In our team, we study human gut viruses, with a particular focus on those infecting bacteria (phages). A substantial majority of gut bacteria harbor phages in their genomes (prophages). These phages can be activated (induced), through mechanisms not yet fully understood, and have the strong potential to shape the gut microbiota. A primary focus of our team is to unravel how diet influences the composition of phages in the gut. To achieve this, we utilize metagenomics on samples from various cohorts, including the French gut, and conduct systematic analyses using bioreactors. The team’s core objectives include identifying metabolites and responsive phages that positively impact a healthy gut microbiota, while also understanding the underlying mechanisms for potential use as pre- and probiotics.
A balanced and diverse gut microbiota is associated with good health, while dysbiosis, (imbalance), is linked to severe diseases such as inflammatory bowel diseases (IBD), diabetes, and arterial stiffness. Gut viruses, collectively referred as the gut virome, are emerging as significant factors influencing health and disease with potential therapeutic applications. The gut virome includes eukaryotic viruses (1-2%) and phages (ca. 98%). Phages follow different life cycles, including the lytic cycle, where they infect, replicate, and lyse the host cell, and the lysogenic cycle, where they integrate the bacterial genome as (mostly dormant) prophages. These prophages can be triggered through various ways (induction) causing a switch to lytic cycle and ultimately get released with host lysis. Nearly 80% of gut bacteria are lysogens, i.e. they encode one or more phages in their genomes.
Temperate phages play a significant role in modulating host numbers through the abovementioned infection and induction processes, making them a compelling focus in gut microbiome research. The composition of the gut virome is unique to each individual and broadly stable over years in healthy adults. However, variations within the gut virome (as reported for the full microbiome) have been linked to diseases such as IBD, diabetes, obesity, and liver disorders. We believe that temperate phages drive variations in the gut microbiota and are key players in the bacterio-phage-host interactions.
To study the impact of temperate phages on the human gut microbiota, we apply metagenomics on in-vivo samples gained from diverse cohorts and systematically investigate their influence using in-vitro cultivation systems.
In metagenomics, various methods are employed to study the virome, including sequencing of whole microbial DNA and of viral fractions (samples in which viral-like particles (VLPs) were purified). Each method has its advantages and drawbacks. While bulk sequencing approaches primarily yield signals derived from bacterial genomes (such as prophages), DNA obtained from VLPs is assigned mostly to active viral particles. Therefore, combining these methods offers the most comprehensive depiction of the virome landscape, facilitating insights into the active and dormant states of temperate phages.
In our team, we are applying these two methods on samples from controlled bioreactor experiments or from specific cohorts having different diets. By systematically comparing the viral signals, we aim to understand when and why temperate viruses are induced or remain silent in the bacterial genome (Figure 2).
Assessing the diversity of a microbiome is crucial for pinpointing its key players and unraveling their functional roles. Given the significant influence of food on gut diversity, it’s essential to recognize that the composition of our diet shapes microbial gut populations. However, the impact of food and gut viruses on the gut microbiome remains poorly understood. To better understand these interactions, it is imperative to classify the various types of phages present in the gut (double-stranded vs. single-stranded DNA, virulent vs. temperate, generalist vs. specialist), to spot the abundant ones, and, at the same time, to not neglect rare species with the potential to disrupt the system. However, the vast diversity of phages imposes a significant challenge in comprehensively assessing their types and abundances, especially given the high prevalence of poorly studied cases (often referred to as “viral dark matter”). Over recent years, a steady stream of new tools has emerged on an almost monthly basis to address this knowledge gap. Many of these tools benefit from large-scale sequencing projects and cutting-edge technologies based on artificial intelligence.
A further important point within our team’s scope is the establishment and maintenance of a comprehensive gut virome database. This catalog will be created by integrating the latest, public gut virome databases to a unified one, employing state-of-the art tools to classify the viral genomes, and update the unified database by adding newly identified viral species from experimental set-ups (Figure 3). Moreover, recognizing the integral role of food in driving gut diversity, our research will extend beyond the gut to encompass the viromes in food-related environments, ensuring a comprehensive understanding of viral diversity across relevant ecosystems.
All the team publications are available in the NUTRIPHAGE-MICALIS HAL collection
