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The assembly of the gut microbiota in early life is critical to the health trajectory of human hosts. Breast feeding selects for a Bifidobacterium -rich community, adapted to efficiently utilize human milk oligosaccharides (HMOs) from mother's milk. Industrial scale production of HMOs for infant formula fortification has mainly considered fucosyllactoses, whereas fucosylated type 1 HMO blocks have hitherto not been explored. Our work sheds light on the uptake facet, central to the utilization of fucosylated HMOs with type 1 LNB building blocks. These type I blocks are efficiently internalized and assimilated by B. infantis , which has been recently shown to secrete immune-modulatory aromatic-lactate metabolites that mediate immune-priming of hosts in early life. This study contributes to our understanding of the utilization of HMOs and highlights fucosylated LNB blocks, as hitherto unexplored prebiotic candidates that support the growth of B. infantis and other beneficial gut bacteria in early life.

β-Mannans are plant cell wall polysaccharides that are commonly found in human diets. However, a mechanistic understanding into the key populations that degrade this glycan is absent, especially for the dominant Firmicutes phylum. Here, we show that the prominent butyrate-producing Firmicute Roseburia intestinalis expresses two loci conferring metabolism of β-mannans. We combine multi-“omic” analyses and detailed biochemical studies to comprehensively characterize loci-encoded proteins that are involved in β-mannan capturing, importation, de-branching and degradation into monosaccharides. In mixed cultures, R. intestinalis shares the available β-mannan with Bacteroides ovatus , demonstrating that the apparatus allows coexistence in a competitive environment. In murine experiments, β-mannan selectively promotes beneficial gut bacteria, exemplified by increased R. intestinalis , and reduction of mucus-degraders. Our findings highlight that R. intestinalis is a primary degrader of this dietary fiber and that this metabolic capacity could be exploited to selectively promote key members of the healthy microbiota using β-mannan-based therapeutic interventions. How dietary β-mannans are utilized by gut Gram-positive bacteria is unclear. Here, the authors uncover the enzymatic pathway for β-mannan metabolism in Roseburia intestinalis and show that these polysaccharides promote beneficial gut bacteria, highlighting a potential for β-mannan-based therapeutic interventions.

Human milk oligosaccharides (HMOs) are uniquely rich in the type 1 building block disaccharide lacto-N-biose I (LNB, Galβ1,3GlcNAc), as compared to other mammals. Most HMOs are fucosylated, e.g., α1,2 and α1,4 fucosylations on LNB blocks, resulting in H type 1 (H1) and Lewis a (Lea) epitopes, respectively. The dominance of Bifidobacterium in breastfed infant guts hinges on efficient uptake of HMOs by specific ATP-binding cassette (ABC) importers. However, molecular insight into uptake of fucosylated LNB blocks is lacking. Here, we analyzed the uptake of LNB and its fucosylated H1 and Lea trisaccharides, as well as the mucin-derived disaccharide galacto-N-biose (GNB, Galβ1,3GalNAc) by an ABC importer form the HMO-utilization specialist Bifidobacterium longum subsp. infantis. Structural analyses and molecular dynamics simulations explained how fucosylated and non-fucosylated LNB forms are recognized with similar affinities by the binding protein of this importer. Strikingly, we showed that two ABC importers confer to the uptake of LNB, while the Lea trisaccharide is efficiently internalized by a single importer in B. infantis. Phylogenetic and structural analyses of bifidobacterial ABC-associated binding proteins showed that the Lea clade harbors homologues possessing internal cavities, which allows for the accommodation of branched oligosaccharides. Our work provides unique insight into the evolution and molecular basis of capture and uptake of key HMO and host-derived saccharide blocks, highlighting these compounds as hitherto unexplored candidates for fortification of infant formula.