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Abstract

Human milk oligosaccharides (HMOs) are abundant and structurally diverse glycans that shape the development of infant gut microbiota. Yet, how individual HMOs and bacterial genes drive the community assembly remain elusive. Here, we reconstructed an eight-member infant Bacterial Community (iBaCo) from representing dominant taxa in human infant feces. When individual HMOs were the sole carbohydrate source, they showed deterministic effects on the iBaCo composition and metabolic output. Notably, the tetramer HMO lacto-N-tetraose (LNT), in spite of its identical monomer composition as lacto-N-neotetraose (LNnT), showed a strong effect on maintaining Bifidobacterium breve abundance in iBaCo, whereas LNnT did not. Monoculture growth profiling, proteomics, enzymatic kinetic assay, and molecular docking revealed that {beta}-galactosidase D4BMY8 and the relevant downstream pathways are induced by LNT and that D4BMY8 has substrate preference on LNT over LNnT, enabling a faster growth of Bi. breve and accumulation of acetate and lactate in LNT compared to LNnT. Metabolic flux analysis indicated that the substrate-preference of {beta}-galactosidase D4BMY8 drives the skewed energy cost toward lactate/acetate metabolic output. Finally, the D4BMY8-encoding gene lacZ5 is widely spread in all isolated Bi. breve genomes, but divergently distributed in infant metagenome-assembled Bi. breve genomes. Together, we demonstrated that a single enzyme-substrate interaction could orchestrate the composition and metabolic function of an infant bacterial community, which may contribute to the assembly of dynamic infant gut microbiota. Our integrative approach provides a mechanistic framework for understanding the interaction between diet, microbial community, and infant gut health.

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