The gut microbiome is made up of different taxonomic groups that include bacteria, archaea, microbial eukaryotes (fungi and protozoa) and viruses. Bacteriophages or phages are prokaryotic viruses that represent a substantial fraction of the microorganisms residing in the gut, although their interactions with gut bacteria have remained largely underexplored due to the challenge of characterizing phages encountered in previous research.
A new study of mice with a defined gut microbiota, led by Dr. Georg K. Gerber at Brigham and Women’s Hospital at Harvard Medical School (Massachusetts, USA), characterizes the impact of bacteriophages in gut bacterial populations at composition and metabolome levels.
The researchers administered 4 lytic phages to mice previously colonized with a defined set of 10 selected bacterial species, which include species from Firmicutes, Bacteroidetes, Proteobacteria and Verrucomicrobia phyla that usually inhabit the human gut microbiome.
Murine fecal samples were collected for 44 days with the aim of longitudinally tracking and characterizing changes in gut bacterial populations before and after phage administration. Both phages and their targeted bacteria were detectable in stool samples throughout the experiment.
The authors also determined in vitro that, whereas a subsample of Enterococcus faecalis present in the mice gut microbiota was sensitive to phages, another population acquired resistance 2 and 10 days after phage administration. Just like gut microbiota may be involved in transferring antibiotic resistance genes, bacteria residing in the gut can also acquire resistance to phages.
Although the ability of phages to specifically lyse the inoculated human gut bacteria was initially confirmed, Hsu and colleagues found that phages also had a different effect on low and high abundance bacterial species in the gut microbiota that were not directly targeted. As a result of phages’ stimulatory or inhibitory effects on the surrounding gut microbiota beyond targeted bacteria, there was both a rapid increase and depletion of certain gut commensal bacteria.
When phage-targeted bacteria (Escherichia coli, Clostridium sporogenes, Bacteroides fragilis and Enterococcus faecalis) were individually excluded, the surrounding gut microbiota responded by increasing or decreasing their densities in order to normalize the full microbial ecosystem. These findings show that phages not only act specifically in sensitive bacteria, but they can also have facilitative and inhibitory functions in the surrounding gut microbiota.
For instance, Escherichia coli promoted the growth of Bacteroides fragilis and repressed B. vulgatus. Such changes did not persist when the researchers later administered phages that were not specific to E. coli. That suggests bacterial interactions have a role at the ecological level in explaining the finely-tuned crosstalk between phages, sensitive gut bacteria and the surrounding microbiota.
Nevertheless, phages were unable to eliminate gut bacterial populations present in the background gut microbiota. These results highlight the specificity of phage effects in the host and support the idea that phages can contribute to the stability of the gut microbial ecosystem.
Phage modulation of gut bacteria also led to modest changes in the gut metabolome, which reflects a metabolic redundancy of the overall gut ecosystem. Specific compounds related to particular bacterial species were sensitive to shifts in gut bacteria, however. For instance, the fall in C. sporogenes and E. faecalis was accompanied by a reduction in tryptamine and tyramine metabolites, respectively.
Furthermore, phages also modulated metabolites with known mammalian host effects, such as bile salts, which were associated with specific bacteria in the surrounding gut microbiota.
On the whole, these findings show the complexity of interactions between bacteria and phages in the gut ecosystem in mice when ensuring the proper stability and functions of the ecosystem. Interestingly, the authors showed that bacteriophages not only have an impact on their bacterial targets, but can also affect surrounding gut bacteria that are non-susceptible. This effect extends beyond composition level and affects the gut metabolome. Furthermore, the authors highlighted that studying the role of phages in the gut ecosystem may help with developing personalized treatments that provide a precise modulation of the gut microbiome.
Hsu BB, Gibson TE, Yeliseyev V, et al. Dynamic modulation oft he gut microbiota and metabolome by bacteriophages in a mouse model. Cell Host Microbe. 2019; 25:1-12. doi: 10.1016/j.chom.2019.05.001.