Elucidation of a unique sialic acid metabolism pathway in mucus-foraging Ruminococcus gnavus unravels mechanisms of bacterial adaptation to the gut

Sialic acid (Neu5Ac) is commonly found in terminal location of colonic mucins glycans where it is a much-coveted nutrient for gut bacteria including Ruminococcus gnavus. R. gnavus is part of the healthy gut microbiota in humans but shows a disproportionate representation in diseases. There is therefore a need in understanding the molecular mechanisms underpinning its adaptation to the gut. Previous in vitro work demonstrated that R. gnavus mucin glycan-foraging strategy is strain-dependent and associated with the expression of an intramolecular trans-sialidase releasing 2,7-anhydro-Neu5Ac instead of Neu5Ac from mucins. Here, we have unravelled the metabolism pathway of 2,7-anhydro-Neu5Ac in R. gnavus which is underpinned by the exquisite specificity of the sialic transporter for 2,7-anhydro-Neu5Ac, and by the action of an oxidoreductase converting 2,7-anhydro-Neu5Ac into Neu5Ac which then becomes substrate of a Neu5Ac-specific aldolase. Having generated a R. gnavus nan cluster deletion mutant that lost the ability to grow on sialylated substrates, we showed that in gnotobiotic mice colonised with R. gnavus wild-type and mutant strains, the fitness of the nan mutant was significantly impaired with a reduced ability to colonise the mucus layer. Overall, our study revealed a unique sialic acid pathway in bacteria, with significant implications for the spatial adaptation of mucin-foraging gut symbionts in health and disease.