Sweet enzymes from gut bacteria: from discovery to diagnostics

1st May 2020

An enzyme that helps specific bacteria colonise the human gut by giving them access to breast milk sugars and intestinal mucins has been identified.

As well as providing information about how a healthy microbiome is established and maintained, the new enzyme might be useful in diagnosing diabetes and certain cancers.

The gut microbiome plays an important role in human health and understanding how changes in the population of bacteria and other microbes affects this role is crucial to understanding its influence. The composition of the microbiome is affected by its source of nutrition, which is predominantly complex carbohydrates sourced either from the diet or from mucus that lines the gut.

Gut bacteria breakdown carbohydrates using glycoenzymes, and different bacteria possess different types of glycoenzyme specific to certain carbohydrates. Professor Nathalie Juge from the Quadram Institute has been leading a team investigating these glycoenzymes, and how their specificity for certain carbohydrate residues lets them exploit particular niches in the gut.

They have previously shown that in the mucus layer that lines the gut, mucin proteins are decorated with long carbohydrate chains that favour bacteria with the glyocenzymes to break them down.

Glycoenzymes are also useful as biocatalysts for industrial applications and they have potential uses in diagnostics, biologics and nutraceuticals. But to date few glycoenzymes are commercially available.

In a new study Prof. Juge and her team investigated glycoenzymes produced by different strains of the human gut symbiont Ruminococcus gnavus. The study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UKRI, and published in the journal Cellular and Molecular Life Sciences.

R. gnavus strains are some of the earliest colonisers of infants’ guts, and can use the Human Milk Oligosaccharide (HMO) fucosyllactose as a nutrient source. This is a trait shared with other early inhabitants of the human GI tract including various bifidobacteria species.

To access this nutrient source, gut bacteria have evolved to express a wide range of fucosidases with distinct specificity, contributing to their fitness across nutritional niches.

Using a combination of approaches, the researchers identified a fucosidase able to recognise sialic acid-terminated fucosylated glycans and hydrolyse specific linkages in these substrates without the need to remove sialic acid. The glycan analysis was carried in collaboration with the Oxford-based Contract Research Organisation Ludger Ltd who specialise in glycosylation profiling.

R. gnavus fucosidase

The crystal structure of the enzyme was solved by collaborators at Diamond Light Source in Harwell.  Molecular dynamics simulation and docking, carried out by colleagues at the University of East Anglia, showed that the fucosylated glycans could be accommodated within the binding site of the enzyme.

This unique specificity is a major advantage for colonising bacteria as it gives them access to an abundant nutrient source. Providing a similar nutrient source in mucin proteins in gut mucus helps these bacteria to be maintained throughout life.

This characterisation of newly identified fucosidase also adds to the toolkit of glycoenzymes suitable for industrial applications.

Ludger Ltd will be using the fucosidase characterised in this study to identify in patient samples those that have unusually higher, or lower levels of N-glycan antennary fucosylation. These are features of diseases such as MODY diabetes (Maturation Onset of Diabetes in the Young) as well as many cancers, expanding their portfolio of glycoprotein-based biopharmaceuticals and biomarkers.


Reference: Wu, H., Rebello, O., Crost, E.H. et al. Fucosidases from the human gut symbiont Ruminococcus gnavus. Cell. Mol. Life Sci. (2020). DOI: 10.1007/s00018-020-03514-x

Related Targets

Targeting the understanding of the microbiome

Understanding the Microbiome

Targeting cancer

Cancer

Related Research Groups

Juge group

Nathalie Juge

Related Research Areas

Research area: microbes and health

Gut Microbes & Health