Prominent members of the human gut microbiota express endo-acting O-glycanases to initiate mucin breakdown

Lucy I. Crouch, et al.

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Received Date: 8th January 20

Lucy I. Crouch,  Marcelo V. Liberato,  Paulina A. Urbanowicz,  Arnaud Baslé,  Christopher A. Lamb,  Christopher J. Stewart, Katie Cooke, Mary Doona, Stephanie Needham, Richard R. Brady, Janet E. Berrington, Katarina Madunic,  Manfred Wuhrer,  Peter Chater,  Jeffery P. Pearson, Robert Glowacki,  Eric C. Martens, Fuming Zhang,  Robert J. Linhardt, Daniel I. R. Spencer,  David N. Bolam

The human gut microbiota (HGM) are closely associated with health, development and disease. The thick intestinal mucus layer, especially in the colon, is the key barrier between the contents of the lumen and the epithelial cells, providing protection against infiltration by the microbiota as well potential pathogens. The upper layer of the colonic mucus is a niche for a subset of the microbiota which utilise the mucin glycoproteins as a nutrient source, but we lack understanding about the mechanisms by which gut bacteria access this complex macromolecule. Deciphering this is fundamental to understanding the intimate syntrophic relationship between the HGM and host. The current model for mucin degradation by the microbiota involves exclusively exo-acting glycosidases that sequentially trim monosaccharides from the termini of the glycan chains. However, this model is in direct contrast to our current understanding of the mechanism of glycan breakdown by the microbiota, particularly by Bacteroidetes, one of the two main phyla of the HGM. Here we describe the discovery and detailed biochemical and structural characterisation of endo-acting enzymes from prominent mucin-degrading bacteria that target the polyLacNAc structures within oligosaccharide side chains of both animal and human mucins. These O-glycanases are found in several Bacteroides spp. as well as Akkermansia muciniphila and are a part of the large and diverse glycoside hydrolase 16 (GH16) family. These enzymes are often lipoproteins indicating they are surface located and are thus likely involved in the initial step in mucin breakdown. Overall the data provides a significant advance in our knowledge of the mechanism of mucin breakdown by the normal microbiota. We also explore the potential for these enzymes to be used as tools to explore changes that occur in O-glycan structure in intestinal disorders such as inflammatory bowel disease (IBD) and colorectal cancer (CRC).

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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