S100-alarmins are crucial host factors for the postnatal development of gut homeostasis. human

The immune system experiences considerable reprogramming after birth, especially by interacting with the colonizing microbiota. Host factors involved in this mutually developing relationship are largely unknown. Our studies in two infant cohorts and newborn mice reveal that the early life abundance of fecal S100A8/A9-alarmin primes the inflammatory and regulatory phenotype of colonic lamina propria macrophages. S100A8/A9-alarmin deficiency in the neonatal period results in an impaired expression of Cx3cr1, Il-10 and Tgf-, reduced intestinal 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 in newborn infants. One-time feeding of S100A8 to murine neonates at birth averts gut dysbiosis and sepsis. Our results establish S100A8/A9 as an important host factor involved in the development of gut homeostasis and suggest S100-alarmins as a promising target for enteral supplementation in newborn infants to prevent dysbiosis-mediated conditions