Viruses in the gut have been largely overlooked, while playing a potential role in health
Over the past decades, there has been an increasing interest on the role of gut microbiota in early life. The prominence of bacteria for infants’ gut microbiota development and later health outcomes can be accessed elsewhere. In most cases, we evaluate the role of bacteria, and only very recently the role of viruses in the human gut, i.e. the virome, got under the microscope of researchers in the field.
That is mainly because reproducible protocols to analyse faecal viruses have only recently emerged and scientists realized that not all viruses residing in the human gut infect host cells. Instead, many of them infect their close-by neighbors in the niche, namely the bacteria, and are therefore called bacteriophages or simply phages. Phages can affect human health in a double fashion. Directly, phages can elicit immune responses. Indirectly, they can alter gut microbiota composition by lysing the bacterial wall, and thus alter the steady state of the human immune system. Of course, most bacteria do possess some tools to defend themselves against phages, using advanced DNA editing, including CRISPR-cas systems. Yet, phages are often still capable of infecting them and thus influencing the gut microbiota.
After acknowledging this double potential of viruses, scientists hypothesized that phages may play a beneficial role in human health. And this, so far, seems to be the case when employing fecal filtrate transplantation (FFT), a micropore filtering that removes bacterial components from a fecal sample and thus reduces bacterial load in the transplant. Using FFT, scientists already proved the beneficial role of phages against recurrent Clostridioides difficile infections and metabolic syndrome in human, and diet-induced obesity and necrotizing enterocolitis in preclinical models.
None of this would be possible without the great advances in the sequencing apparatuses and bioinformatics tools that allow for elaborate exploration of the gut virome. Traditionally, characterizing and defining viruses was very difficult, for it required laboratory isolation of both the virus, e.g. phage, and the host, e.g. bacterium. The International Committee for the Taxonomy of Viruses (ICTV), founded in 1971, organized this process in a very structural manner, yet the task remained challenging. Only recently, the ICTV made it possible to define a new viral taxa on the basis of sequence information, following the guidelines for Minimum Information about an Uncultivated Virus Genome. Despite the initial challenge of a limited number of distinctive genes, the remarkable progress in the field of bioinformatics has led to a surge in available genetic sequences. This suggests that the virome in our gut is now recognized as potentially as, if not more, important than the bacteriome.
Scientists identify new harmless viruses in infant faeces
In a recent study, published in Nature Microbiology, an international collaboration of scientists from Denmark, Canada and France evaluated the virome of 647 one-year-old healthy babies from the Copenhagen Prospective Studies on Asthma in Childhood 2010. This large number of nappy samples allowed to unravel 248 families of viruses, 232 of which were unknown before. The scientists were astonished by the number of unknown taxa and named the newly identified families of viruses after the names of the babies.
When comparing the 10,021 viruses of this new research with the three currently-available databases (i.e., the Gut Virome Database, the Gut Phage Database, and the Metagenomic Gut Virus catalogue), the researchers found that only about 800 of these viruses had been found before. This suggested that “most large gut phage clades in databases are only occasionally found in the infant gut viromes, and vice versa”. This is the first report to highlight the difference in the diversity of the adult versus the infant virome, meaning that baby bacteriophages are gradually replaced with adult bacteriophages.
Considering the functions that phages exert in the context of GM, this significant difference between adult and infant virome turned out explainable. So called crAssphages, typically abundant in the adult virome, were outnumbered by previously unknown families of phages infecting Clostridiales and Bifidobacterium. These results make sense as Bifidobacterium species are crucial for infants’ health and decrease as we age. Meanwhile Crossvirales-one of the most abundant bacteriophages in the adult gut- were less prevalent in the infant virome and will be acquired later in life.
Resolution of the phages lifestyle into virulent and temperate allowed the scientists to further highlight the massive diversity of the human gut viral community. Virulent phages enter immediately the lytic cycle and kill their host cell directly, releasing new virions into the ecosystem. Temperate phages, on the other hand, require certain environmental conditions to induce the prophage to enter the lytic cycle, and thereafter kill the host cell. In the new study, it was reported that temperate phages dominate the 1-year-old gut virome and were more diverse compared to virulent phages.
Contemplating on the strengths of the study, the investigators report that they introduced a new amplification protocol which, when compared to other so-far used protocols, unraveled relevant information on viral abundances at least for double strand DNA viruses. It might also partially explain the large number of viruses that were never described before. How different are they truly to the adult virome though? Is this great amount of unknown in the past viral families indeed missing from the adult virome, or the new techniques allowed them to unravel them? Considering the beautiful experimental design of the new study, and the paired fecal samples from the mothers of these babies, it would be worth considering a sequel analysis in the fecal samples of the mothers and study the impact of viruses in shaping health later in life.
References
Ott S.J., Waetzig G.H. et al. Efficacy of Sterile Fecal Filtrate Transfer for Treating Patients With Clostridium difficile Infection. Gastroenterology 2017. doi: 10.1053/j.gastro.2016.11.010
Rasmussen T.S., Mentzel C.M.J. et al. Faecal virome transplantation decreases symptoms of type 2 diabetes and obesity in a murine model. Gut 2020 doi: 10.1136/gutjnl-2019-320005
Wortelboer K., de Jonge P.A. et al. Sterile faecal filtrate transplantation alters phage-microbe dynamics in individuals with metabolic syndrome: a double blind, randomised, placebo-controlled clinical trial assessing efficacy and safety. medRxiv 2023 doi: 10.1101/2023.03.22.23287570
Brunse A., Deng L. et al. Fecal filtrate transplantation protects against necrotizing enterocolitis. ISME J 2022 doi: 10.1038/s41396-021-01107-5
Roux S., Adriaenssens E., Dutilh B. et al. Minimum Information about an Uncultivated Virus Genome (MIUViG). Nat Biotechnol 2019 doi:10.1038/nbt.4306
Shah S.A., Deng L., et al. Expanding known viral diversity in the healthy infant gut. Nat Microbiol 2023 doi:10.1038/s41564-023-01345-7
Bisgaard H. The Copenhagen Prospective Study on Asthma in Childhood (COPSAC): design, rationale, and baseline data from a longitudinal birth cohort study. Ann Allergy Asthma Immunol 2004 doi: 10.1016/S1081-1206(10)61398-1
Gregory A.C., Zablocki O. et al. The Gut Virome Database Reveals Age-Dependent Patterns of Virome Diversity in the Human Gut. Cell Host Microbe 2020 doi: 10.1016/j.chom.2020.08.003
Camarillo-Guerrero L.F. et al. Massive expansion of human gut bacteriophage diversity. Cell 2021 doi: 10.1016/j.cell.2021.01.029
Bayfield O.W., Shkoporov A.N. et al. Structural atlas of a human gut crassvirus. Nature 2023 doi: 10.1038/s41586-023-06019-2
