Early-life microbiota direct an epithelial S100 program required for neonatal immunity

Despite appreciation that neonatal immune responses differ markedly from those of adults, the mechanisms that enable early-life immunity remain poorly understood. Here, we find that healthy newborn mice express high concentrations of the S100 calcium-binding protein A8/A9 (S100A8/S100A9) antimicrobial heterodimer calprotectin and that this early up-regulation in the intestine is driven by initial exposure to commensal bacteria. Impaired calprotectin expression or microbiota colonization at birth increased susceptibility of neonatal mice to sepsis and death postinfection; however, calprotectin administration rescued microbiota-depleted pups from infection. Microbiota colonization induced S100A9 expression by intestinal epithelial cells (IECs), and epithelial cells represented the main source of calprotectin in the neonatal intestine. Consistent with a critical role in early-life defense, neonatal IEC-specific S100A9 knockout pups were highly susceptible to infection, phenocopying S100A8/A9 full knockout and antibiotic-exposed neonatal mice. IEC-intrinsic S100A9 expression mediated microbiota-sensitive defense in neonatal mice, and commensal bacteria, such as Lactobacillus, were sufficient to prime this epithelial defense pathway. Mechanistically, indole-3-lactic acid produced by initial colonizers directed IEC intrinsic up-regulation of S100A9 in both mice and human intestinal organoids. Thus, microbiota-epithelial dynamics that occur at birth are essential for programming early-life immunity and suggest that probiotic approaches targeting epithelial cells could prevent neonatal sepsis and death.