S100-Alarmins are Crucial Host Factors for the Postnatal Development of Gut Homeostasis

SummaryAfter birth, the immune system experiences considerable reprogramming by interacting with the colonizing microbiota. Host factors involved in this relationship are largely unknown. Our studies in two infant cohorts and newborn mice reveal that abundant enteral S100A8/A9 trains the inflammatory and regulatory phenotype of colonic lamina propria macrophages. Neonatal S100A8/A9-alarmin deficiency results in an impaired expression of Cx3cr1, Il-10 and Tgf-β, reduced expansion of regulatory T cells, and dominant gut colonization with aerobes and facultative anaerobes, translating into a higher risk of gut dysbiosis and septic diseases preventable by one-time feeding of S100A8 at birth. Our results establish S100A8/A9 as an important host factor for developing gut homeostasis and a promising target for enteral supplementation aiming to prevent dysbiosis and associated diseases.