NCBI: National Center for Biotechnology
Information; HIV: Human immunodeficiency virus; MDA-5: Melanoma
differentiation-associated protein 5
The authors would like to thank Hajera Amatullah and Roshan Ahmed for
editorial comments.
KLJ conceived and FA and KLJ wrote the manuscript. All authors read and
approved the final manuscript.
Kenneth Rainin Foundation (Innovator and Synergy Awards to KLJ), NIH
R21AI144877 (KLJ), NIH R01DK119996 (KLJ), Harvard Catalyst | The Harvard
Clinical and Translational Science Center (National Center for Advancing
Translational Sciences, National Institutes of Health Award UL 1TR002541)
and financial contributions from Harvard University and its affiliated
academic healthcare centers (KLJ), MGH Research Scholar, class of 2020 (KLJ).
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Received: 15 July 2020 Accepted: 16 July 2020
1. Barry JM. The great influenza: the epic story of the deadliest plague in
history. New York: Penguin Books; 2005. 546 p.
2. Norman JM, et al. Disease-specific alterations in the enteric virome in
inflammatory bowel disease. Cell. 2015;160(3):44760.
3. Clooney AG, et al. Whole-virome analysis sheds light on viral dark matter in
inflammatory bowel disease. Cell Host Microbe. 2019;26(6):76478.e5.
4. Schmidt C. The virome hunters. Nat Biotechnol. 2018;36(10):9169.
5. Neil JA, Cadwell K. The intestinal virome and immunity. J Immunol. 2018;
6. Liang G, et al. The stepwise assembly of the neonatal virome is modulated
by breastfeeding. Nature. 2020;581(7809):4704.
7. Dutilh BE, et al. A highly abundant bacteriophage discovered in the
unknown sequences of human faecal metagenomes. Nat Commun. 2014;5:
8. International Committee on Taxonomy of Viruses Executive, C. The new
scope of virus taxonomy: partitioning the virosphere into 15 hierarchical
ranks. Nat Microbiol. 2020;5(5):66874.
9. Sweere JM, et al. Bacteriophage trigger antiviral immunity and prevent
clearance of bacterial infection. Science. 2019;363(6434):eaat9691.
10. Ott SJ, et al. Efficacy of sterile fecal filtrate transfer for treating patients with
Clostridium difficile infection. Gastroenterology. 2017;152(4):799811 e7.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Adiliaghdam and Jeffrey Genome Medicine (2020) 12:66 Page 3 of 3
... The human intestinal virome is established at birth and is dominated by bacteriophages, whereas eukaryotic viruses gradually emerge after birth, as measured in feces that contains ~10 9 virus-like particles (VLPs) per gram (2,6). Despite hurdles in identifying the constituents of a normal human virome (7), robust fluctuations of the virome have been reported in inflammatory bowel disease (IBD) (1,(8)(9)(10), colorectal cancer (11,12), type 1 diabetes (13), nonalcoholic fatty liver disease (14), cystic fibrosis (15), graft-versus-host disease (16), HIV infection (17), and a range of other diseases (18). However, the rapid cataloging of viral genomes in human tissues by sequencing and computational methods has vastly outpaced any mechanistic understanding we have of virome biology and whether these fluctuations contribute to disease. ...
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... This technique significantly lowers the sequencing cost and reduces the computational time. Nevertheless, since the virome consists of both temperate bacteriophages within bacterial genomes and free VLPs, both total and VLP sequencing should provide greater representation of all viruses [43]. ...
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It is estimated that human body is inhabited by approximately 380 trillions of viruses, which exist in the form of viral communities and are collectively termed as human virome. How virome is assembled and what kind of forces maintain the composition and diversity of viral communities is still an open question. The question is of obvious importance because of its implications to human health and diseases. Here we address the question by harnessing the power of Hubbell’s unified neutral theory of biodiversity (UNTB) in terms of three neutral models including standard Hubbell’s neutral model (HNM), Sloan’s near-neutral model (SNM) and Harris et al [17] multi-site neutral model (MSN), further augmented by Ning et al [39] normalized stochasticity ratio (NSR) and Hammal et al [16] power analysis for the neutral test (PNT). With the five models applied to 179 virome samples, we aim to obtain robust findings given both Type-I and Type-II errors are addressed and possible alternative, non-neutral processes are detected. It was found that stochastic neutral drifts seem prevalent: approximately 65%-92% at metacommunity/landscape scales and 67%-80% at virus species scale. The non-neutral selection is approximately 26%-28% at community scale and 23% at species scale. The false negative rate is about 2%-3%, which suggested rather limited confounding effects of non-neutral process on neutrality tests. We postulate that prevalence of neutrality in human virome is likely due to extremely simple structure of viruses (stands of DNA/RNA) and their inter-species homogeneities, forming the foundation of species equivalence—the hallmark of neutral theory.
