Supplementation of S100a8 after birth protects against severe gastrointestinal infections and developing environmental enteropathy under malnutrition conditions

Protein-energy-malnutrition (PEM) remains a major health burden linked to 45% of global childhood mortality. Common medical complications are severe gastrointestinal infections and the development of environmental enteropathy (EE), a chronic inflammatory gut dysfunction that further aggravates malnutrition and sequelae related to stunting. Frequent uptake of pathogens and altered intestinal colonization are discussed as major contributors to EE, however, the crucial pathogenetic factors and the temporal resolution of the course of EE are still elusive. In this study, we used a murine model of parental PEM and show that early-life PEM without additional pathogen challenge is sufficient to induce chronic intestinal inflammation starting in the neonatal period, which predisposes the offspring to severe courses of enteric infections. Immunological hallmarks of this early-life PEM-associated enteropathy are an early influx of inflammatory myeloid cells, aberrant development of inflammatory instead of regulatory macrophages, and deficient postnatal expansion of regulatory T cells in the gut of malnourished compared to the well-nourished pups. This comes with an altered gut colonization including a premature expansion of pathobionts, especially Enterobacteriaceae, and a reduced abundance of commensal Clostridiaceae. Furthermore, we identify deficient S100a8/a9-priming of the neonatal gut as pathogenetic factor of PEM-associated EE. A single nutritional supply of S100a8 directly after birth abrogates the aberrant development of both gut mucosal immunity and microbiota colonization in malnourished pups and protects them sustainably against later inflammatory exacerbations during infectious as well as non-infectious bowl diseases. Our data suggest that nutritional S100a8 supplementation to neonates raised under malnutrition conditions is a promising, cost-efficient treatment to protect against the development of PEM-associated EE and therewith related lifelong health risks.