After analyzing human stool samples, scientists identified 54,118 types of viruses, most of which turned out to be bacterial viruses – bacteriophages.

Recently, scientists have shown growing interest in the human microbiota—the microorganisms that inhabit our skin and mucous membranes and significantly influence our health. Perhaps the largest concentration of symbiotic flora lives in the human intestine: it participates in digestion, protection against pathogens, immune system maturation and modulation, and even influences higher nervous system function.

Today, the human intestinal microbiota is the most thoroughly studied microbial ecosystem in the world, although more than 70% of bacterial species have yet to be cultured in the laboratory. This is known thanks to metagenomics—the genetic analysis of material obtained from a given environment. Sequencing the entire DNA of such material provides an instantaneous "snapshot" of all life present in the sample at a specific moment. Metagenomics has revealed how far modern science is from identifying and isolating all intestinal bacteria, and even further from understanding intestinal viruses.

Scientists used computer programs to analyze 11,810 fecal metagenomes from people in 24 countries*. Their goal was to determine what proportion of the genomes of gut bacteria consisted of viruses. The study resulted in the creation of the Metagenomic Gut Virus Catalog, the largest resource of its kind to date. The catalog contains 189,680 viral genomes, representing over 50,000 viral species. Interestingly, over 90% of these are unknown to science. Together, they encode over 450,000 different proteins, which can be beneficial or harmful to bacteria and, therefore, have various effects on humans.

The most common genetic elements in the analyzed phage genomes are so-called "diversity-generating retroelements" (DGRs). They induce mutations in specific target genes to generate as many variants as possible for the constant selection of the optimal ones in the evolutionary race with their host bacteria.

Once identified, the phages had to be linked to their bacterial hosts. To do this, the scientists exploited the CRISPR system—a unique bacterial immune system that "remembers" viral infections and prevents their recurrence. Bacteria copy and store fragments of viral genes in their genomes to recognize and destroy the virus in the event of a repeat invasion. These copies can reveal which phages the bacteria host in the intestinal ecosystem.

Quite naturally, the most common types of viruses in the intestine were associated with the most common types of bacteria in this ecosystem – primarily representatives of the Firmicutes and Bacteroidota phyla.

What is the benefit of studying intestinal viruses? A very promising application of the information obtained is phage therapy, specifically the targeted manipulation of the human microbiota using bacteriophages. While diet, antibiotics, probiotics, prebiotics, and other modern approaches have a general, nonspecific effect on the microbiota, phage therapy can enable precise modeling of its composition. For example, phages may be an effective treatment for Clostridioides difficile infection, which develops primarily as a result of prolonged antibiotic therapy.

Although the authors already have a large amount of information regarding viruses—components of the normal human intestinal microbiota—they admit that they have only “become acquainted” with a small part of this vast “universe,” and there is still a long way to go to get the full picture.

* Nayfach S, Páez-Espino D, Call L et al. Metagenomic compendium of 189,680 DNA viruses from the human gut microbiome. Nat Microbiol, 2021; 6:960–970. https://doi.org/10.1038/s41564-021-00928-6