In 1997, scientists in Japan discovered a new virus lurking in the blood of patients with unexplained hepatitis (1). At first, they thought the mystery virus might be causing the patients’ symptoms. But since then, study after study failed to link the virus — now known as an anellovirus — to hepatitis. To this day, no one has been able to link anelloviruses to any other disease either.

Lia van der Hoek, a virologist at the University of Amsterdam, said that she ignored anelloviruses for the first few years after researchers discovered them. But eventually, she wondered why she kept finding them in every person’s blood. “Why are they there? If they don't harm, could we benefit from them?” she said. Van der Hoek began studying anelloviruses to find out if we have good and bad viruses within us, just like we have good and bad bacteria. 

Today, more researchers are beginning to study the full set of viruses in our bodies known as the virome to search for ways that they may benefit human health. It still seems counterintuitive to many, given that so many viruses from SARS-CoV-2 to Ebola to HIV bring us nothing but sickness or even death. But with an estimated 380 trillion viruses living inside us (compared to only 38 trillion bacteria), studying the virome could change how we understand our health and how we treat diseases (2).

One of a kind

When we enter the world as babies, our viromes are just beginning to develop. Scientists believe that at first, they’re based solely on viruses that we were exposed to during pregnancy or childbirth. “But the second that you're exposed to the environment… it's kind of like a party,” said David Pride, a microbiologist at the University of California, San Diego. “It's just a new landscape for them to start to inhabit.” 

Last year, in a study published in the Proceedings of the National Academy of Sciences, researchers tracked the emergence of the gut virome from birth through age five (3). They found that each new life event such as starting or stopping breastfeeding or formula, the introduction of plant foods, and going to daycare led to an explosion of new viruses in the gut. Unlike eukaryotic viruses like coronaviruses, the majority of the viruses in the human gut are bacteriophages. 

Massive changes to the gut virome continue to occur throughout early childhood. As adults, the things that impact the virome are plenty. Researchers are just beginning to tease out effects from genetics, the foods we eat, where we live (including urban vs. rural environments), and whether we’ve recently taken antibiotics (4). 

A few years ago, Pride wondered how much the people we live with might influence gut viromes. Given how contagious many viruses are, he reasoned that we likely transmit viruses between individuals in a household. In a Microbiome  paper published in 2016, Pride’s team reported that nonrelated roommates shared a substantial number of bacteriophages within only a matter of days after moving in together (5). “That shocked us,” said Pride. “This stuff happens quickly.”

Over the years, teams like Pride’s have studied virome in the mouth, gut, lungs, skin, and more. The gut virome is the most abundant and the most studied around the world, but many organs have their own sets of resident viruses that play a role in their overall ecosystems. Pride’s team has even found viruses in the one place that scientists expected them not to be: cerebrospinal fluid (6). These viruses must have diffused across the blood-brain barrier. “Just because you're good enough to prevent most bacteria from getting in, doesn't mean you're good enough to prevent many of these teeny tiny viruses from getting in,” Pride said.

Harnessing the virome for health

One of the first clues that human viromes play a role in keeping us healthy comes from data on the oldest members of our society. Centenarians carry a larger variety of viruses in their gut viromes, as well as a substantial presence of specific bacteriophages that play important roles in the metabolism of sulfur (which is crucial to many cellular processes), than their younger counterparts (7).

This may confer benefits, and researchers have already begun exploring fecal transfers from one human to another. So far, the potential benefits appear to be greatest for people with gut disorders. Researchers led by Kate Jeffrey, an immunologist at Moderna, revealed that viruses present in the guts of patients with inflammatory bowel disease (IBD) directly contribute to the disease, while the viruses in healthy guts protect against intestinal problems (8). “It definitely shows that much like the microbiome, potentially fecal transfers containing healthy viruses could be beneficial,” said Jeffrey. 

A recent July 2023 study from Pride’s lab proved that fecal virome transfers (which don’t include bacteria, unlike fecal microbiome transfers) can even influence weight, at least in mice (9). When researchers gave mice fecal transfers from other mice eating a healthy diet, they stayed lean even when they themselves were eating high-fat diets. The reverse was also true; mice on healthier diets often became obese when they received fecal transfers from mice eating high-fat diets.

