Uncovering the molecular strategies that allow human gut symbionts to degrade insoluble dietary and host glycans
Lead Research Organisation:
Quadram Institute
Department Name: Gut Microbes and Health
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
The human colonic microbiota gains most its energy by degrading insoluble substrates such as non-digestible plant fibre, starch particles and mucin. Fermentation of these substrates has important consequences for gut metabolism and human health, but is initiated by a few specialised 'keystone' species. This project will investigate for the first time the enzyme systems and attachment mechanisms that enable keystone species of human intestinal ruminococci to degrade insoluble resistant starches (R. bromii), cereal bran (R. champanellensis) and mucin (R. gnavus). This will require functional characterisation of carbohydrate-active systems identified by bioinformatic analysis of draft genomes as playing a key role in the degradation pathways of these insoluble substrates. These include catalytic domains and modules that may be involved in binding to carbohydrate substrates, in protein:protein interactions and in attachment to the bacterial cell surface. In particular the project will investigate the putative roles of dockerin and cohesin modules in assembling enzyme complexes, which are likely to include the first case of an 'amylosome' in any microorganism, and the first case of a 'cellulosome' in a human colonic bacterium; and determine for the first time, the complement of enzymes required for mucin degradation in Firmicutes. The project will also use anaerobic co-culture studies to investigate interactions with other dominant members of the human intestinal microbiota, specifically with hydrogen-utilizing organisms, and with 'secondary' carbohydrate-utilizing species such as Bacteroides thetaiotaomicron. The impact of co-cultures and cross-feeding will be assessed upon bacterial growth, metabolite production and gene expression. Finally, selected co-culture experiments will be translated into gnotobiotic mice in order to relate bacterial utilization of insoluble substrates under in vivo conditions to changes in enzymes and metabolites relevant to health.
Planned Impact
BBSRC Strategy
The research fits with the BBSRC's Bioscience Underpinning Health priority and its Grand Challenge 3 - Fundamental bioscience enhancing lives and improving wellbeing (BBSRC Delivery Plan 2011-15). The work also has potential to benefit the food production and processing sector, and is therefore also relevant to the Food Security Priority.
National Health Service & Consumers
The research has the potential to impact on the nation's health and welfare through reducing the onset and progression of gut-associated diseases. Variation in microbiota composition has been suggested to underlie intolerance of high-fibre diets in certain groups (eg. IBS sufferers) that is associated with excessive fermentation. Irritable bowel syndrome (IBS) is one of the commonest long-term gastrointestinal conditions. It is estimated that 10-20% of the UK's population is affected by IBS at any one time, although this figure may be higher because many people with the condition do not report their symptoms to their GP.
IBS is twice as common in women as it is in men. The condition normally develops in people who are between 20 and 30 years of age, but it can affect people of any age. It is estimated that three out of four people with IBS will have at least one bout of depression, and just over half will develop generalised anxiety disorder (a condition that can cause overwhelming feelings of anxiety, fear and dread). These have a major adverse impact on the potential economic contribution of this demographic.
Prebiotics are selectively fermented, dietary ingredients that result in specific changes in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health. Unlike probiotics, a prebiotic targets the microbiota already present within the ecosystem, acting as a 'food' for the target microbes seen as beneficial. To date, the majority of prebiotic strategies have been based on an empirical approach to manipulate levels of bifidobacteria, lactic acid bacteria that make up a small proportion of the adult microbiota. Thus, the potential to specifically manipulate other beneficial members of the gut microbial community remains largely unexplored. The data generated in the project will provide us with the unparalleled opportunity of developing prebiotic strategies, specifically targeted to distinct members of the microbiota, with the aim of modulating levels of metabolites and host-microbe interactions that provide significant health benefits. Such preventive treatments will significantly reduce NHS costs, and improve the health of the nation.
Policy makers & Government
Prebiotics are currently being discussed by working parties of international scientific organizations such as the Food and Agriculture Organization of the WHO and the International Life Sciences Institute and changes to the definition and concept may follow in time. For now, their use as food ingredients or supplements is currently popular and gaining momentum. The research is likely to provide evidence for use of experts who sit on advisory panels that contribute to policy or dietary advice.
Food & Biotech industry,
The outcomes of this project will thus be of direct interest to enzyme companies involved in the development of commercial and non-commercial (e.g. academic enzymes) enzymes. CAZymes are used as biocatalysts in a wide range of industrial biotechnology sectors based on processing of plant and cell wall polysaccharides, encompassing business segments such as Fabric and Household Care (enzymes for laundry and dishwashing detergents), Technical Enzymes (enzymes for carbohydrate processing as well as textile treatment), Pulp and Paper, and Food and Animal Nutrition (enzymes for bread, feed and brewing applications).
The research fits with the BBSRC's Bioscience Underpinning Health priority and its Grand Challenge 3 - Fundamental bioscience enhancing lives and improving wellbeing (BBSRC Delivery Plan 2011-15). The work also has potential to benefit the food production and processing sector, and is therefore also relevant to the Food Security Priority.
