Research published today in Nature Microbiology has identified 54,118 species of virus living in the human gut - 92 percent of which were previously unknown.
But as we
and our colleagues from the Joint Genome Institute and Stanford
University in California found, the great majority of these were
bacteriophages, or "phages" for short. These viruses "eat" bacteria and can't attack human cells.
of us think of viruses, we think of organisms that infect our cells
with diseases such as mumps, measles or, more recently, COVID-19.
However, there are a vast number of these microscopic parasites in our
bodies - mostly in our gut - that target the microbes that live there.
There has recently been much interest in the human gut microbiome: the collection of microorganisms that live in our gut.
helping us digest our food, these microbes have many other important
roles. They protect us against pathogenic bacteria, modulate our mental
well-being, prime our immune system when we are children, and have an
ongoing role in immune regulation into adulthood.
It's fair to say the human gut is now the most well-studied microbial ecosystem on the planet. Yet more than 70 percent of the microbial species that live there have yet to be grown in the laboratory.
We know this because we can access the genetic blueprints of the gut microbiome via an approach known as metagenomics.
This is a powerful technique whereby DNA is directly extracted from an
environment and randomly sequenced, giving us a snapshot of what is
present within and what it might be doing.
studies have revealed how far we still have to go to catalog and
isolate all the microbial species in the human gut - and even further to
go when it comes to viruses.
our new research, we and our colleagues computationally mined viral
sequences from 11,810 publicly available fecal metagenomes, taken from
people in 24 different countries. We wanted to get an idea of the extent
to which viruses have taken up residence in the human gut.
effort resulted in the Metagenomic Gut Virus catalog, the largest such
resource to date. This catalog comprises 189,680 viral genomes which
represent more than 50,000 distinct viral species.
(but perhaps predictably), more than 90 percent of these viral species
are new to science. They collectively encode more than 450,000 distinct
proteins - a huge reservoir of functional potential that may either be
beneficial or detrimental to their microbial, and in turn human, hosts.
drilled down into subspecies of different viruses and found some showed
striking geographical patterns across the 24 countries surveyed.
For example, a subspecies of the recently described and enigmatic crAssphage was
prevalent in Asia, but was rare or absent in samples from Europe and
North America. This may be due to localized expansion of this virus in
specific human populations.
the most common functions we discovered in our molecular field trip were
diversity-generating retroelements (DGRs). These are a class of genetic
elements that mutate specific target genes in order to generate
variation that can be beneficial to the host. In the case of DGRs in
viruses, this may help in the ongoing evolutionary arms race with their
we found one-third of the most common virally-encoded proteins have
unknown functions, including more than 11,000 genes distantly related to
"beta-lactamases", which enable resistance to antibiotics such as
Having identified the phages, our next task was to link them to their microbial hosts. CRISPRs,
best known for their many applications in gene editing, are bacterial
immune systems that "remember" past viral infections and prevent them
from happening again.
this by copying and storing fragments of the invading virus into their
own genomes, which can then be used to specifically target and destroy
the virus in future encounters.
this record of past attacks to link many of the viral sequences to their
hosts in the gut ecosystem. Unsurprisingly, highly abundant viral
species were linked to highly abundant bacterial species in the gut,
mostly belonging to the bacterial phyla Firmicutes and Bacteroidota.
can we do with all of this new information? One promising application of
an inventory of gut viruses and their hosts is phage therapy. Phage therapy is
an old concept predating antibiotics, in which viruses are used to
selectively target bacterial pathogens in order to treat infections.
There has been discussion of
potentially customizing people's gut microbiomes using dietary
interventions, probiotics, prebiotics or even "transpoosions" (fecal
microbiota transplants), to improve an individual's health.
therapy may be a useful addition to this objective, by adding species or
even subspecies-level precision to microbiome manipulation. For
example, the bacterial pathogen Clostridioides difficile (or Cdiff for short) is a leading cause of hospital-acquired diarrhea that could be specifically targeted by phages.
subtle manipulation of non-pathogenic bacterial populations in the gut
may be achievable through phage therapy. A complete compendium of gut
viruses is a useful first step for such applied goals.
worth noting, however, that projections from our data suggest we've only
investigated a fraction of the total gut viral diversity. So we've
still got a long way to go.