Your body has ten times more bacterial cells than human cells containing 150 times as much genetic material. I’ve written several posts about how our gut bacteria, the microbiome, can influence the development of allergies, obesity and type-2 diabetes. We’ve only recently started studying the microbiome and there’s still a lot to learn; it’s quite an active area of research. For example, just last year scientists discovered that individuals could be divided into three groups based on the composition of their microbiome, but new research has cast doubt on that idea. And yet, like a matryoshka doll, our biology has still another surprise in store for us: wherever bacteria are found, there are viruses which infect them. As we learn more about the microbiome and its implications, some scientists have turned their attention to the the viral microbiome, the viruses that prey on our gut bacteria and shape their community.
Bacteria are infected by a class of viruses called bacteriophage (usually shortened to phage). Phage attach to the surface of bacteria and, like a hypodermic syringe, inject their genetic material into the cell. What happens next depends on the life cycle of the phage. Lytic phage replicate immediately; their genetic material is translated into proteins which are assembled into phage particles that burst out of the host cell, killing it. Lysogenic phage take a longer view; their genetic material gets integrated into the host’s genome where it replicates alongside the host’s genes. The integrated phage material, called a prophage, gets a free ride, being copied by the host cell and passed along to daughter cells. Under the right conditions, the prophage become activated and get translated into proteins which form phage that burst out of the host cell to infect new cells. Phage are amongst the most common and diverse organisms on the planet. They’re found everywhere bacteria live, often outnumbering them ten to one; the rich bacterial community of the human gut is no exception, as we’re beginning to discover.
Naturally, bacteria defend themselves from phage in a variety of ways; one mechanism involves incorporating short fragments of the phage genome into the CRISPR defense system which then interferes with phage replication. Using these CRISPR fragments as bait, Adi Stern and her colleagues at the Weizmann Institute of Science in Israel went looking for evidence of phage in MetaHIT, a database of sequence data from the microbiomes of 124 European individuals. Because the MetaHIT project sequenced entire microbiomes, the resulting data includes sequences from our gut bacteria and their phage. The team was able to fish out nearly 1,000 potential phage genomes from this data set, though they caution that they probably missed many rare phage since the technique they used is best at finding common phage of relatively abundant bacteria. Although 29% of these phage were found in one out of every ten people and nearly 80% of them were shared by at least two people, the researchers couldn’t cluster individuals into groups based on their viral microbiome. Many individuals had rare phage in their microbiome in addition to the common ones; there was also a lot of variation between individuals in the abundance of particular phage. Most of the common phage were present as inactive prophage, integrated into the host bacteria’s genome to form a common reservoir of bacterial viruses in our microbiome.
Lora Hooper led a team of scientists at the University of Texas Southwestern Medical Center who looked more carefully at the role of some of these prophages. They found that Enterococcus faecalis, a common bacteria in our intestines, carries two prophage fragments encoding different parts of the phage particles. When activated, one prophage produces the structural components of the phage while the other produces the molecular machinery it will need to replicate and infect new cells. Hooper and her colleagues found that the prophage are activated when E. faecalis is fed with amino acids which it can’t produce; the bacteria probably take up these amino acids from its normal environment in the intestine. Suspecting that phage production might be giving E. faecalis a competitive edge, the team grew it with other bacteria and confirmed that phage-producing E. faecalis were able to out-compete other strains, but only if the prophage were intact; E. faecalis carrying a mutated, non-infectious prophage did no better than other bacteria. Finally, the researchers fed germ-free mice different combinations of bacteria; by measuring the amount of bacteria in the feces, they confirmed that phage production also gives E. faecalis a competitive advantage in the intestine, its native environment. In other words, one of the common bacteria in our intestine has evolved to use a virus as a weapon against other bacteria that might want to move in on it.
Phage are abundant and important in the biosphere, so it’s hardly surprising that the bacterial ecosystem in our gut is rife with viruses that infect them. Nevertheless, uncovering the viral microbiome should remind us how much we still have to learn about our own biology, let alone the world around us. Phage are predators of bacteria; they can have a major impact on the composition of a bacterial community and have been used to treat bacterial infections with some success. As we learn more about the rich and complex web of connections between our gut bacteria and their phage, we’re beginning to piece together the dynamics of the ecosystem that we call our body.
Duerkop, B., Clements, C., Rollins, D., Rodrigues, J., & Hooper, L. (2012). A composite bacteriophage alters colonization by an intestinal commensal bacterium Proceedings of the National Academy of Sciences, 109 (43), 17621-17626 DOI: 10.1073/pnas.1206136109
Stern, A., Mick, E., Tirosh, I., Sagy, O., & Sorek, R. (2012). CRISPR targeting reveals a reservoir of common phages associated with the human gut microbiome Genome Research, 22 (10), 1985-1994 DOI: 10.1101/gr.138297.112