... Several studies have presented evidence of temperate Caudovirales viruses increasing in Crohn's disease (CD) and ulcerative colitis (UC) patients 6,8,10,11 . However, it has been left unanswered if this phage expansion was due to alterations in host-bacterial abundance, thus viral-host dynamics remains another unexplored facet of the gut virome in diseases such as IBD 12 . ...
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Despite the accelerating number of uncultivated virus sequences discovered in metagenomics and their apparent importance for health and disease, the human gut virome and its interactions with bacteria in the gastrointestinal tract are not well understood. This is partly due to a paucity of whole-virome datasets and limitations in current approaches for identifying viral sequences in metagenomics data. Here, combining a deep-learning based metagenomics binning algorithm with paired metagenome and metavirome datasets, we develop Phages from Metagenomics Binning (PHAMB), an approach that allows the binning of thousands of viral genomes directly from bulk metagenomics data, while simultaneously enabling clustering of viral genomes into accurate taxonomic viral populations. When applied on the Human Microbiome Project 2 (HMP2) dataset, PHAMB recovered 6,077 high-quality genomes from 1,024 viral populations, and identified viral-microbial host interactions. PHAMB can be advantageously applied to existing and future metagenomes to illuminate viral ecological dynamics with other microbiome constituents. Here, Johansen et al. develop an approach, Phages from Metagenomics Binning (PHAMB), that allows the binning of thousands of viral genomes directly from bulk metagenomics data, while simultaneously enabling clustering of viral genomes into accurate taxonomic viral populations, unveiling viral-microbial host interactions in the gut.
... GPCR involvement in ion channel action might also prove an avenue of research for potential therapeutics. Viruses or the virome play an important, as yet not fully understood, role in the body 126 . It is thus conceivable that long COVID is a manifestation of some aspect of the SARS-CoV-2 virus being incorporated into host cells even beyond the infected stage. ...
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The SARS-CoV-2 pandemic has added new urgency to the study of viral mechanisms of infection. But while vaccines offer a measure of protection against this specific outbreak, a new era of pandemics has been predicted. In addition to this, COVID-19 has drawn attention to post-viral syndromes and the healthcare burden they entail. It seems integral that knowledge of viral mechanisms is increased through as wide a research field as possible. To this end we propose that quantum biology might offer essential new insights into the problem, especially with regards to the important first step of virus-host invasion. Research in quantum biology often centres around energy or charge transfer. While this is predominantly in the context of photosynthesis there has also been some suggestion that cellular receptors such as olfactory or neural receptors might employ vibration assisted electron tunnelling to augment the lock-and-key mechanism. Quantum tunnelling has also been observed in enzyme function. Enzymes are implicated in the invasion of host cells by the SARS-CoV-2 virus. Receptors such as olfactory receptors also appear to be disrupted by COVID-19. Building on these observations we investigate the evidence that quantum tunnelling might be important in the context of infection with SARS-CoV-2. We illustrate this with a simple model relating the vibronic mode of, for example, a viral spike protein to the likelihood of charge transfer in an idealised receptor. Our results show a distinct parameter regime in which the vibronic mode of the spike protein enhances electron transfer. With this in mind, novel therapeutics to prevent SARS-CoV-2 transmission could potentially be identified by their vibrational spectra.
... Some of these viruses are known to be pathogenic and cause disease in humans, while others are omnipresent and infect a large part of the human population without any evidence of disease association. The characterization of what constitutes a healthy or diseased virome is still in its infancy [158]. The complete eukaryotic virome colonizing the intestinal mucosa of UC patients still needs to be defined. ...
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Ulcerative colitis is characterized by relapsing and remitting colonic mucosal inflammation. During the early stages of viral infection, innate immune defenses are activated, leading to the rapid release of cytokines and the subsequent initiation of downstream responses including inflammation. Previously, intestinal viruses were thought to be either detrimental or neutral to the host. However, persisting viruses may have a role as resident commensals and confer protective immunity during inflammation. On the other hand, the dysregulation of gut mucosal immune responses to viruses can trigger excessive, pathogenic inflammation. The purpose of this review is to discuss virus-induced innate immune responses that are at play in ulcerative colitis.
... Several studies have presented evidence of temperate Caudovirales viruses increasing in Crohn's disease (CD) and ulcerative colitis (UC) patients 6,8,10-12 . However, it has been left unanswered if this phage expansion was due to alterations in host-bacterial abundance, thus viral-host dynamics remains another unexplored facet of the gut virome in diseases such as IBD 13 . ...
