Science

The Viral Elephant in the Room

The past few years has garnered a lot of public attention on the roughly three pounds of tiny inhabitants that occupy the human gut. And rightly so, our microbiota (which outnumbers our human cells by a factor of 10) are proving to be a vital key to understanding the human not as a sterile organism but as a complex ecosystem that relies on its microscopic participants for health both physically and mentally.

As our species redefines itself as being in symbiosis with other organisms, the potential for massive health breakthroughs have already been realized from curing chronic bacterial infections like Clostridium difficile through fecal transplants to new insights on the mechanism for obesity and other metabolic disorders. Further, as our body of knowledge enables us to look at our actual bodies holistically, we anticipate an era of personalized health and medicine where doctors routinely examine the microbial contents of our guts before prescribing medication or a change in diet or living that can specifically address our needs as individuals.

However, in this brave new world of microbial possibilities with such bacteria in it, we are overlooking another component of our microbiota that has ten times the numbers of our bacterial residents: our viruses. Usually associated with disease, viruses get a bad rap. Sub-microscopic yet with a combined genetic power that dwarfs our human and bacterial cells combined, viruses are the proverbial red-and-gold-painted elephant in the room. And this genetic power is proving to be driving force of the human ecosystem in both health and disease.

We’ve spent a lot of research resources in figuring out just which bacterial species are operating in the gut, but that direction of research (while important for what it added to our knowledge) is proving to be a residual artifact of thinking like a macrospecies whose genetics are fairly stable. Microbes don’t behave like humans (and other multicellular organisms) with genes that are locked into a single species. Rather, on the microscopic level, microbes behave a bit like lovesick middle schoolers, handing genes around as if they were those mix tapes we used to make for our school crushes (some types of these mobile genes are actually called “cassettes”). With this free genetic love, what microbes do becomes a much more important question than who the microbe is, and viruses (particularly bacterial viruses called phage) are a big influence on that doing.

In the course of researching the human gut ecosystem, we have found that most individuals have very different compositions of their microbiota based on the type of bacteria that is living and working in their guts–sort of like a microbial fingerprint: our species composition of bacteria unique for everyone. However, the jobs the microbes do in the human ecosystem don’t differ too greatly from human to human. Think of our bodies like a restaurant. There are a finite number of jobs in a restaurant–host, server, cook, chef, manager, dishwasher, baker, janitor, etc…–that can be filled by anyone who is able to do the work. For microbes, that ability is in their genetic code. If a resident microbe has a gene that lets it do a better job of making a soufflé, that microbe will thrive best in the soufflé-making niche. If a completely different microbe in a completely different person has that same soufflé-making gene, then it will be doing the same job.

But how are these genes getting into different species of microbes, enabling them do similar things? Who is delivering these mix tapes? The mechanism of moving genes from one microbial cell to another is called Lateral Gene Transfer (LGT), and scientists have found that the occurrences of LGT is very high in the human body. There are more than one way for bacteria to share their genes with each other (one even involves a version of bacterial sex) but one of the most prevalent ways is through viral infection.

Phages are numerous in our guts and like our bacterial population seem to be genetically unique for each individual: even if two people have similar types of bacteria in their guts, their viral population will be very different . Phages often hang out in the mucus layer of our guts, waiting for the right bacterium to pass by (full article here). Once a phage finds the perfect host, it injects its genes into the cell and then takes one of two paths: lytic or lysogenic. The lytic path is one of violent massacre where the virus hijacks the cellular machinery to make more and more copies of itself which then burst from the now dead cell, scattering cell guts and a horde of new viruses that are rabid for hosts. In this path, an entire population of susceptible cells can be wiped out, leaving holes in the ecosystem that can be filled by yet another bacteria with the right genes.

The second path, the lysogenic one, is more common in the human gut: here is where the mixed tapes get handed about. In this path, a temperate phage injects its genes into the cell and these genes incorporate into the cell’s genome, allowing the cell access to any genes that might give it the ability to do new jobs. Since soufflé-making skills are not actually necessary in the gut, often these new genes give the cell the power to better resist antibiotics or to grow faster or to turn into virulent hulks that wreak havoc on our human body; sometimes these new genes even have a specific and aberrant metabolic profile this is unique to a diseased ecosystem like cystic fibrosis lungs (full article here).

In both diseased and healthy human ecosystems, despite bacteria’s freely sharing genes that allow them to do diverse things and respond to their changing environment, the genetics of phages stay remarkably stable in each individual, allowing phages to act as a stable reservoir of genes that the bacterial population can draw upon when needed. This reservoir imparts stability, continuity, and the adaptability to our gut microbial community even in times of great unrest like when you ate that whole bowl of ice-cream even though you know you are lactose intolerant.

The traditional narrative about LGT is that it is limited by how closely related the exchanging bacteria were, but in recent years, we are finding that in the microbial world, such boundaries are often ignored when it comes to free love gene sharing. In other ecosystems, scientists have found that phage-mediated LGT even enables bacteria in different genera to pass genes from one another. In the dark colon, all microbes look alike; so we might nod sagely and think that such a transfer of genes from one bacterium to another is not a big deal (after all, they are all bacteria). However, such an exchange of genes is equivalent to a giraffe passing the genes for giant neck vertebrae to a hippopotamus via a viral infection–and then that hippo’s neck grows 15 feet in the next 20 minutes, allowing it to chomp on tall trees and causing all the giraffes to flee in horror.

Even more mind boggling is that there is evidence that phages may even be able to move genes between bacterial phyla— as if a virus could transfer the genes for venom from a black widow spider to your Newfoundland who suddenly begins drooling neurotoxin. This possibility has serious implications in human health when dealing with antibiotic resistance or virulence factors. If the gap between the genetic divide in our microbiota is so narrow, the difference between a “friendly” microbe and a pathogenic one could be a single transferable gene. A recent study showed that when we take antibiotics, it actually increases the sharing of genes that confer antibiotic resistance to the administered antibiotic as well as other antibiotics that aren’t even being used. Thus, taking an antibiotic may empower your resident bacteria (the good, the bad, and the ugly) to be resistant to antibiotics you may take in the future (full article here). Further, even seemingly innocuous foods seem able to trigger viral action like the cellular massacre that ensues when certain phages are induced by eating soy sauce (full article here).

Considering our viruses as a vital part of our human ecosystem rather than agents of disease and death is such a new concept that we don’t even have set words for it. Are viruses included in the general microbiota (the answer is yes, but we tend to associate bacteria and other single-celled organisms with this term)? Are they virobiota? Whatever we call them, they are not static players in our human ecosystem, and we need to account for their effect on our health.

Traditionally, we approach viruses from the pathogenic motivation: they make us sick or our “good” bacteria sick, so we need to get rid of them. When we are not sick, we pretty much ignore them. As the gatekeeper and key-master of important genes in our bodies, we need to stop avoiding the elephant in the room and begin looking at the viral consequences of our actions.

*Phage art by Ben Darby

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