Investigating the role of the human phageome in relation to AMR

The Microbiology Society is undertaking a project entitled A Sustainable Future as part of our 75th Anniversary, which aims to highlight the Sustainable Development Goals (SDGs) to our members and empower them to use their research to evidence and impact the goals. Earlier this year, we put a call out to our members to submit case studies in the following three areas: antimicrobial resistance, soil health and the circular economy.

This case study is written by Julie Callanan, who is a final year PhD student at the APC Microbiome Ireland SFI Research Centre, University College Cork, Ireland, and a member of the Microbiology Society. It focuses on antimicrobial resistance; a naturally occurring process, whereby micro-organisms (bacteria, viruses, fungi and parasites) can change and adapt over time, either by modifying the target of the antimicrobial, or by developing and exchanging resistance genes.

What are the challenges/needs that this research addresses?

The surge in antimicrobial resistance (AMR) is an extremely pressing public health matter that threatens human wellbeing, agriculture and other environments on a global scale. In order to combat this danger, efforts to develop a deeper understanding of the microbes involved and ways AMR can arise are fundamental.

Bacteriophages (phages) are viruses that infect and destroy specific bacteria. The idea to utilise these viruses as a combinational treatment with antibiotics or an alternative treatment for antibiotic resistant bacterial infections is not a novel one. Since their discovery, phages have been applied in humans and in agriculture, primarily across Eastern Europe. The resurgence in interest in western society is driven by the exponential rise in AMR. There are many aspects to this research, including the examination of the phage consortium of the human gut (phageome) and the influence this may have in terms of individual and global health.

What findings and solutions were provided by this research?

The majority of phages found in the human gut possess DNA genomes, in particular double-stranded DNA. Phages with RNA genomes have remained a mystery in terms of their influence and contribution to overall human health. My work focuses on attempting to understand the role RNA phages may play in maintaining a diverse microbiome.

It has long been suggested that within the human gut the abundance of phages carrying antibiotic resistance genes (ARGs) is quite high [1]. This was thought to contribute to the rise in AMR. However, recent studies have found that this data may be an over-representation of the true number of ARGs due to high levels of bacterial contamination in these samples [2, 1].The presence of these contaminants within viral datasets has impacted the findings of some studies and their associated conclusions.

Reports have also shown that the detection of ARGs released from phage particles is enhanced in the presence of antibiotics [3, 4]. This suggests that the improper administration of antibiotics can have detrimental effects, as it induces the uptake of phage-carried ARGs, resulting in an increase in AMR within the human gut.

Another fascinating aspect of this research is the hypothesis that the phageome can offer some degree of protection from disease. It should be noted that commentaries in Science have described the way in which phages “protect our health” and “keep us healthy” from external antagonists such as antibiotic resistant bacteria [5].This is an extremely interesting attribute as it may allow us to manipulate the phageome to prevent an AMR infection from arising or minimise the severity of the disease. Research has also revealed that multi-drug resistant (MDR) bacteria can revert back to antibiotic-sensitive in the presence of a phage which will allow for reduced AMR incidences and an expansion in the lifespan of antibiotics [6].

How can this research support the transition to a more sustainable future?

In an effort to transition into a more sustainable future, a more comprehensive view of the human gut phageome is essential. Given that the mismanagement of antibiotics is known to be responsible for a surge in AMR, the understanding of how antibiotic treatments could promote the integration of ARGs from phage to bacteria is crucial. It will also allow for an understanding of the impact phages have in human health and the protection they offer us from infection by antibiotic resistant bacteria. We could potentially engineer and harness the phageome to offer a degree of protection by identifying those that control pathogenic bacteria and those involved in protecting the gut flora, as discussed by Modi and colleagues [3]. We could also use phage in combination with antibiotics as an antibacterial to target MDR bacteria and make these antibiotic-susceptible again.

What is the future for research and innovation in this area?

The future of human gut phage research aims to deliver a comprehensive overview of phages that influence the human gut microbiome, including those with RNA genomes. This will have serious implications for understanding AMR, as it will allow us to assess the spread of ARGs within the human gut and the potential role that phage play in maintaining a healthy environment. This research is of particular importance, especially in times of antibiotic stress.

References

1.            Debroas D, Siguret C (2019) Viruses as key reservoirs of antibiotic resistance genes in the environment. The ISME Journal 13:2856–2867. https://doi.org/10.1038/s41396-019-0478-9

2.            Enault F, Briet A, Bouteille L, et al (2017) Phages rarely encode antibiotic resistance genes: a cautionary tale for virome analyses. The ISME Journal 11:237–247. https://doi.org/10.1038/ismej.2016.90

3.            Modi SR, Lee HH, Spina CS, Collins JJ (2013) Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature 499:219–222. https://doi.org/10.1038/nature12212

4.            Fernández-Orth D, Miró E, Brown-Jaque M, et al (2019) Faecal phageome of healthy individuals: presence of antibiotic resistance genes and variations caused by ciprofloxacin treatment. J Antimicrob Chemother 74:854–864. https://doi.org/10.1093/jac/dky540

5.            Guglielmi G (2017) Do bacteriophage guests protect human health? Science 358:982–983. https://doi.org/10.1126/science.358.6366.982

6.            Chan BK, Sistrom M, Wertz JE, et al (2016) Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Sci Rep 6:. https://doi.org/10.1038/srep26717

 About the author

Julie Callanan is a final year PhD student at the APC Microbiome Ireland SFI Research Centre, University College Cork, Ireland and a member of the Microbiology Society. Her work focuses on using bacteriophage, viruses that target bacteria, in terms of human health and how they can be utilised in a variety of ways, including in combating antimicrobial resistance amongst bacteria. She is also extremely interested in the concept of sustainability and would love to transition into this area after her PhD. More information about her work is available here.