To understand the microbiome’s role in keeping us healthy, we need to understand what keeps it healthy, including its sources of nutrition. One source is sialic acid, a sugar-based molecule produced by the host organism in the mucus that lines the gut.

In this blog Professor Nathalie Juge from Quadram Institute Bioscience talks about a new collaborative study that has uncovered a way some bacteria scavenge sialic acid derivatives produced exclusively by a keystone member of the microbiota community.  

Sialic acid is a generic term for a family of derivatives of neuraminic acid, an acidic sugar found in human secretions such as intestinal mucus. It is also the name for the most common member of this group, N-acetylneuraminic acid (Neu5Ac). Bacteria that can use the sialic acids found in mucus rich environments have a competitive advantage to colonise and persist within the gut. This applies to bacteria that cause disease as well as those that form a healthy microbiota, so understanding how these bacteria colonise and survive is of great interest.

Ruminococcus gnavus is a prevalent member of the human gut microbiota.  R. gnavus colonises the infant gut and persists in adulthood where it is widely distributed amongst individuals.  Further, R. gnavus has been associated with an increasing number of intestinal or extra-intestinal diseases including inflammatory bowel disease. There is therefore great interest in defining the mechanisms by which R. gnavus adapt to the gut so to be able to devise strategies to modulate human health.

Crystal structure of RgNanOx, jbc.RA120.014454

We previously showed that R. gnavus strains can scavenge sialic acid sugars from host mucus by converting them in a form that they have preferentially access to, providing them with a nutritional advantage. These strains possess an enzyme that can break down mucus-associated sialic acid, producing 2,7-anhydro-Neu5Ac instead of Neu5Ac.  We also showed that these strains express an oxidoreductase enzyme we called RgNanOx that converts this 2,7-anhydro-Neu5Ac back into the Neu5Ac form once inside the bacteria, which can be processed as a source of energy using a well-established pathway (Bell et al . Nat Microbial 2019).

In our latest study, published in the Journal of Biological Chemistry, working in collaboration with Jim Naismith at Oxford University, Jesus Angulo at the University of East Anglia and Gavin Thomas at University of York, we unravelled the mechanism of action of RgNanOx.

We also showed that this enzyme is present in other bacteria that commonly inhabit the gut. We identified both the transporter and oxidoreductase enzyme required for E. coli to uptake and catabolise 2,7-anhydro-Neu5Ac.

But E. coli does not encode the enzyme releasing 2,7-anhydro-Neu5Ac from the mucus. What does this mean for our understanding of what is happening in the gut microbiota? It’s likely that for this strain of E. coli to use 2,7-anhydro-Neu5Ac as a metabolic substrate would rely on cross-feeding in the mucosal environment. It needs R. gnavus to do the primary degrading step and share the products of this.

Resource sharing is an important ecological feature of microbial communities living in the gut. Some bacteria present in the mucus might not be primary degraders but might cross-feed on glycan degradation products released by other bacteria.

Together, this work demonstrates that 2,7-anhydro-Neu5Ac catabolism is not exclusive to R. gnavus and may help shape microbial communities in the gut. This also now completes the functional characterisation of all NanR-regulated genes in E. coli, giving us a broader picture of the sialic acid molecules it likely encounters in its natural environment.

From an ecological point of view, since R. gnavus is the only strain reported to produce 2,7-anhydro-Neu5Ac in the gut, the strict specificity of its sialic acid transporter may give it a nutritional advantage while maintaining its keystone status in the mucus niche by providing an important nutrient to the microbial community.

References

Uncovering a novel molecular mechanism for scavenging sialic acids in bacteria

Andrew Bell,#, Emmanuele Severi#, Micah Lee, Serena Monaco, Dimitrios Latousakis, Jesus Angulo, Gavin H. Thomas, James Naismith and Nathalie Juge*

DOI: 10.1074/jbc.RA120.014454

# contributed equally to this work

*Corresponding author: Nathalie Juge

Bell A, Brunt J, Crost E, Vaux L, Nepravishta R, Owen CD, Latousakis D, Xiao A, Li W, Chen X, Walsh MA, Claesen J, Angulo J, Thomas GH, Juge N. Elucidation of a sialic acid metabolism pathway in mucus-foraging Ruminococcus gnavus unravels mechanisms of bacterial adaptation to the gut. Nat Microbiol. (2019) 4 (12), 2393-2404  DOI: 10.1038/s41564-019-0590-7