A Weaning Reaction to Microbiota Is Required for Resistance to Immunopathologies in the Adult

Microbes colonize all body surfaces at birth and participate in the development of the immune system. In newborn mammals, the intestinal microbiota is first shaped by the dietary and immunological components of milk and then changes upon the introduction of solid food during weaning. Here, we explored the reactivity of the mouse intestinal immune system during the first weeks after birth and into adulthood. At weaning, the intestinal microbiota induced a vigorous immune response—a “weaning reaction”—that was programmed in time. Inhibition of the weaning reaction led to pathological imprinting and increased susceptibility to colitis, allergic inflammation, and cancer later in life. Prevention of this pathological imprinting was associated with the generation of RORγt+ regulatory T cells, which required bacterial and dietary metabolites—short-chain fatty acids and retinoic acid. Thus, the weaning reaction to microbiota is required for immune ontogeny, the perturbation of which leads to increased susceptibility to immunopathologies later in life. [Display omitted] •The expanding microbiota at weaning induces a vigorous immune reaction•The weaning reaction occurs during a specific time window•The weaning reaction prevents susceptibility to inflammatory pathologies in the adult•Microbiota-induced Treg cells are required for a protective weaning reaction Al Nabhani et al. find that the changes in the intestinal microbiota at weaning induced a vigorous immune response—a “weaning reaction”—that is programmed in time. The weaning reaction is associated with the induction of regulatory T cells, and its perturbation results in increased susceptibility to immunopathologies later in life.