Beyond fecal transfers, Jeffrey and her colleagues at Moderna are studying another possible solution for improving our viromes: the use of mRNA vaccines to target bad viruses. This includes a collection of known harmful gut viruses and those that are now being discovered to target cancer and complex autoimmune diseases like AIDS (10,11). “A therapeutic vaccination approach to these diseases is definitely something that we are, and particularly I am excited about,” said Jeffrey. 

Other microbiologists like Evelien Adriaenssens at the Quadram Institute are interested in the therapeutic use of bacteriophages that keep bad bacteria in check. But there’s still a long way to go before these reach clinical care. Scholars like Adriaenssens are still busy trying to identify the best viruses to use and discover how they alter the microbiome as a whole. “There are many more viruses that we don't know compared to the ones we do know,” she said.

“The next phase of virome [research] is really going to be trying to sequence more viruses. Give them a sequence and give them a name,” said Jeffrey. “It's new territory, which is exciting and daunting.”

A curious part 

Research on the virome continues to increase, but its role within the full microbiome is still understudied. Part of the problem is that viruses are much harder to study. Bacteria, like all cellular life, have a 16S RNA gene with conserved sequences that scientists can use to quickly identify any bacterial species. But viruses don’t have one gene they share because they’ve evolved independently. To find a virus, you have to investigate its entire genome. 

In addition to sequencing more viruses, Jeffrey said that another equally important direction in virome research will be improving the ability to culture viruses in the laboratory so that scientists can better study what they do. For gut viruses, Pride’s team has had success using a method called chemostat systems to grow gut viruses from feces, but these sophisticated systems are expensive and not widely available. 

Van der Hoek thinks that a culture that starts from just one cell type won’t ever be enough. “[Being] too much adapted to us means that we are the culture vessel, more or less,” she said. Therefore, scientists may need to design a system that reflects the complexity of the whole human body to culture them correctly. Without the ability to study and manipulate them in the lab, the mystery of the anelloviruses that began in 1997 will likely remain unsolved for years to come. They could be helping humans, or using the body to replicate. 

Regardless of whether we understand them, the trillions of viruses in each of our personal viromes are here to stay. “We are walking bags of viruses,” said Pride. “What are they doing? It's really, really difficult to understand because the answer is probably 100 or 1000-fold different things.”

References

1. Nishizawa, T. et al. A novel DNA virus (TTV) associated with elevated transaminase levels in posttransfusion hepatitis of unknown etiology. Biochemical and Biophysical Research Communications  241, 92-7 (1997).
2. Sender, R. et al. Revised estimates for the number of human and bacteria cells in the body. PLoS Biology  14 (2016). 
3. Beller, L. et al. The virota and its transkingdom interactions in the healthy infant gut. Proceedings of the National Academy of Sciences  119 (2022).
4. Liang, G. et al. The human virome: assembly, composition and host interactions. Nature Reviews Microbiology  19, 514-527 (2021).
5. Ly, M. et al. Transmission of viruses via our microbiomes. Microbiome  4 (2016).
6. Ghose, C. et al. The virome of cerebrospinal fluid: viruses where we once thought there were none. Frontiers in Microbiology  10 (2019).
7. Johansen, J. et al. Centenarians have a diverse gut virome with the potential to modulate metabolism and promote healthy lifespan. Nature Microbiology  8, 1064–1078 (2023).
8. Adiliaghdam, F. et al. Human enteric viruses autonomously shape inflammatory bowel disease phenotype through divergent innate immunomodulation. Science Immunology  7 (2022).
9. Borin, J. et al. Fecal virome transplantation is sufficient to alter fecal microbiota and drive lean and obese body phenotypes in mice. Gut Microbes  15 (2023).
10. Nakatsu, G., et al. Alterations in enteric virome are associated with colorectal cancer and survival outcomes. Gastroenterology  155, 529-541 (2018).
11. Monaco, C. et al. Altered virome and bacterial microbiome in human immunodeficiency virus-associated acquired immunodeficiency syndrome. Cell Host & Microbe  19, 311-322 (2016).