Bacteriophages (or phages) are viruses that selectively target and kill bacteria. They are abundant, commonly occurring natural entities that play crucial roles in regulating bacterial populations and influencing microbial ecosystems.

Structurally, they consist of a nucleic acid genome – either DNA or RNA – encased within a protective protein capsid. Unlike free-living organisms, phages rely entirely on their bacterial hosts for replication.

Upon infection, a phage hijacks the bacterium’s cellular machinery, redirecting it from normal bacterial functions to producing viral components. This process ultimately leads to the assembly of new phage particles, which can either be released through bacterial lysis or persist within the host cell, depending on the phage’s life cycle.

Phages are useful as they can destroy bacteria resistant to drugs such as antibiotics. They infect their bacterial hosts with great specificity and do not infect human cells. Currently, phages are primarily used on compassionate grounds, in life-threatening situations, when all other treatments have been exhausted. Further evidence from clinical studies is needed before phages can become widely available for human use.

Phage infection strategies

Bacteriophages follow two primary infection strategies: the lytic and temperate (lysogenic) cycles.

Strictly lytic phages infect their host cell and cause it to burst, thus killing the bacterium. Temperate phages don't kill bacteria outright – they integrate their genome into the host cell. The phage may eventually lyse the cell, but this does little to immediately prevent bacterial infection and may contribute to the spread of antimicrobial resistance and other virulence genes due to the potential harboring of antimicrobial resistance or toxin genes. As such, it is critical to ensure strictly lytic phages are used for phage therapies.

The underexplored role of phages in human health

Bacteriophages play a significant role in shaping microbial ecosystems, including the human gut microbiota. The gut microbiota refers to the dynamic and complex community of microorganisms residing in the gastrointestinal tract, influencing digestion, metabolism, immune responses and overall health.

Phages constantly interact with their bacterial hosts, shaping microbial populations through predation, horizontal gene transfer and modulation of bacterial virulence. These interactions have profound implications for human health, particularly in the context of gut-related diseases. Understanding the role of phages in regulating gut microbiota composition and function could unlock novel strategies for controlling bacterial infections and restoring microbial equilibrium in disease states.

Disruptions to gut microbiota balance – known as dysbiosis – have been linked to a variety of health conditions, including inflammatory bowel disease (IBD), metabolic disorders and cardiovascular diseases. For example, IBD – such as Crohn’s disease and ulcerative colitis – often results from an immune response to dysbiosis, leading to an increase in potentially pathogenic bacteria (e.g., Pseudomonadota and Enterobacteriaceae) and a decrease in beneficial bacteria (e.g., Lactobacillaceae and Bifidobacteria).

Beyond gut health, the microbiota exerts systemic effects on metabolic and neurological functions. Accumulating evidence suggests that gut microbial metabolites influence insulin sensitivity and subsequent development of type 2 diabetes, and play an important role in brain and central nervous system functions, which regulate gastrointestinal physiology and emotional behaviors. The gut microbiota is also implicated in cardiovascular health, with studies linking dysbiosis to increased blood pressure – a major risk factor for heart disease.

Despite growing interest in phage–bacteria interactions and their relevance to human health, our understanding remains fragmented and the current literature lacks comprehensive synthesis. A deeper understanding of these interactions may lead to innovative therapeutic applications, such as phage therapy for gut-implicated bacterial diseases, precision microbiome modulation and novel strategies to restore microbial balance in dysbiosis-related disorders.

Do phages increase type 1 diabetes risk?

While the role of bacteria in the gut microbiome has been extensively studied, the contribution of viruses – particularly phages – to the gut microbiome remains less understood. However, a recent study published in Nature Microbiology is  revealing how these viral entities may shape microbiome dynamics and, potentially, human disease.

Given that phages regulate bacterial populations and some carry genes encoding virulence factors and toxins, their potential impact on human health is plausible. Researchers at Baylor College of Medicine investigated whether certain phages contribute to the development of type 1 diabetes (T1D) in young children, to determine whether phages play a role in the early-life microbial changes associated with T1D onset.

The team revisited data from The Environmental Determinants of Diabetes in the Young (TEDDY) study, which follows children genetically predisposed to developing immune responses against insulin-producing cells, potentially leading to T1D. Previous research from TEDDY studies examined the influence of gut bacteria and human viruses on disease development, establishing an association with human viruses but finding no definitive link to gut bacterial composition. While phage genetic data has been available, its extreme diversity and lack of clear evolutionary patterns have made systematic analysis challenging.

To overcome these hurdles, the researchers employed a novel analytical approach to examine the interplay between phages and bacteria. "Using our new analytical tool, we analyzed 12,262 stool samples from 887 TEDDY participants during their first four years of life," said Dr. Sara Javornik Cregeen, assistant professor of molecular virology and microbiology at Baylor. "This allowed us to track dynamic shifts in phage and bacterial communities and gain new insights into their interactions."

Their findings revealed that specific bacterial species thrive at different stages of early childhood, a pattern also observed among phages. However, phage communities exhibited more rapid change than their bacterial counterparts, suggesting a dynamic and responsive viral ecosystem.

“We think this points to an arms race between bacteria and their phages in which the bacteria evolve acquiring mutations that allow them to escape predation from the phages that were infecting them, and then that opens up an opportunity for a new phage to infect the bacteria,” said Dr. Michael Tisza, assistant professor of molecular virology and microbiology at Baylor.

Despite these insights, the study did not identify any dominant phages or phage communities significantly associated with an increased or decreased risk of developing T1D. However, the findings contribute to a broader understanding of microbiome development and the intricate interplay between bacteria and their viral predators.

While the study did not establish a direct link between phages and T1D, it underscores the importance of considering bacteriophage dynamics in future microbiome research. Understanding how phages shape bacterial populations and interact with the host immune system could provide new perspectives on disease mechanisms and potential therapeutic interventions.

“Manipulation of the microbiome continues to be a promising path to treat a variety of diseases that involve the immune response, cardiovascular health and brain function, among others,” said Dr. Joseph Petrosino, chair and professor of molecular virology and microbiology and director of the Center for Metagenomics and Microbiome Research at Baylor.

“As clinicians try to limit unnecessary antibiotic use as a primary means to combat the rise of antibiotic-resistant infections, studies such as this enable phage-based strategies to shape microbial communities to improve health and fight infectious diseases,” Petrosino concluded.