Akkermansia muciniphila exoglycosidases target extended blood group antigens to generate ABO-universal blood.

Matching donor and recipient blood groups based on red blood cell (RBC) surface ABO glycans and antibodies in plasma is crucial to avoid potentially fatal reactions during transfusions. Enzymatic conversion of RBC glycans to the universal group O is an attractive solution to simplify blood logistics and prevent ABO-mismatched transfusions. The gut symbiont Akkermansia muciniphila can degrade mucin O-glycans including ABO epitopes. Here we biochemically evaluated 23 Akkermansia glycosyl hydrolases and identified exoglycosidase combinations which efficiently transformed both A and B antigens and four of their carbohydrate extensions. Enzymatic removal of canonical and extended ABO antigens on RBCs significantly improved compatibility with group O plasmas, compared to conversion of A or B antigens alone. Finally, structural analyses of two B-converting enzymes identified a previously unknown putative carbohydrate-binding module. This study demonstrates the potential utility of mucin-degrading gut bacteria as valuable sources of enzymes for production of universal blood for transfusions.

Butyrate-producing colonic clostridia: picky glycan utilization specialists.

Butyrate-producing human gut microbiota members are recognized for their strong association with a healthy immune-homeostasis and protection from inflammatory disorders and colorectal cancer. These effects are attributed to butyrate, the terminal electron sink of glycan fermentation by prevalent and abundant colonic Firmicutes from the Lachnospiraceae and Oscillospiraceae families. Remarkably, our insight into the glycan utilization mechanisms and preferences of butyrogenic Firmicutes remains very limited as compared with other gut symbionts, especially from the Bacteroides, Bifidobacterium, and Lactobacillus genera. Here, we summarize recent findings on the strategies that colonic butyrate producers have evolved to harvest energy from major dietary fibres, especially plant structural and storage glycans, such as resistant starch, xylans, and mannans. Besides dietary fibre, we also present the unexpected discovery of a conserved protein apparatus that confers the growth of butyrate producers on human milk oligosaccharides (HMOs), which are unique to mother's milk. The dual dietary fibre/HMO utilization machinery attests the adaptation of this group to both the infant and adult guts. These finding are discussed in relation to the early colonization of butyrogenic bacteria and the maturation of the microbiota during the transition from mother's milk to solid food. To date, the described butyrogenic Firmicutes are glycan utilization specialists that target only a few glycans in a highly competitive manner relying on co-regulated glycan utilization loci. We describe the common pillars of this machinery, highlighting butyrate producers as a source for discovery of biochemically and structurally novel carbohydrate active enzymes.

Butyrate producing colonic Clostridiales metabolise human milk oligosaccharides and cross feed on mucin via conserved pathways.

The early life human gut microbiota exerts life-long health effects on the host, but the mechanisms underpinning its assembly remain elusive. Particularly, the early colonization of Clostridiales from the Roseburia-Eubacterium group, associated with protection from colorectal cancer, immune- and metabolic disorders is enigmatic. Here, we describe catabolic pathways that support the growth of Roseburia and Eubacterium members on distinct human milk oligosaccharides (HMOs). The HMO pathways, which include enzymes with a previously unknown structural fold and specificity, were upregulated together with additional glycan-utilization loci during growth on selected HMOs and in co-cultures with Akkermansia muciniphila on mucin, suggesting an additional role in enabling cross-feeding and access to mucin O-glycans. Analyses of 4599 Roseburia genomes underscored the preponderance and diversity of the HMO utilization loci within the genus. The catabolism of HMOs by butyrate-producing Clostridiales may contribute to the competitiveness of this group during the weaning-triggered maturation of the microbiota.