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Despite the accelerating number of uncultivated virus sequences discovered in metagenomics and their apparent importance for health and disease, the human gut virome and its interactions with bacteria in the gastrointestinal are not well understood. In addition, a paucity of whole-virome datasets from subjects with gastrointestinal diseases is preventing a deeper understanding of the virome role in disease and in gastrointestinal ecology as a whole. By combining a deep-learning based metagenomics binning algorithm with paired metagenome and metavirome datasets we developed the Phages from Metagenomics Binning (PHAMB) approach for binning thousands of viral genomes directly from bulk metagenomics data. Simultaneously our methodology enables clustering of viral genomes into accurate taxonomic viral populations. We applied this methodology on the Human Microbiome Project 2 (HMP2) cohort and recovered 6,077 HQ genomes from 1,024 viral populations and explored viral-host interactions. We show that binning can be advantageously applied to existing and future metagenomes to illuminate viral ecological dynamics with other microbiome constituents.
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Viruses are ubiquitous, essential components of any ecosystem, and of multicellular organism holobionts. Numerous viruses cause acute infection, killing the host or being cleared by immune system. In many other cases, viruses coexist with the host as symbionts, either temporarily or for the duration of the host's life. Apparently, virus–host relationships span the entire range from aggressive parasitism to mutualism. Here we attempt to delineate the healthy human virome, that is, the entirety of viruses that are present in a healthy human body. The bulk of the healthy virome consists of bacteriophages infecting bacteria in the intestine and other locations. However, a variety of viruses, such as anelloviruses and herpesviruses, and the numerous endogenous retroviruses, persist by replicating in human cells, and these are our primary focus. Crucially, the boundary between symbiotic and pathogenic viruses is fluid such that members of the healthy virome can become pathogens under changing conditions.
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Virus taxonomy emerged as a discipline in the middle of the twentieth century. Traditionally, classification by virus taxonomists has been focussed on the grouping of relatively closely related viruses. However, during the past few years, the International Committee on Taxonomy of Viruses (ICTV) has recognized that the taxonomy it develops can be usefully extended to include the basal evolutionary relationships among distantly related viruses. Consequently, the ICTV has changed its Code to allow a 15-rank classification hierarchy that closely aligns with the Linnaean taxonomic system and may accommodate the entire spectrum of genetic divergence in the virosphere. The current taxonomies of three human pathogens, Ebola virus, severe acute respiratory syndrome coronavirus and herpes simplex virus 1 are used to illustrate the impact of the expanded rank structure. This new rank hierarchy of virus taxonomy will stimulate further research on virus origins and evolution, and vice versa, and could promote crosstalk with the taxonomies of cellular organisms.
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The gut of healthy human neonates is usually devoid of viruses at birth, but quickly becomes colonized, which—in some cases—leads to gastrointestinal disorders1–4. Here we show that the assembly of the viral community in neonates takes place in distinct steps. Fluorescent staining of virus-like particles purified from infant meconium or early stool samples shows few or no particles, but by one month of life particle numbers increase to 10⁹ per gram, and these numbers seem to persist throughout life5–7. We investigated the origin of these viral populations using shotgun metagenomic sequencing of virus-enriched preparations and whole microbial communities, followed by targeted microbiological analyses. Results indicate that, early after birth, pioneer bacteria colonize the infant gut and by one month prophages induced from these bacteria provide the predominant population of virus-like particles. By four months of life, identifiable viruses that replicate in human cells become more prominent. Multiple human viruses were more abundant in stool samples from babies who were exclusively fed on formula milk compared with those fed partially or fully on breast milk, paralleling reports that breast milk can be protective against viral infections8–10. Bacteriophage populations also differed depending on whether or not the infant was breastfed. We show that the colonization of the infant gut is stepwise, first mainly by temperate bacteriophages induced from pioneer bacteria, and later by viruses that replicate in human cells; this second phase is modulated by breastfeeding.
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Bacteriophage are abundant at sites of bacterial infection, but their effects on mammalian hosts are unclear. We have identified pathogenic roles for filamentous Pf bacteriophage produced by Pseudomonas aeruginosa (Pa) in suppression of immunity against bacterial infection. Pf promote Pa wound infection in mice and are associated with chronic human Pa wound infections. Murine and human leukocytes endocytose Pf, and internalization of this single-stranded DNA virus results in phage RNA production. This triggers Toll-like receptor 3 (TLR3)– and TIR domain–containing adapter-inducing interferon-β (TRIF)–dependent type I interferon production, inhibition of tumor necrosis factor (TNF), and the suppression of phagocytosis. Conversely, immunization of mice against Pf prevents Pa wound infection. Thus, Pf triggers maladaptive innate viral pattern-recognition responses, which impair bacterial clearance. Vaccination against phage virions represents a potential strategy to prevent bacterial infection.