National Health Service & Consumers
The research has the potential to impact on the nation's health and welfare through reducing the onset and progression of gut-associated diseases. Variation in microbiota composition has been suggested to underlie intolerance of high-fibre diets in certain groups (eg. IBS sufferers) that is associated with excessive fermentation. Irritable bowel syndrome (IBS) is one of the commonest long-term gastrointestinal conditions. It is estimated that 10-20% of the UK's population is affected by IBS at any one time, although this figure may be higher because many people with the condition do not report their symptoms to their GP.
IBS is twice as common in women as it is in men. The condition normally develops in people who are between 20 and 30 years of age, but it can affect people of any age. It is estimated that three out of four people with IBS will have at least one bout of depression, and just over half will develop generalised anxiety disorder (a condition that can cause overwhelming feelings of anxiety, fear and dread). These have a major adverse impact on the potential economic contribution of this demographic.
Prebiotics are selectively fermented, dietary ingredients that result in specific changes in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health. Unlike probiotics, a prebiotic targets the microbiota already present within the ecosystem, acting as a 'food' for the target microbes seen as beneficial. To date, the majority of prebiotic strategies have been based on an empirical approach to manipulate levels of bifidobacteria, lactic acid bacteria that make up a small proportion of the adult microbiota. Thus, the potential to specifically manipulate other beneficial members of the gut microbial community remains largely unexplored. The data generated in the project will provide us with the unparalleled opportunity of developing prebiotic strategies, specifically targeted to distinct members of the microbiota, with the aim of modulating levels of metabolites and host-microbe interactions that provide significant health benefits. Such preventive treatments will significantly reduce NHS costs, and improve the health of the nation.
Policy makers & Government
Prebiotics are currently being discussed by working parties of international scientific organizations such as the Food and Agriculture Organization of the WHO and the International Life Sciences Institute and changes to the definition and concept may follow in time. For now, their use as food ingredients or supplements is currently popular and gaining momentum. The research is likely to provide evidence for use of experts who sit on advisory panels that contribute to policy or dietary advice.
Food & Biotech industry,
The outcomes of this project will thus be of direct interest to enzyme companies involved in the development of commercial and non-commercial (e.g. academic enzymes) enzymes. CAZymes are used as biocatalysts in a wide range of industrial biotechnology sectors based on processing of plant and cell wall polysaccharides, encompassing business segments such as Fabric and Household Care (enzymes for laundry and dishwashing detergents), Technical Enzymes (enzymes for carbohydrate processing as well as textile treatment), Pulp and Paper, and Food and Animal Nutrition (enzymes for bread, feed and brewing applications).
People |
ORCID iD |
Nathalie Juge (Principal Investigator) |
Publications
Crost EH
(2018)
Mechanistic Insights Into the Cross-Feeding of Ruminococcus gnavus and Ruminococcus bromii on Host and Dietary Carbohydrates.
in Frontiers in microbiology
Crost EH
(2016)
The mucin-degradation strategy of Ruminococcus gnavus: The importance of intramolecular trans-sialidases.
in Gut microbes
Flint H
(2015)
The role of microbes in carbohydrate digestion
in Food Science & Technology
Laverde Gomez JA
(2019)
Formate cross-feeding and cooperative metabolic interactions revealed by transcriptomics in co-cultures of acetogenic and amylolytic human colonic bacteria.
in Environmental microbiology
Mukhopadhya I
(2018)
Sporulation capability and amylosome conservation among diverse human colonic and rumen isolates of the keystone starch-degrader Ruminococcus bromii.
in Environmental microbiology
Tailford LE
(2015)
Discovery of intramolecular trans-sialidases in human gut microbiota suggests novel mechanisms of mucosal adaptation.
in Nature communications
Tailford LE
(2015)
Mucin glycan foraging in the human gut microbiome.
