Impact of bacterial sialic acid metabolism on gut homeostasis
Lead Research Organisation:
University of East Anglia
Department Name: Graduate Office
Abstract
The gastrointestinal (GI) tract is colonized by a diverse community of microbes catabolizing dietary and host carbohydrates during their expansion within the gut. In particular some gut bacteria have the ability to forage on host glycans provided by the mucus layer via specific glycoside hydrolases. Alterations in mucosal carbohydrate availability impact on the composition of microbial species including enteric pathogens. We recently showed for the first time that some gut symbionts express intramolecular trans-sialidases allowing bacteria to thrive within mucosal environments by scavenging sialic acid from mucus in a form which may not be readily accessible to surrounding bacteria. The PhD project will explore the molecular basis for IT-sialidase mediated metabolism by gut bacteria and how it influences bacterial colonisation and pathogen expansion in the gut. This work will provide molecular targets to devise dietary strategies for reducing or preventing GI infection.
The student will receive expert training in anaerobic microbiology, bacterial infection, heterologous expression, carbohydrate biotransformations, separation and structural characterisation techniques (HPLC, MS- and NMR-based methods), enzymatic assays, bioinformatics and statistical analysis. There will be opportunities to collaborate with structural biologists. The techniques are well-established and there is considerable expertise in conducting research on glycobiology and gut microbiology. This interdisciplinary project will benefit from the established international network of academic and industrial collaborations of the NRP Labs in these areas of research. Training will embrace research practice and theory, management, communication (to scientific and lay audiences), teamwork, and technical writing. The student will present his/her work to internal seminars and to relevant International meetings. The possible commercial issues relating to the impact of this research on human health will be highlighted and the student will be encouraged to present his/her results to the general public.
The student will receive expert training in anaerobic microbiology, bacterial infection, heterologous expression, carbohydrate biotransformations, separation and structural characterisation techniques (HPLC, MS- and NMR-based methods), enzymatic assays, bioinformatics and statistical analysis. There will be opportunities to collaborate with structural biologists. The techniques are well-established and there is considerable expertise in conducting research on glycobiology and gut microbiology. This interdisciplinary project will benefit from the established international network of academic and industrial collaborations of the NRP Labs in these areas of research. Training will embrace research practice and theory, management, communication (to scientific and lay audiences), teamwork, and technical writing. The student will present his/her work to internal seminars and to relevant International meetings. The possible commercial issues relating to the impact of this research on human health will be highlighted and the student will be encouraged to present his/her results to the general public.
People |
ORCID iD |
Nathalie Juge (Primary Supervisor) | |
Andrew Bell (Student) |
Publications
Bell A
(2019)
Elucidation of a sialic acid metabolism pathway in mucus-foraging Ruminococcus gnavus unravels mechanisms of bacterial adaptation to the gut.
in Nature microbiology
Bell A
(2020)
Uncovering a novel molecular mechanism for scavenging sialic acids in bacteria.
in The Journal of biological chemistry
Monestier M
(2017)
Membrane-enclosed multienzyme (MEME) synthesis of 2,7-anhydro-sialic acid derivatives.
in Carbohydrate research
Owen CD
(2017)
Unravelling the specificity and mechanism of sialic acid recognition by the gut symbiont Ruminococcus gnavus.