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Background & aims: Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridium difficile infection (CDI). However, transferring undefined living bacteria entails uncontrollable risks for infectious and metabolic or malignant diseases, particularly in immunocompromised patients. We investigated whether sterile fecal filtrates (containing bacterial debris, proteins, antimicrobial compounds, metabolic products and oligonucleotides/DNA), rather than intact microorganisms, are effective in patients with CDI. Methods: We performed a clinical case series to investigate the effects of fecal filtrate transfer (FFT) in 5 patients with symptomatic chronic-relapsing CDI at the Department of Internal Medicine I at the University Hospital Schleswig-Holstein (Kiel, Germany). Patients were followed for at least 6 months and up to 33 months. Stool was collected from 5 donors selected by the patients, and fully characterized according to FMT standards. Stool was sterile-filtered to remove small particles and bacteria; the filtrate was transferred to patients in a single administration via nasojejunal tube. Fecal samples were collected from patients before and 1 week and 6 weeks after FFT. Microbiome, virome, and proteome profiles of donors and patients were compared. Results: In all 5 patients, FFT restored normal stool habits and eliminated symptoms of CDI for a minimum period of 6 months. Proteome analyses of selected FFT filtrates revealed no obvious protein candidates associated with therapeutic efficacy. 16S rRNA gene sequencing detected diverse bacterial DNA signatures in the filtrates. Analysis of virus-like particles from a filtrate found to reduce symptoms of CDI revealed a complex signature of bacteriophages. Bacterial phylogeny and virome profile analyses of fecal samples from recipients indicated longitudinal changes in microbial and viral community structures after FFT. Conclusions: A preliminary investigation of 5 patients with CDI shows that transfer of sterile filtrates from donor stool (FFT), rather than fecal microbiota, can be sufficient to restore normal stool habits and eliminate symptoms. This finding indicates that bacterial components, metabolites or bacteriophages mediate many of the effects of FMT, and that FFT might be an alternative approach, particularly for immunocompromised patients.
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Metagenomics, or sequencing of the genetic material from a complete microbial community, is a promising tool to discover novel microbes and viruses. Viral metagenomes typically contain many unknown sequences. Here we describe the discovery of a previously unidentified bacteriophage present in the majority of published human faecal metagenomes, which we refer to as crAssphage. Its ~97 kbp genome is six times more abundant in publicly available metagenomes than all other known phages together; it comprises up to 90% and 22% of all reads in virus-like particle (VLP)-derived metagenomes and total community metagenomes, respectively; and it totals 1.68% of all human faecal metagenomic sequencing reads in the public databases. The majority of crAssphage-encoded proteins match no known sequences in the database, which is why it was not detected before. Using a new co-occurrence profiling approach, we predict a Bacteroides host for this phage, consistent with Bacteroides-related protein homologues and a unique carbohydrate-binding domain encoded in the phage genome.
The human gut virome is thought to significantly impact the microbiome and human health. However, most virome analyses have been performed on a limited fraction of known viruses. Using whole-virome analysis on a published keystone inflammatory bowel disease (IBD) cohort and an in-house ulcerative colitis dataset, we shed light on the composition of the human gut virome in IBD beyond this identifiable minority. We observe IBD-specific changes to the virome and increased numbers of temperate phage sequences in individuals with Crohn's disease. Unlike prior database-dependent methods, no changes in viral richness were observed. Among IBD subjects, the changes in virome composition reflected alterations in bacterial composition. Furthermore, incorporating both bacteriome and virome composition offered greater classification power between health and disease. This approach to analyzing whole virome across cohorts highlights significant IBD signals, which may be crucial for developing future biomarkers and therapeutics.
Ambitious efforts to catalog viruses across the globe may facilitate our understanding of viral communities and ecology, boost infectious disease diagnostics and surveillance, and spur new therapeutics. Charles Schmidt investigates.
The composition of the human microbiome is considered a major source of interindividual variation in immunity and, by extension, susceptibility to diseases. Intestinal bacteria have been the major focus of research. However, diverse communities of viruses that infect microbes and the animal host cohabitate the gastrointestinal tract and collectively constitute the gut virome. Although viruses are typically investigated as pathogens, recent studies highlight a relationship between the host and animal viruses in the gut that is more akin to host-microbiome interactions and includes both beneficial and detrimental outcomes for the host. These viruses are likely sources of immune variation, both locally and extraintestinally. In this review, we describe the components of the gut virome, in particular mammalian viruses, and their ability to modulate host responses during homeostasis and disease.
Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn's disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases. We show that the enteric virome is abnormal in CD and UC patients. In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages. The viromes of CD and UC patients were disease and cohort specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations. These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis. We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases.