Microbiota-Driven Intestinal Calprotectin Programs Neonatal Immunity Against Sepsis

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Summary of  Science Translational Medicine https://doi.org/10.1126/scitranslmed.adx6147 
Dr. Shikha Negi et al.

Points

Researchers investigated how initial commensal bacterial colonization in the newborn gut prepares the immature neonatal immune system to defend against life threatening systemic pathogen infections.
Experimental models demonstrated that healthy neonatal mice express high intestinal concentrations of calprotectin which is produced primarily by intestinal epithelial cells rather than immune white blood cells.
Commensal Lactobacillus species release the metabolite indole three lactic acid which activates aryl hydrocarbon receptors on gut lining cells to stimulate protective calprotectin expression.
Antibiotic exposure or genetic ablation of intestinal epithelial calprotectin severely impaired mucosal defense mechanisms and rendered neonatal mice highly susceptible to fatal bacterial sepsis.
Administration of recombinant calprotectin or probiotic metabolites successfully rescued microbiota depleted neonatal pups from infection while human intestinal organoids confirmed conserved signaling pathways.

Summary

This study evaluated the mechanisms by which early gut microbial colonization programs neonatal immunity against life-threatening infections. Published in Science Translational Medicine by an international research team, the investigation addressed why neonates exhibit heightened vulnerability to pathogens despite immature adaptive immune systems. Given that infections and birth complications account for approximately 40% of deaths in children under 5 years of age, the research sought to determine how commensal bacteria instruct intestinal mucosal defenses during early life.

Using murine models, intestinal epithelial-specific gene knockouts, and germ-free systems, researchers demonstrated that healthy newborns express high concentrations of the S100A8/S100A9 antimicrobial heterodimer calprotectin, produced primarily by intestinal epithelial cells rather than neutrophils. Initial colonization by commensal Lactobacillus species drives this epithelial defense program. Mechanistically, Lactobacillus-derived indole-3-lactic acid (ILA) activates the aryl hydrocarbon receptor (AhR) on intestinal epithelial cells, stimulating mucosal calprotectin up-regulation. Disrupting this axis via broad-spectrum antibiotics or genetic ablation of epithelial S100A9 severely impaired mucosal defense, rendering neonatal mice highly susceptible to systemic dissemination and fatal sepsis.

Conversely, oral administration of recombinant calprotectin, ILA, or probiotic bacteria successfully rescued microbiota-depleted neonatal pups from infection. Human intestinal organoid assays confirmed that infant stool, Lactobacillus, and ILA similarly induced calprotectin through the conserved AhR pathway. The authors conclude that microbiota-epithelial dynamics at birth are essential for programming early-life immunity, offering a promising therapeutic framework for probiotic and protein-based interventions to prevent neonatal sepsis in clinical practice.

Link to the article: https://www.science.org/doi/10.1126/scitranslmed.adx6147?referrer=https%3A%2F%2Fmedicalxpress.com%2F

References

Negi, S., Hashimoto-Hill, S., Waddell, A., Engleman, L., Lutz, M., Rice, T., Denson, L. A., Vallance, B. A., Azouz, N. P., Tessier, P. A., Grivennikov, S. I., Deshmukh, H., & Alenghat, T. (2026). Early-life microbiota direct an epithelial S100 program required for neonatal immunity. Science Translational Medicine, 18(870), eadx6147. https://doi.org/10.1126/scitranslmed.adx6147