So far, most of what scientists know about the gut microbiome comes from examining the bacterial fraction of the community (the bacteriome). However, with roughly 108-1010 virus-like particles (VLPs) per gram of intestinal content, viruses make up a hefty sum of the microbial population. This diverse viral community, collectively called the virome, is emerging as a key modulator of health and disease with promising therapeutic potential. Still, the more scientists learn about the virome, the clearer it becomes that there is much left to uncover.
Development of the Gut Virome
The gut virome consists of eukaryotic viruses (those that largely infect human cells), viruses that infect bacteria (i.e., bacteriophages, or phages, which make up over 90% of the viral community), archaeal viruses and plant viruses sourced from food and the environment.
Like the bacteriome, the composition of the gut virome changes over time. At birth, there are few, if any, detectable VLPs in the meconimum (the first poop) or early stool of infants. Phages are the first viruses to appear, likely introduced by the initial bacterial colonizers of the gut. As such, the composition of the phage community shifts as a baby grows, perhaps in response to changes in the gut bacteriome over the course of development. After about 4 months, eukaryotic viruses, like anelloviruses (small single-strand DNA viruses common in healthy adults), become more prevalent.
Diet may influence which viruses set up shop in the gut, and when. For example, scientists found that breastfed infants had fewer eukaryotic viruses in their gut compared to formula-fed infants, likely because of protective immune factors (e.g., antibodies) passed from the parent to infant during feeding. Birth mode (i.e., vaginal delivery versus delivery via Cesarean section) may also play a role, though this link is less clear and depends on the study.
In any case, the gut virome becomes less dynamic as an individual ages, eventually stabilizing in adulthood. Stable does not mean identical, however-everyone’s virome looks a little different. In fact, the gut virome may vary more than the bacteriome in healthy populations. Various factors, including age, sex, diet, geographic location, urbanization and stress can all influence virome structure.
The Gut Virome in Health: A Key Immune Regulator
Why is the gut virome important? That’s a question scientists are working diligently to answer. What they do know is that, among its other plausible functions, the virome is an important regulator of immune system development and responses. For instance, infection of antibiotic-treated mice with a single eukaryotic virus (murine norovirus) protected the mice against antibiotic-associated intestinal injury and bacterial infection. These findings highlight the ability of eukaryotic viruses to shape mucosal immunity. Both eukaryotic viruses and phages also facilitate development of intraepithelial lymphocytes, which, along with intestinal epithelial cells, form a front line of defense against pathogens.
Gut virome-mediated immune regulation can be both direct and indirect. Phages, for example, can travel through the intestinal epithelium to directly interact with underlying immune cells. They can also regulate the release of immunomodulatory compounds, like short chain fatty acids and bile salts, by shaping the composition, and thus metabolic output, of the gut bacteriome. These metabolic effects may extend beyond the immune system, or gut for that matter. A recent study found that people with increased gut concentrations of Caudovirales phages (a diverse group of phages abundant in the gut) performed better in executive processing and verbal memory than those with higher abundances of Microviridae, another group of prevalent gut phages. The researchers posit that the ratio of these 2 phages may alter host bacterial metabolism and, by way of the gut-brain axis, influence cognitive function.
The Gut Virome in Disease
While the gut virome undoubtedly benefits the host in numerous ways, it has its dark sides. Gut viruses have also been implicated in development of various diseases, including colorectal cancer, obesity and type 2 diabetes (T2D) and inflammatory bowel disease (IBD). Indeed, the composition of the gut virome in people with IBD is unique from that of healthy individuals. The mechanisms underlying these compositional shifts, and how they relate to disease development and progression, are still unclear. One hypothesis is that perturbations in the gut virome lead to altered interactions with the immune system, which contributes to inflammation and IBD pathogenesis.
The gut virome may also play a part in extraintestinal diseases, including liver diseases, rheumatoid arthritis and COVID-19. Research suggests COVID-19 is associated with alterations in the fecal virome-including an enrichment in environment-derived eukaryotic viruses and bacteriophages implicated in intestinal inflammation-that can persist even after disease resolution. Moreover, some of these changes may correlate with disease severity and immune responses, again hinting at the immunomodulatory functions of the gut virome, both locally and systemically.
The Therapeutic Potential of the Gut Virome
The emerging ties between gut virome and disease have made it an attractive therapeutic target, particularly in the form of fecal virome transplantation (FVT). FVT is a refined version of fecal microbiota transplantation (FMT). During FMT, all types of microbes from a healthy donor’s gut are transferred to a recipient. It is an effective strategy for preventing recurrent infection by the diarrhea-inducing bacterial pathogen, Clostridioides difficile and has also been explored for treating IBD, sepsis and more. Notably, the virome of FMT recipients changes post-transplant, which may be tied to the procedure’s efficacy.
With that, FVT involves filtering out and transferring just the viral component (i.e., phages and eukaryotic viruses) of a donor’s gut microbial community. The goal is to modulate gut virome composition to restore homeostasis-and, so far, the treatment looks promising. Studies with animal models suggest FVT may be effective for managing antibiotic-associated gut microbiome dysbiosis, obesity and T2D and necrotizing enterocolitis (a condition characterized by inflammation and destruction of the gut that mostly affects premature infants). Furthermore, fecal filtrates, extracts lacking live bacteria but containing viruses, microbial metabolic products and other compounds, could eliminate symptoms of recurrent C. difficile infection in human patients.
Still, there are risks. It is possible that potentially pathogenic eukaryotic viruses could be transferred from donor to recipient during FVT. Researchers need to learn more about the viral make-up of FVT material, and its health implications, for the procedure to be applied on a broad scale. It may also be possible to take an even narrower approach than FVT to managing gastrointestinal disease and infection via phage therapy. Rather than the entire viral community, phages targeting specific problematic bacteria, like adherent invasive Escherichia coli, a bacterium that causes persistent diarrhea with ties to IBD, are isolated and administered to a patient. However, as with FVT, continued investigation and standardization of phage therapy is required.
If there’s one thing scientists know about the gut virome, it’s that they really don’t know much of anything (yet). So far, researchers have only been able to identify 10% of the viral sequences in the gut-the remaining 90% are largely unannotated (referred to as “viral dark matter”). Refining genomic sequencing approaches to capture a greater proportion of the community will help shine light on this dark matter, bringing many of the gut virome’s members out of the shadows. Coupling these technologies with the isolation, cultivation and functional analyses of phages and eukaryotic viruses will provide insight into not only which viruses are present, but also what they do. This reflects a key goal in gut virome research, and the microbiome overall: to move beyond associations to understand how gut microbes regulate health and disease. Such knowledge bolsters efforts to therapeutically tune the microbiome to keep the gut, and rest of the body, in tip-top shape.