Gut bacteria are central to human health. They are a key player in contributing to immune regulation, pathogen protection, food and drug metabolism, and vitamin synthesis. Another supporting actor in the gut, however, are bacteriophages or short phages. Despite of their extremely high abundance they have been relatively unexplored.
Researchers expect that phages play essential roles in maintaining the gut homeostasis via regulating the complex microbial networks in this habitat – so do Li Deng and Mohammadali Khan Mirzaei from the Institute of Virology at Helmholtz Zentrum München who have dedicated a great part of their research on phages. Improving our understanding of how phages regulate microbial networks in the human body might pave the way for the development of novel phage-based therapeutics. These could be used for re-establishing of health in diseases associated with gut dysbiosis or treating complicated infections by multi-resistant bacteria – a growing threat to health worldwide.
In a short interview, Li and Mohammadali give insight into the latest developments of their research.
Why should we learn more about gut phages?
Li: Phages are viruses which use bacteria as their hosts. They are probably the most abundant, most diverse, and most undescribed members of every ecosystem. The human gut is not an exception. In the environment, phages play a significant role by shaping the microbial diversity and abundance, even reprogramming the bacterial metabolism. We gain more and more evidence that phages play a similar role in the human body. Also, as phages can infect and eradicate host bacteria, they have attracted a lot of attention for therapeutic applications.
You had developed a novel technology to identify host-phage relationships called ‘viral tagging’. What is it about?
Li: Viral tagging is a high-throughput culture-free method to study phage-bacteria interactions on a single-cell level. It is a very complex technology but it allows us to distinguish the bacteria and the attached phages from non-infected cells and phages.
What did you discover using viral tagging?
Li: We discovered 363 unique bacteria-phage pairings in the human gut – most of them were novel gut phages infecting known bacterial hosts. Together with Phil Hugenholtz’s group at the Australian Centre for Ecogenomics we found that the majority of the bacterial hosts are targeted by more than one phage. This reveals how complex bacteria-phage interactions in the human gut are! What is also interesting, is that we found infection patterns of previously unknown phages which infect bacteria producing butyrate, a preferred energy sources for epithelial cells. A lack of those specific bacteria has been previously correlated with multiple diseases including type 2 diabetes.
Phages might become an efficient tool to treat multiple diseases by manipulating the human microbiota. Can you explain more?
Mohommadali: That is correct. One example we had a closer look at is stunting disease. Stunting is a severe growth impairment. It affects 22 per cent of children under the age of 5 years, mostly in countries where kids do not have regular access to nutrient-rich or nutrient-balanced foods. We already knew that there is a correlation between an alteration in the gut microbiota and stunting. However, despite these links, the role of phages in stunting was not explored yet. In a multi-institutional collaboration led by Corinne Maurice at McGill University Canada we found that stunted children actually showed distinct gut phages compared to non-stunted ones. In vitro, we saw that these specific phages can regulate abundance and composition of bacteria associated with stunting. This is why we expect a role of phages in the pathophysiology of child stunting. Also, we observed different bacteria-phage interactions in dependent on the age of the child. It will be crucial to learn more about these interactions and age-specific effects. Ultimately, our goal is to refine an intervention window for a potential phage-based treatment for stunting in the future.
According to you, what are the next essential steps in phage research?
Li: There is a lot we still don't know about phages, most of all their interactions with their bacterial hosts in the clinical context. With the advances in single-cell technologies and by joining forces with clinicians, we expect to get closer in understanding the complex phage-hosts interactions in near future. This is central to the success of personalized, phage-based therapeutics. It might help us to intervene the complex bacterial ecosystem in case of disease and engineer the microbiome to become a healthier one. Also, phages might be the key to treat antibiotic-resistant bacterial infections.