in Frontiers in genetics
Description | We have obtained novel mechanistic insights into the ability of some gut bacteria to utilise mucin glycans. We suggested a novel strategy by which gut bacteria adapt to the mucosal environment. Our new data support the hypothesis that mucin-degraders such as Ruminococcus gnavus play a key role in establishing cross-feeding activities to sustain a mucosa-associated microbiota (Crost et al. 2018 Front Microbiol.). In collaboration with Aberdeen we have contributed to unravelling the molecular pathways resulting in resistant starch utilisation in gut bacteria (Laverde Gomez Environ Microbiol. 2019; Mukhopadhya et al., Environ Microbiol. 2018). |
Exploitation Route | The mechanisms identified during this study provide molecular leads that can be used to establish new strategies to modulate the gut microbiota. The glycoenzymes characterised as part of this study may have industrial applications in the biotech and biopharmaceutical sectors. |
Sectors | Agriculture Food and Drink Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
URL | https://quadram.ac.uk/juge-flint-grant/ |
Description | EDESIA PhD studentship |
Amount | £24,000 (GBP) |
Organisation | Quadram Institute Bioscience |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2020 |
End | 09/2024 |
Description | Training interdisciplinary glycoscientists to get a molecular- level grip on glycocodes at the human mucosa-microbiota |
Amount | £466,300 (GBP) |
Funding ID | 814102 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 01/2019 |
End | 12/2022 |
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 | Carbohydrate synthesis |
Organisation | University of California |
Country | United States |
Sector | Academic/University |
PI Contribution | Utilised carbohydrates provided by collaborator in scientific research projects |
Collaborator Contribution | Provided bespoke carbohydrates upon request |
Impact | Carbohydr Res. 2017 Nov 8;451:110-117. doi: 10.1016/j.carres.2017.08.008; Nat Commun. 2017 Dec 19;8(1):2196. doi: 10.1038/s41467-017-02109-8. |
Start Year | 2015 |
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 | Rowett |
Organisation | University of Aberdeen |
Department | The Rowett Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provided expertise in transcriptomics, metabolomics and access to germ-free mouse facility |
Collaborator Contribution | Provided resistant starch degrading bacteria |
Impact | Environ Microbiol. 2018 Jan;20(1):324-336. doi: 10.1111/1462-2920.14000; MBio. 2015 Sep 29;6(5):e01058-15. doi: 10.1128/mBio.01058-15. Food Science & Technology , pp. 24-26 |
Start Year | 2014 |
Description | STD-NMR |
Organisation | University of East Anglia |
Department | Schools of Pharmacy and Medicine UEA |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We provided proteins and ligands for analysis by STD NMR to complement some of our data on mechanisms of host-bacteria interactions. This collaboration resulted in high impact joint publications led by QIB (Proc Natl Acad Sci U S A. 2018 pii: 201715016; Nat Commun. 2017 ;8(1):2196) |
Collaborator Contribution | STD- NMR analysis of proteins and ligands we provided. Some of this work led to the development of DEEP STD NMR, leading to a joint publication led by UEA (Angew Chem Int Ed Engl. 2017 56:15289-15293). |
Impact | Proc Natl Acad Sci U S A. 2018 pii: 201715016; Nat Commun. 2017 ;8(1):2196; Angew Chem Int Ed Engl. 2017 56:15289-15293 |
Start Year | 2014 |
Description | Synchrotron Oxford |
Organisation | Diamond Light Source |
Country | United Kingdom |
Sector | Private |
PI Contribution | Provided collaborator with proteins and ligands for X-ray crystallography and cryo-EM |
Collaborator Contribution | X-ray crystallography of proteins free and in complex |
Impact | Nat Commun. 2017 Dec 19;8(1):2196. doi: 10.1038/s41467-017-02109-8. |
Start Year | 2016 |
Description | 4th Annual European Microbiome Congress |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Attendance to 4th Annual European Microbiome Congress. This Conference has a high representation from the Industry: Pharmaceutical companies and Biotechnology companies and provided an excellent opportunity to make contact and discuss work relevant to the Institute Strategic Programmes. The PROMOTING WOMEN IN SCIENCE lunch session was inspiring. |
Year(s) Of Engagement Activity | 2018 |
Description | Academia-Industry Networking CarboMet event |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | I co-organised and chaired a two day workshop on 'The Role of Carbohydrates in the Gut Microbiome' June 2018 in Brussels attended by 40 delegates from academia and industry as apart of CarboMet. CarboMet (Metrology of Carbohydrates for European Bioindustries) is a four-year Coordination and Support Action (CSA) funded by Horizon 2020 FET-OPEN. It is an European Network that facilitates engagement between key players and stakeholders of the glycoscience community across Europe to identify the current state of the art and in particular future innovation and technological challenges in carbohydrate metrology. I co-wrote and edited the CarboMet positioning paper on 'The Essential Roles of Carbohydrates in Promoting Gut Microbiota Function Through All Stages of Life' which summarises discussions that took place during the workshop. |
Year(s) Of Engagement Activity | 2018 |
URL | https://carbomet.eu/news/positioning-paper-on-role-of-carbohydrates-in-gut-microbiota-function/ |
Description | IBCarb |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Contributed to the final IBCarb workshop Glycobiotechnology 2018. IBCarb (Glycoscience Tools for Biotechnology and Bioenergy) is a growing network of glycoscientists from academia and industry. IBCarb was one of the Networks in Industrial Biotechnology and Bioenergy funded by the BBSRC. The workshop was very successful and attracted around 150 attendees (international audience from academia and industry) . This was an opportunity to showcase the Glycosciences carried out in the UK and in partnership with industrial/business partners. |
Year(s) Of Engagement Activity | 2018 |
URL | https://ibcarb.com/events/ |
Description | Science Festival in Norwich |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Presentation of an interactive stand and posters at the Science Festival at the Norwich Cathedral on 'Mucus and gut microbes: a sweet relationship to keep us healthy' |
Year(s) Of Engagement Activity | 2016 |