The immune systems of newborns are incredibly different from adults, however, the mechanisms that enable early-life immunity remain poorly understood. Because infection is a leading cause of neonatal morbidity and mortality, and infants are particularly vulnerable, understanding the immune mechanisms in early life is of the utmost importance. In addition, despite recognition that acquisition of the microbiota alters early host defense, there is limited understanding of the commensal-induced mechanisms that play a role in the neonate.

Now, a new study shows that the antimicrobial protein calprotectin, found in high concentrations in the guts of newborn mice, is expressed by intestinal epithelial cells in response to commensal bacteria colonizing the gut. More specifically, the healthy newborn mice “express high concentrations of the S100 calcium-binding protein A8/A9 antimicrobial heterodimer calprotectin” and that this early up-regulation in the intestine is driven by initial exposure to commensal bacteria.

They also found that newborn mice with impaired calprotectin expression or poor microbiota colonization were more susceptible to sepsis and death post-infection. However, when the mice were given calprotectin, it rescued the microbiota-depleted pups from infection.

This work is published in Science Translational Medicine in the paper, “Early-life microbiota direct an epithelial S100 program required for neonatal immunity.”

The main source of calprotectin in the neonatal intestine was found to be microbiota colonization induced S100A9 expression by intestinal epithelial cells (IECs) and epithelial cells. And neonatal IEC-specific S100A9 knockout pups were highly susceptible to infection.

The study also sheds light on the specific mechanisms that provide early-life immunity against potentially deadly pathogens such as Staphylococcus aureus, Listeria monocytogenes, and Streptococcus pneumoniae, at a crucial time when newborns lack other immune defenses.

In mice and in human intestinal organoids, the researchers demonstrated that commensal microbes such as Lactobacillus produce the metabolite indole-3-lactic acid (ILA), which activates signaling in neonatal epithelial cells to increase the production of intestinal calprotectin.

Together, these findings suggest that microbiota-epithelial dynamics at birth can help program early-life immunity, the researchers write, with potential implications for probiotic approaches that target epithelial cells to prevent neonatal sepsis. This result, plus the authors’ finding that calprotectin is present in the guts of human newborns less than two days old (but not in seven-year-old infants), suggests a similar early-life immune mechanism may be at play in humans.