Arresting microbiome development limits immune system maturation and resistance to infection

Abstract

Abstract The transition from milk to solid food is a critical period in post-natal human development. Weaning coincides with a dramatic and rapid maturation of both the microbiome and immune system. Whether these weaning induced changes in commensal communities shape immune system development and susceptibility to enteric infection remains unknown. Here we find maturation of the microbiome during weaning is required for proper immune system development and protection against enteric infection. To this end, we developed a stable gnotobiotic mouse model of the early-life microbiome composed of a representative nine-member consortium of phylogenetically diverse microbes found pre-weaning, designated as Pediatric Community (PedsCom). PedsCom efficiently colonized germfree adult mice and was vertically transmitted to offspring. Unexpectedly, the composition of PedsCom was unaffected by the transition from a milk-based to a fiber rich solid food diet. This permitted us to study adult mice with a pre-weaning intestinal microbiome. We find that arresting intestinal microbiome maturation in PedsCom mice limited immune system development. PedsCom mice displayed decreased both peripheral regulatory T cells accumulation and Immunoglobulin A production, hallmarks of microbiota-driven immune development. Consistent with defects in maturation, adult PedsCom mice retain high susceptibility to Salmonella infection characteristic of young mice and humans. Altogether, our work illustrates how the post-weaning transition in intestinal microbiome composition is essential for normal immune maturation, and protection from enteric infection. Supported by 1R21AI146629-01A1