A mouse model of colitis shows the relevance of phages on intestinal inflammation

An imbalance in gut microbial communities has been associated with inflammatory bowel diseases (IBD) and research aimed at elucidating the contribution of the microbiota to inflammatory diseases has primarily focused on bacteria. Subsequent and ongoing research has characterized the fungal microbiota (called mycobiome) in patients with IBD. However, even though bacterial and fungal microbiota might be altered in IBD patients, little is known about the role of prokaryotic viruses known as bacteriophages (phages)—the viral component of the microbiota, also called the human gut virome—in intestinal inflammation.

A new study, led by Dr. Lora Hooper from the University of Texas Southwestern Medical Center in Dallas (Texas, USA), has found that compositional changes in intestinal phage communities occur during colitis in mice.

The researchers first used a sequence-independent approach to validate that overlapping genomic sequence data recovered from mice feces have a viral origin and to select viral sequences for further study. They then applied quantitative metagenomics to study intestinal phages in a mouse model of T-cell-mediated colitis.

Quantitative metagenomics revealed that, during colitis, the intestinal phage population was altered toward a random distribution as colitis progressed, with the most marked shift occurring 42 days after T-cell treatment when compared with control mice.

Phage community alterations during colitis were observed by comparing genomic reads with curated virus-like particles databases. Colitis was associated with a significant expansion of Caudovirales phages together with a marked imbalance in bacterial communities and an increase in Proteobacteria, which coincides with previous data. These findings show that the abundance of intestinal phages is altered during colitis and correlates with disease status.

Different abundances of phages that infect both commensals and pathobionts during colitis were also revealed. Specifically, the most relevant changes were reported in phages predicted to infect pathobionts associated with intestinal disease. A decreased abundance of Clostridiales phages was observed, whereas during colitis there was an increase of phages predicted to infect Streptococcus sp. and Alistipes, along with Clostridiales phages predicted to infect C. difficile. Members of the Spounaviridae subfamily known to infect pathogens such as Staphylococcus aureus also increased and the authors argue that they could be used as disease markers. These data support the role of defined phage communities during colitis and their potential role as indicators of colitis in mice.

Finally, compositional shifts in the intestinal phage communities in mice with colitis resembled those observed in IBD patients. Streptococcus sp. phages and an expansion of Caudovirales phages was previously revealed in the gut microbiome of Crohn’s disease and ulcerative colitis patients.

These findings show the complexity of the IBD-microbiome picture in which phage communities have now emerged as a new player. As such, changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis in mice, highlighting how the virome is a candidate for contributing to microbiome-specific alterations in IBD.

Reference:

Duerkop BA, Kleiner M, Paez-Espino D, et al. Murine colitis reveals a disease-associated bacteriophage community. Nat Microbiol. 2018; doi: 10.1038/s41564-018-0210-y.