in Nature communications
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/M011216/1 | 30/09/2015 | 31/03/2024 | |||
1653419 | Studentship | BB/M011216/1 | 30/09/2015 | 29/09/2019 | Andrew Bell |
Description | The work has discovered the metabolic pathway for the utilisation of a unique sugar (2,7-anhydro-Neu5Ac) in gut microbes. This adds to the growing knowledge of the interaction between the host and gut microbes. For the first time a mutagenesis strategy for the gut commensal microbe Rumincoccus gnavus was demonstrated, this increases the research communities ability to assess the impact of this important microbe on gut health and homeostasis |
Exploitation Route | The work in this study can be taken forward to further investigate the role of 2,7-anhydro-Neu5Ac on gut microbes. Furthermore, the ability to genetically manipulate R. gnavus will lead to exciting new discoveries in mucosal adhesion and utilisation by this important member of the gut microbiome. |
Sectors | Healthcare Manufacturing including Industrial Biotechology |
Description | Development of multi-step enzymatic routes for the synthesis of sialic acid derivatives |
Amount | £103,000 (GBP) |
Funding ID | IBCarb-PoC-0315-009 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2015 |
End | 05/2016 |
Description | Microbiology Society - Society Conference Grants - Microbes and Mucosal Surfaces |
Amount | £300 (GBP) |
Funding ID | GA000825 |
Organisation | Microbiology Society |
Sector | Learned Society |
Country | United Kingdom |
Start | 05/2018 |
End | 06/2018 |
Description | Norwich Research Park Bioscience Doctoral Training Partnership |
Amount | £100,000 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2015 |
End | 09/2019 |
Title | Membrane-enclosed multienzyme (MEME) synthesis of 2,7-anhydro-sialic acid derivatives. |
Description | A facile one-pot two-enzyme approach has been established for the synthesis of 2,7-anhydro-sialic acid derivatives including those containing different sialic acid forms such as Neu5Ac and N-glycolylneuraminic acid (Neu5Gc). This synthetic method, which is based on a membrane-enclosed enzymatic synthesis, can be performed on a preparative scale. Using fetuin as a substrate, high-yield and cost-effective production of 2,7-anhydro-Neu5Ac was obtained to high-purity. This method was also applied to the synthesis of 2,7-anhydro-Neu5Gc. The membrane-enclosed multienzyme (MEME) strategy reported here provides an efficient approach to produce a variety of sialic acid derivatives. |
Type Of Material | Technology assay or reagent |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | The method allowed to produce 2,7-anhydro-sialic acid derivatives (not commercially available) in amount and purity allowing further mechanistic studies and exploring applications in the health sector |
Description | Carbohydrate analysis |
Organisation | John Innes Centre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Supervised and coordinated research project |
Collaborator Contribution | Provided expertise and access to NMR facility |
Impact | WO2017134466A1. Patent Application on intramolecular trans-sialidase; Carbohydr Res. 2017 Nov 8;451:110-117. doi: 10.1016/j.carres.2017.08.008. |
Start Year | 2007 |
Description | Chemical glycobiology |
Organisation | Utrecht University |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | Contributed to successful multidisciplinary European Training Network Sweetcrosstalk proposal Supervising tow ESRs on the project WP leader |
Collaborator Contribution | Coordinator of ITN Host of one of my ESRs |
Impact | Chemistry, Glycobiology, Microbiology |
Start Year | 2018 |
Description | Sialic acid recognition |
Organisation | University of York |
Department | Department of Biology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Initiated collaboration on sialic acid transport and metabolism in bacteria |
Collaborator Contribution | Provided materials and contributed to data analysis |
Impact | Scientific publications |
Start Year | 2018 |
Description | Structural biology |
Organisation | University of Oxford |
Department | Oxford Hub |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Identified and functionally characterised a novel enzyme activity in gut bacteria |
Collaborator Contribution | Crystallisation of metabolic enzyme involved in carbohydrate utilisation by bacteria |
Impact | Manuscript in preparation 3D Structure |
Start Year | 2019 |
Description | External presentation (London School of Hygiene & Tropical Medicine) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | The purpose of the presentation was to explore ground for scientific collaboration. |
Year(s) Of Engagement Activity | 2019 |
Description | Oral Presentation (Dublin) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Selected Oral presentation at the microbiology society Microbes and Mucosal Surfaces conference. |
Year(s) Of Engagement Activity | 2018 |
Description | Oral presentation at Microbial Glycobiology Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Oral presentation at the Microbial Glycobiology Meeting. |
Year(s) Of Engagement Activity | 2020 |
Description | Poster Presentation (Canada) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Poster presentation to an international academic audience, at a conference on Microbiome, Host Resistance and Disease |
Year(s) Of Engagement Activity | 2018 |