As well as providing new information about the symbiotic relationship we have with our gut bacteria, uncovering this pathway may also provide new targets for biomarkers or therapies for conditions linked to imbalances in the microbiota.
Our digestive tract is home to trillions of microbes, collectively known as the microbiota, and they play a vital role in maintaining good health. The lining of the gut is covered in mucus. This has a dual role: it helps prevent bacteria accessing and crossing the gut lining, but also provides nutrients for the microbiota.
Mucus is made up of proteins called mucins. The mucins are heavily “decorated” with sugar molecules called glycans. Previous studies have indicated that these glycans are an important source of sugars for bacterial metabolism. The type of glycan changes moving down the digestive tract, with the sialic acid glycans predominating in mucus in the colon in humans. As this is the major site for the gut microbiota, bacteria that can metabolise sialic acid have a distinct advantage.
Bacteria (red) colonising the colon mucus layer (green). Image by Laura Vaux, the Quadram Institute
Several gut bacteria species have the gene cluster needed to metabolise sialic acid, including Ruminococcus gnavus. This is one of the early colonisers of the infant gut and it persists into adulthood. R. gnavus is found in around 90% of humans and is considered to be a prevalent member of a ‘normal’ gut microbiota. It is also overrepresented in the microbiota of people suffering from a number of conditions including inflammatory bowel disease (IBD).
With R. gnavus apparently having important roles in both a healthy microbiota as well as in diseased conditions, there has been a lot of interest in understanding its ability to forage nutrients in the gut. This new study reveals the unique metabolic pathway and uncovers why it has a particular advantage over other microbes.
Prof Nathalie Juge and her group at the Quadram Institute previously found that R. gnavus can cleave off sialic acid from mucin molecules, but unlike other bacteria, in doing so they chemically modify it.
In a new study, published in the journal Nature Microbiology, the team showed how this modification allows the bacteria to keep the sialic acid for itself. Whilst other bacteria release free sialic acid for other members of the microbiota to metabolise, R. gnavus acts selfishly so it can primarily benefit.
In collaboration with colleagues at Diamond Light Source, University of East Anglia (UEA), University of York, and University of California, Andrew Bell, PhD student in the Juge team, identified the genes and characterised the proteins used to transport and metabolise the modified sialic acid. The scientists found that R. gnavus has a protein that specifically transports the modified sialic acid into its cells. The study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the US National Institutes of Health (NIH).
Dr Jesus Angulo, from UEA’s School of Pharmacy, said: “An important aspect of this remarkable ‘selfish’ mechanism is understanding how it can selectively transport the nutrient inside the cell. Here at UEA we have developed a new method and have applied it to see how a key protein in this important gut symbiont works at atomic detail”.
Once inside the cell, the bacteria can remove the modification, allowing them to metabolise sialic acid. The researchers at the Quadram Institute then knocked out the genes for this exclusive metabolic pathway, which severely impaired R. gnavus’ ability to colonise the mucus layer, indicating its importance to these bacteria.
“We think that by modifying the sialic acid, R. gnavus makes sure it always keeps a slice of the pie for itself” said Prof. Juge.
Bioinformatic analysis with colleagues at Lerner Research Institute, Cleveland showed that very few other bacteria have these genes.
“This strategy contributes to R. gnavus’ success in colonising the mucus layer and is likely to be behind its prevalence in the human gut microbiota.”
This new mechanistic knowledge can now be applied to develop strain-specific biomarkers of diseases such as IBD and next-generation prebiotic-based approaches targeting R. gnavus strains.
Reference: ‘Elucidation of a sialic acid metabolism pathway in mucus-foraging Ruminococcus gnavus unravels mechanisms of bacterial adaptation to the gut’, Andrew Bell, Jason Brunt, Emmanuelle Crost, Laura Vaux, Ridvan Nepravishta, C. David Owen, Dimitrios Latousakis, An Xiao, Wanqing Li, Xi Chen, Martin A. Walsh3 Jan Claesen, Jesus Angulo, Gavin H. Thomas, and Nathalie Juge has been scheduled for publication in Nature Microbiology on 21 October 2019 at 16:00 (London time), 21 October 2019 at 11:00 (US Eastern Time) DOI: 10.1038/s41564-019-0590-7 https://www.nature.com/articles/s41564-019-0590-7