Early antibiotic exposure weakens infant immune development

A new study led by researchers at the University of Rochester Medical Center (URMC) found that early-life exposure to antibiotics can impair an infant's developing immune system, and that a naturally occurring metabolite may hold the key to reversing that damage. 

Published in Cell, the study uncovered how antibiotic exposure during pregnancy and infancy may permanently weaken the immune system's ability to fight respiratory infections like the flu. By analyzing both mouse models and human infant lung tissue, the researchers discovered that early antibiotics disrupt the gut microbiome's ability to produce inosine, a molecule that serves as an important signal for developing immune cells. 

By supplementing inosine in mice, however, the researchers were able to correct the immune system issues caused by antibiotics. The finding opens the door to potential therapeutic strategies to bolster immune memory in vulnerable infants. 

Think of inosine as a molecular messenger. It travels from the gut to developing immune cells, telling them how to mature properly and prepare for future infections."

Hitesh Deshmukh, MD, PhD, senior author, chief of the Division of Neonatology at UR Medicine Golisano Children's Hospital (GCH) 

The project was part of a long-term R35-funded NIH initiative - which are distributed to experienced investigators to study long-term projects - to investigate how early-life exposures shape lifelong disease risk, including asthma and chronic lung disease.

"We know that antibiotics can be lifesaving for infants, but they also disrupt the microbiome during a critical window of immune development," said Deshmukh. "Our study identifies one way that disruption affects lung immunity, and more importantly, a way to potentially fix it." 

The disruption ultimately affects the formation of tissue-resident memory T cells, a specialized population of immune cells that reside in the lungs and provide long-term protection against viral infections. Without these cells, infants may remain vulnerable to severe respiratory illness well into adulthood. 

"We've discovered that the gut microbiome acts as a teacher for the developing immune system," Deshmukh explained. "When antibiotics disrupt this natural education process, it's like removing key chapters from a textbook: the immune system never learns crucial lessons about fighting respiratory infections." 

The study compared infant mice exposed to common antibiotics (ampicillin, gentamicin, and vancomycin-the same ones frequently used in pregnant women and newborns) with those that maintained their natural gut bacteria. The following differences were found: 

• Antibiotic-exposed infant mice had significantly reduced populations of protective CD8+ T cells in their lungs 

• These mice showed impaired ability to form tissue-resident memory cells, specialized immune cells that live in the lungs and provide rapid protection against reinfection 

• The immune deficits persisted into adulthood, suggesting permanent changes to immune development 

Using lung samples from an NIH-funded biobank run by URMC (BRINDL biobank), the team confirmed that similar immune deficits were present in human infants exposed to antibiotics. These infants not only showed fewer memory T cells but also demonstrated gene expression patterns similar to older adults, who are also at greater risk for respiratory infections. 

Most importantly, supplementing antibiotic-exposed mice with inosine largely restored their ability to develop functional memory T cells and mount effective immune responses, offering a promising future avenue for potential therapies. 

"This suggests we might be able to protect at-risk infants through targeted supplementation," said Deshmukh. "While much more research is needed before this approach could be applied clinically, it gives us a path forward." 

The findings could influence future research on how to design interventions-including dietary supplements, metabolite therapies, or microbiome-supportive strategies-to help newborns develop stronger immune memory without relying solely on antibiotics or risky probiotics. The study also underscores the importance of balancing the life-saving benefits of antibiotics with careful stewardship, particularly during sensitive windows of immune development. 

Deshmukh credits GCH neonatologist Gloria Pryhuber, MD, as instrumental in the research. Pryhuber's BRINDL biobank of infant lung samples, collected through a 15-year NIH-funded effort, allowed the team to test their findings in human cells. 

"This paper wouldn't have been possible without Dr. Pryhuber's generosity and expertise," Deshmukh said. "The ability to compare our mouse model results to human cells was absolutely critical. It was one of the main reasons I came to Rochester (from Cincinnati Children's Hospital) -to collaborate with her."