SummaryEpidemiological data suggest that early life exposures are key determinants of immune-mediated disease later in life. Young children are also particularly susceptible to infections, warranting more analyses of immune system development early in life. Such analyses mostly have been performed in mouse models or human cord blood samples, but these cannot account for the complex environmental exposures influencing human newborns after birth. Here, we performed longitudinal analyses in 100 newborn children, sampled up to 4 times during their first 3 months of life. From 100 μL of blood, we analyze the development of 58 immune cell populations by mass cytometry and 267 plasma proteins by immunoassays, uncovering drastic changes not predictable from cord blood measurements but following a stereotypic pattern. Preterm and term children differ at birth but converge onto a shared trajectory, seemingly driven by microbial interactions and hampered by early gut bacterial dysbiosis.

Highlights d An ordered sequence of immune changes after birth driven by microbial interactions d Lack of gut bifidobacteria and HMO-utilization genes correlates with systemic inflammation d Feeding B. infantis EVC001 upregulates IFNb and silences intestinal Th2 and Th17 d EVC001-associated indole-3-lactic acid upregulates inhibitory galectin-1 in T cells