Research Highlights

Early Antibiotic Exposure Weakens Infant Lung Immunity

Published in Cell, 2025

Antibiotics given to pregnant women or newborns can disrupt beneficial gut bacteria—leaving infants more vulnerable to respiratory infections like influenza. Our research traced this vulnerability to a specific molecular pathway: antibiotic exposure depletes Bifidobacterium species in the gut, which in turn reduces production of inosine, a critical microbial metabolite. Inosine plays a key role in programming lung-resident immune cells that protect against viral infections.

This work offers a mechanistic foundation for rethinking how we protect newborns from respiratory disease—from the NICU to the pediatrician’s office.”
~ Hitesh Deshmukh, M.D., Ph.D.

Using neonatal mouse models and human infant lung tissue samples, we found that this microbial-immune disconnect leads to:

• Fewer effective innate and adaptive immune cells in the lungs
• Impaired formation of long-term immune memory
• Increased susceptibility to respiratory viruses

Importantly, we demonstrated that supplementing with inosine or restoring beneficial gut bacteria can reverse these defects—opening new therapeutic avenues to protect high-risk newborns.

This study reframes the notion of the infant immune system as merely “immature.” Instead, it shows that early-life immunity is actively sculpted by microbial signals during a narrow developmental window.

Led by Joseph "Jake" Stevens, a physician-scientist in training, this project was supported by the NIH F30 program and the prestigious Albert Ryan Fellowship. Jake also received the Albert B. Sabin Fellowship for excellence in infectious disease research.

Microbiota-Immune-Epithelial Cross-Talk in Viral Lung Injury

We are dissecting how perinatal antibiotic (ABX) exposure disrupts lung regeneration by impairing the communication between intestinal microbiota and alveolar epithelial cells. This project focuses on:

• NFIL3, a transcription factor that integrates microbial signals with epithelial circadian and inflammatory responses
• Lineage-traced mouse models and iPSC-derived alveolar organoids
• Mechanistic studies showing that loss of NFIL3 leads to accumulation of dysfunctional progenitor cells (DATPs), impaired AT2→AT1 differentiation, and prolonged lung injury

Epigenetic Remodeling of Lung Repair Programs

This project investigates how ABX exposure alters epigenomic landscapes in alveolar epithelial cells:

• NFIL3–C/EBPα competition for chromatin binding sites in AT2 cells
• CUT&RUN, ChIP-seq, and metabolic flux assays in murine and human iPSC systems
• Exploring transcriptional remodeling of inflammatory and repair programs, including metabolic pathways and AT2 identity gene networks (e.g., Abca3)

Treg Cells and Microbiota-Driven Lung Regeneration

We are defining how regulatory T cells (Tregs) support alveolar epithelial repair after influenza-induced injury:

• AT2–Treg interactions via IL-33 (AT2-derived) and AREG (Treg-derived)
• Adoptive transfer and depletion models (Foxp3EGFP/DTR mice)
• Demonstrating that ABX-exposed Tregs exhibit exhausted phenotypes and diminished pro-repair capacity

Epigenetic Programming of Treg Function in Early Life

This work aims to reverse ABX-induced dysfunction in Tregs via:

• Genome-wide bisulfite sequencing and RNA-seq of Treg cells
• DNA demethylation strategies (e.g., decitabine) to restore FOXP3 stability and suppressive function
• Evaluating CRISPR-edited Treg and alveolar co-cultures to test methylation-dependent mechanisms