Maternal malnutrition induces in the neonate a lifelong enteropathy avoidable by postnatal S100a8/a9-conditioning

Abstract

Protein-energy-malnutrition (PEM) is linked to 45% of global childhood mortality, however, the impact of maternal PEM on the child’s health remains elusive. Previous studies suggested that maternal PEM does not affect breast milk composition. Yet, malnourished children often develop a so-called environmental enteropathy that is assumed to be triggered by frequent uptake of pathogens together with unfavorable gut colonization. Here, we show in a murine model that maternal PEM induces without additional pathogen challenge in the offspring a persistent intestinal inflammatory gut dysfunction that establishes during nursing and does not recover after weaning onto standard diet. Early intestinal influx of neutrophils, impaired postnatal development of gut-regulatory functions, and expansion of Enterobacteriaceae were hallmarks of the maternal PEM-mediated enteropathy. This resembled the gut phenotype developing upon deficient S100a8/a9-supply via breast milk and allowed revealing a lack of S100a8/A9 in the breast milk of malnourished mothers and consequently the offspring’s intestine. Nutritional supply of S100a8 to neonates of malnourished mothers abrogated the aberrant development of gut mucosal immunity and microbiota colonization and protected them lifelong against severe enteric infections and non-infectious bowel diseases. S100a8 supplementation after birth might be a promising measure to counteract deleterious imprinting of gut immunity by maternal PEM.