The New Microbiome Frontier: Your Blood

The first time I donated blood, I was surprised by how long the nurse scrubbed my arm with alcohol before inserting the needle. I wanted that dreaded pinch to be over already, but she kept disinfecting, ensuring that the microbes on my skin didn't contaminate the needle and my soon-to-be-donated blood. The underlying premise was, in my mind, that blood is naturally pure and free of microbes.

Yet a surprising new body of research suggests that blood is anything but. "Although we don't think about it in this way, blood is not sterile," says Louis Katz, the chief medical officer of America's Blood Centers, the largest network of non-profit community blood centers in North America. Thanks to sensitive new molecular tools, researchers are finding that blood—even that of perfectly healthy people—is peppered with tiny bacteria and viruses, many of which scientists know very little about.

In a study published this year in the journal PLoS Pathogens, researchers at Human Longevity, Inc., a San Diego-based company founded by genome leader J. Craig Venter, and other institutions analyzed the blood of 8,240 people and found that 42 percent harbored genetic material from viruses—in total, 19 different human types. Some were common viruses that people are usually exposed to during childhood, such as the herpesvirus (HHV 6, different from the cold-sore or genital strains) that causes the common childhood virus roseola. But they also found evidence of Merkel cell polyomavirus, a virus that can cause a rare and aggressive form of skin cancer, and Epstein-Barr virus, the cause of mononucleosis, which is linked to an increased risk for autoimmune disease.

Bacteria, too, populate human blood. In a May 2016 study, researchers in France analyzed the blood of 30 healthy French blood donors and discovered the equivalent of one complete bacterial genome per human blood cell. "What is striking is the amount and diversity of the microbiome we found," explains co-author Benjamin Lelouvier, chief scientific officer of biotech company Vaiomer SAS in Labege, France. "It is still much less than in the gut, but much more than anyone would have guessed."

Blood banks do, of course, screen donated blood for evidence of infectious diseases that can be transmitted through transfusions—HIV, hepatitis B and C, syphilis and West Nile virus among them. But these tests are infection-specific, so they don't detect other bacteria or viruses that might be lurking, which is one of the reasons few people know much about the "blood microbiome," as it's called. Blood banks also perform more general tests on donated samples to find evidence of high levels of bacterial contamination—as in, enough bacteria to incite a dangerous infection in a transplant patient—but tests these don't always detect smaller amounts of bacteria, as well as microbes that may not be actively growing.

One reason the blood microbiome has largely remained a mystery is that bacteria in blood can live in a dormant, inactive state. "They choose to have a little snooze," perhaps because blood isn't an easy place for bacteria to grow, explains Douglas Kell, a bioanalytical scientist at the University of Manchester in the UK. And when they're not multiplying, they're hard to detect: Bacteria are each so small that researchers can't see them unless they multiply enough to create large, visible colonies. But if the bacteria in blood remain dormant, they won't grow to make colonies in the lab, and researchers may wrongly conclude there are no bacteria at all.

Recently, however, scientists have developed sensitive new molecular tools that allow them to directly hunt for bacterial or viral DNA in blood samples, bypassing the need for any growth. One technique, called real-time PCR, identifies DNA sequences specific to bacteria. Another tool is DNA sequencing, which researchers in the PloS Pathogens study used to sequence the DNA found in the blood sample; after separating out the human sequences, they compared the rest of the DNA with known viral sequences, finding genetic material from 19 distinct viruses.

These tests are so new that biotech companies and academic labs are primarily the ones using them, not blood banks. One important question is whether the microbes that these methods find are medically important or not. Do these bugs actually pose risks to transfusion patients, or are they harmless? If they're no big deal, there's little reason for blood banks to start screening blood with these sensitive methods. "Transfusion medicine experts do careful work before deciding whether enlarging the spectrum of screening is warranted," explains Amalio Telenti, chief scientific officer at Human Longevity, Inc and a co-author of the PloS study. Katz agrees: "Everybody's really cautious about doing organism-finding 'wild goose chases,' in the absence of evidence that there's an issue," he says.

Another concern is that these sensitive tests can find microbes that were not there to begin with but were introduced during the testing itself. In addition to the 19 bloodborne human viruses identified in the PloS paper, the authors found DNA from 75 viruses that they concluded were due to accidental contamination from lab chemicals or the surrounding environment. It can be difficult to figure out which microbes are which.

Still, most scientists agree that some bacteria and viruses do truly circulate in our blood—which raises questions about why they're there and where they come from. Some bacteria probably get transferred into the blood from the gut, where the majority of our bacteria reside. "The blood microbiome is most likely a highly dynamic environment," Lelouvier explains, with microbes crossing into blood and then getting cleared out by the body's immune system. Your blood microbiome might be different one day to the next.

The mouth is another possible port of entry. 'Plaque' is basically a fancy word for bacteria, and bleeding gums give mouth microbes an easy route into the blood. The crossover is particularly common among people with periodontal disease, an inflammatory condition that afflicts half of American adults over 50 and damages the mouth's soft tissue. In a study published in March 2015, researchers at the University of Copenhagen and Copenhagen University Hospital in Denmark found that 23 percent of freshly donated blood harbored a species of bacteria commonly found in the mouth known as Propionibacterium acnes, while 38 percent of the samples contained another common oral bacteria, Staphylococcus epidermidis.

If certain diseases can make microbes more readily cross into the blood, then another important question is whether our blood microbiome reflects—and could reveal details about—our overall health. Certainly, if a person has hepatitis C, the virus will readily be found in his blood, but more subtle relationships between illness and blood microbes could exist, too. In a 2014 study, Japanese researchers found that blood donors with type 2 diabetes had more bacteria in their blood than healthy donors did. No one yet knows, though, whether transfusion patients might be adversely affected by blood from donors afflicted with conditions that have affected their blood microbiome.

And a crucial fact remains: "People have been given blood safely for decades," Kell says, and transfusion-related risks have steadily been dropping over time. According to the Centers for Disease Control and Prevention, in 2015, only 5 Americans died from transfusions with bacterially contaminated blood, yet more than 15 million transfusions took place. Given these trends, many scientists believe that the discovery of the blood microbiome is more fascinating than worrying. "It's not a bad thing, no more than the fact we have a gut microbiome or the fact that a forest has a diverse and abundant fauna and flora," Lelouvier says. Still, if we have learned one thing from research on the gut microbiome, it is that the relationship between our body's microbes and our health is often more complex and profound than we expect.