Researchers have discovered that the composition of gut bacteriophages – the viruses that infect gut bacteria – influence an infant’s risk of developing asthma. A researcher says that administering a combination of bacteriophages to infants in the future may minimise their risk of developing asthma.
Many of the microbes that live in the gut are important for health. For example, having too many or too few of a specific type of bacteria can affect the risk of developing metabolic disorders and conditions such as type 2 diabetes and obesity or immune disorders such as asthma and allergies.
Now a new study shows that the bacteriophages inhabiting the gut are an additional factor influencing the risk of developing various diseases and disorders.
The research shows that the composition of bacteriophages in the gut of infants aged one year affects their risk of developing asthma by the age of five years.
Further, the study shows that these bacteriophages do not affect the risk of asthma exclusively by attacking gut bacteria but also do this by directly interacting with the immune system.
“Our findings are the first of their kind and may in the future, after additional research, have implications for our ability to alter the risk of developing asthma. One can hope that, we in the future, we might be able to give very young children a cocktail of specific viruses, depending on whether they lack these and thereby reduce their risk of developing asthma. Another perspective is that learning more about the mechanisms bacteriophages use to influence the risk of developing asthma could also show how to influence the risk of disease in other ways,” explains a researcher behind the study, Jakob Stokholm, Associate Professor, Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, Denmark.
The research, which was based on the COPSAC 2010 cohort and carried out in collaboration with Dennis S Nielsen’ group at the Department of Food Science at the University of Copenhagen, was spearheaded by Cristina Leal Rodriguez and Shiraz Shah and has been published in Nature Medicine.
The gut is alive
The gut is teeming with life that affects health with about 125 strains of bacteria and up to 1,200 strains of viruses in a healthy person’s gut.
Many other microbes, including fungi, also inhabit the gut, and the gut microbiota varies greatly between people.
The researchers previously investigated the asthma associations of having a mature versus immature composition of gut bacteria in early life. They therefore wanted to investigate whether gut bacteriophages also have the same associations with health, including specifically the risk of developing asthma.
The researchers examined faecal samples from 700 children from the COPSAC 2010 cohort, which are among the most thoroughly studied children regarding health in the world.
The researchers studied the composition of viruses in the infant’s gut at the age of one year and linked this with whether they had developed asthma by the age of five years.
To determine the composition of viruses, the researchers filtered the combined viral DNA from the faecal samples, sequenced it and then assembled it into viral genomes to identify the individual virus families.
19 virus families are associated with asthma risk
Each infant had about 1,200 strains of viruses in their gut. The vast majority were unknown, and the researchers have named 230 new families of viruses so far based on the names of children in the COPSAC 2010 cohort.
Jakob Stokholm explains that 90% of the identified virus strains are bacteriophages, which only attack bacteria and not humans, and therefore affect the composition of gut bacteria.
Further investigation revealed that 19 families of viruses were associated with the risk of developing asthma.
If infants had none or very few of these virus families in their gut at the age of one year, they had a higher risk of developing asthma by age five years.
The researchers previously found for the same children that the composition of gut bacteria is associated with the risk of developing asthma, but they found that the composition of bacteriophages in the gut also appeared to be associated with the risk of developing asthma, independently of the gut bacteria.
“This was very surprising. One could understand if the composition of bacteriophages in the gut alone affects the composition of bacteria and thereby influence the risk of developing asthma. But we found that the composition of bacteriophages itself also seemed to be associated with the risk of developing asthma, which did not immediately make sense,” says Jakob Stokholm.
Receptor may link bacteriophages and asthma risk
In the next part of the project, the researchers searched the literature for a possible explanation of how bacteriophages can affect people’s health and the risk of developing asthma.
They found a study that had investigated the human toll-like receptor (TLR9), which can recognise and bind to viral DNA. That study had shown that bacteriophages can selectively activate TLR9 and thereby initiate an immune response independent of the presence of bacteria.
In the new study, the researchers therefore examined the DNA of the 700 children for genetic variants related to TLR9. They found that the infants could have three variants of the gene related to TLR9 and that only two were associated with an increased risk of developing asthma if the children lacked the 19 virus families in their gut.
“This may explain why the presence of the identified virus families in the gut can be associated with the risk of developing asthma. The results could suggest that infants who have many of these virus families in their gut are likely to train their immune system in a beneficial direction through interactions between bacteriophages and TLR9. This of course needs to be investigated further in future studies,” notes Jakob Stokholm.
The environment affects the composition of gut viruses
In a final twist, the researchers also investigated what can shift the composition of gut viruses to affect the risk of developing asthma.
This showed that having older siblings in the home is associated with a healthier composition of gut viruses and thus less risk of developing asthma. Infants born in the summer versus winter also had a more protective composition of gut viruses.
All these discoveries have now made the researchers more aware of how gut viruses can potentially affect the risk of developing asthma. The researchers are therefore now trying to figure out how to change this.
“An interesting idea is reducing an infant’s risk of developing asthma by ensuring an appropriate composition of gut bacteria and viruses very early in life. Children could perhaps in the future be examined for the presence or absence of the virus families we identified, and children severely deficient in these viruses could perhaps receive a cocktail of these for asthma prevention,” concludes Jakob Stokholm.
He elaborates that this kind of experiment cannot yet involve infants. However, researchers can start with follow-up studies of possible mechanisms in cell and animal models and thereby also learn more about how the composition of gut viruses affects health.
