Early antibiotic exposure disrupts infant immune memory, study shows

Early antibiotic exposure disrupts infant immune memory, study shows | Image Credit: © Anatta_Tan - stock.adobe.com.

Early-life exposure to antibiotics can impair the development of the immune system in infants by disrupting gut microbiota–driven signaling, according to a study published in Cell by researchers at the University of Rochester Medical Center (URMC). The study also identifies inosine, a naturally occurring gut metabolite, as a potential therapeutic target to reverse antibiotic-induced immune dysfunction.^1,2

The investigation demonstrated that antibiotic-induced alterations in the gut microbiome reduced the production of inosine, a purine metabolite involved in immune cell development. In both infant mice and human lung tissue samples, the researchers found that early antibiotic exposure led to long-term impairment in the formation of influenza-specific CD8+ T cells and tissue-resident memory T cells, which are critical for durable respiratory viral immunity.

“Think of inosine as a molecular messenger,” said Hitesh Deshmukh, MD, PhD, senior author and chief of the Division of Neonatology at UR Medicine Golisano Children’s Hospital. “It travels from the gut to developing immune cells, telling them how to mature properly and prepare for future infections.”

The study focused on how perinatal antibiotics—specifically ampicillin, gentamicin, and vancomycin—commonly administered during pregnancy and the neonatal period, affect early immune development. Infant mice exposed to these antibiotics demonstrated significant reductions in CD8+ T cells in lung tissue, diminished TRM cell formation, and sustained defects in influenza-specific immune responses. These changes persisted into adulthood, suggesting permanent immunological alterations.

Using lung samples from the NIH-funded Biobank for Research in Neonatal Development and Lung Disease (BRINDL), the research team also observed immune impairments in human infants exposed to antibiotics. These infants had fewer TRM cells and exhibited gene expression profiles resembling those of older adults, who also exhibit increased susceptibility to respiratory infections.

Mechanistically, the authors found that dysbiosis caused by antibiotics suppressed intestinal and circulating inosine levels. Inosine is essential for epigenetic regulation of T cell development via nuclear factor interleukin 3 (NFIL3), which modulates the expression of T cell factor 1 (TCF1). Loss of inosine signaling was shown to disrupt CD8+ T cell differentiation and proliferation, leading to weaker antiviral responses.

To determine whether inosine could mitigate these effects, the researchers administered inosine to dysbiotic mice. Inosine supplementation restored NFIL3-dependent regulation of TCF1 expression, improved the formation of functional CD8+ T cells, and enhanced protection against influenza infection. The same restoration was achieved via colonization with Bifidobacterium, which elevated inosine levels in the gut and lungs.

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

The findings support the idea that the gut microbiome acts as a critical educator for the developing immune system. “We’ve discovered that the gut microbiome acts as a teacher for the developing immune system,” Deshmukh said. “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 research was part of a long-term NIH-funded R35 project aimed at understanding how early-life exposures shape disease susceptibility. Gloria Pryhuber, MD, a neonatologist at URMC, contributed infant lung samples through the BRINDL biobank, enabling human validation of findings first identified in mouse models. “This paper wouldn’t have been possible without Dr. Pryhuber’s generosity and expertise,” Deshmukh noted. “The ability to compare our mouse model results to human cells was absolutely critical.”

The study has implications for future strategies to enhance immune development in infants, particularly those at high risk of infection. Potential interventions could include dietary supplementation with inosine or other microbiota-derived metabolites. The authors emphasize the importance of balancing the clinical necessity of antibiotics with their long-term impact on immune programming during critical developmental windows.

References:

1. Stevens J, Culberson E, Kinder J, et al. Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns. Cell. Published online June 9, 2025. doi:https://doi.org/10.1016/j.cell.2025.05.013
2. University of Rochester Medical Center. Early antibiotics alter immune function in infants. EurekAlert. July 14, 2025. Accessed July 15, 2025. https://www.eurekalert.org/news-releases/1090939

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