Infancy is a critical time when the immune system is learning to fight infections, especially in the lungs. Now, a new study shows that antibiotic exposure in early life disrupts gut microbes, impairing the development and function of lung-protective immune cells. However, this damage can be partially reversed by the microbial metabolite inosine.

The findings, published in Cell, suggest that bacterial metabolites could be used as a therapy to strengthen infant immunity after early microbiota disruption.

“Our results challenge current views of infancy as a window of susceptibility and reimagine it as an opportunity to improve pulmonary health and disease burden throughout childhood,” the researchers say.

During infancy, the gut develops diverse microbial communities that help shape the immune system, including key immune cells. However, antibiotic use in infants can disrupt these microbes, increasing the risk of serious lung infections and long-term health issues. Restoring this balance is difficult—treatments such as fecal microbiota transplants show promise but are risky for infants.

Joseph Stevens at the University of Cincinnati College of Medicine in Ohio and his colleagues investigated how antibiotic use affects immune development in early life, both in mice and humans.

Immune problems

First, the researchers gave pregnant mice common antibiotics and found that this disrupted the natural transfer of beneficial gut bacteria from mothers to their pups. As a result, the infant mice had less diverse gut microbiotas and fewer helpful bacteria. 

When these pups were infected with the flu virus, they had lower levels of specific immune cells called CD8+ T cells, more lung damage, and higher death rates than mice born to mothers that didn’t get antibiotics. These negative effects lasted into adulthood, and they were partly due to problems with CD8+ T cells, which didn’t multiply or function as well. Proteins that typically guide T cell development and function, such as NFIL3, were abnormally regulated in mice with an altered microbiota.

Next, the team engineered mice to lack NFIL3 specifically in their CD8+ T cells. These mice had normal early immune cell development but showed problems in their lungs after flu infection. Without NFIL3, T cells didn’t multiply well, matured slowly, and produced less virus-fighting molecules. 

Boosting immunity

Human infants who had been exposed to antibiotics had fewer specialized lung-resident CD8+ T cells compared to those who hadn’t, the researchers also found. These T cells were less able to multiply and respond effectively to infection, similar to what was seen in mice with disrupted gut bacteria. 

Babies who had been exposed to antibiotics also had lower levels of helpful bacteria such as Bifidobacterium, which produces a molecule called inosine. Inosine appeared to boost the growth and function of CD8+ T cells by increasing NFIL3 and reducing other proteins that block T cell development. 

Treating mice that had been exposed to antibiotics with inosine improved their immune response to flu. These results, the authors say, highlight inosine’s role in restoring healthy immune function when gut bacteria are disrupted early in life.