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How members of the human gut microbiota overcome the sulfation problem posed by glycosaminoglycans

Significance The major nutrients available to the human microbiota are complex carbohydrates. Host glycans are important to this microbial community, particularly when dietary carbohydrates are scarce. The host glycans heparin and heparan sulfate are high-priority carbohydrates for Bacteroides thetaiotaomicron, a member of the human microbiota. The degradation of these complex carbohydrates is challenging, reflecting their highly variable sulfation patterns. How bacteria have adapted to depolymerize the myriad of substructures of this important class of glycosaminoglycan is unknown. Here, we show how enzyme consortia, displaying complementary functions, target the different features of these host glycans. Structural data reveal that the acidic groups of the glycans are key specificity determinants for enzymes and binding proteins that make up the degradative apparatus. The human microbiota, which plays an important role in health and disease, uses complex carbohydrates as a major source of nutrients. Utilization hierarchy indicates that the host glycosaminoglycans heparin (Hep) and heparan sulfate (HS) are high-priority carbohydrates for Bacteroides thetaiotaomicron, a prominent member of the human microbiota. The sulfation patterns of these glycosaminoglycans are highly variable, which presents a significant enzymatic challenge to the polysaccharide lyases and sulfatases that mediate degradation. It is possible that the bacterium recruits lyases with highly plastic specificities and expresses a repertoire of enzymes that target substructures of the glycosaminoglycans with variable sulfation or that the glycans are desulfated before cleavage by the lyases. To distinguish between these mechanisms, the components of the B. thetaiotaomicron Hep/HS degrading apparatus were analyzed. The data showed that the bacterium expressed a single-surface endo-acting lyase that cleaved HS, reflecting its higher molecular weight compared with Hep. Both Hep and HS oligosaccharides imported into the periplasm were degraded by a repertoire of lyases, with each enzyme displaying specificity for substructures within these glycosaminoglycans that display a different degree of sulfation. Furthermore, the crystal structures of a key surface glycan binding protein, which is able to bind both Hep and HS, and periplasmic sulfatases reveal the major specificity determinants for these proteins. The locus described here is highly conserved within the human gut Bacteroides, indicating that the model developed is of generic relevance to this important microbial community.