Microbial succession at weaning is guided by microbial metabolism of host glycans.

The weaning transition from a milk-based to a solid-food diet supports critical developmental changes to the intestinal microbiome and immune system. However, the specific microbial and host features that influence microbial succession at weaning are not well understood. Here, we developed a simple approach to investigate the complex dynamics of microbial succession during weaning by co-housing gnotobiotic mice colonized with the defined pre-weaning community PedsCom and the adult-derived consortium OMM12. As expected, co-housing PedsCom mice with OMM12 recapitulated microbial succession at weaning and induced immune system maturation in PedsCom mice. Unexpectedly, we found that the OMM12 microbes with the highest host glycan utilization profiles were the most adept colonizers of PedsCom mice. Genomic analysis confirmed that PedsCom is deficient in the carbohydrate-active enzymes responsible for degrading host-derived glycans, including mucins, compared to adult-derived consortia. We validated a role for glycan utilization in vivo by demonstrating that the mucus-degrading commensal microbe Akkermansia muciniphila critically depends on the metabolism of mucin glycans for colonization of PedsCom mice. These findings highlight the importance of host-derived glycans in shaping microbial communities during the weaning transition and suggest host glycans as novel targets to modulate intestinal microbial populations, introduce beneficial probiotics, and enhance immune system development during weaning.