The role of mucus in the cross-talk between gut bacteria and the host

Lead Research Organisation: Institute of Food Research
Department Name: Contracts

Abstract

Our core-research focuses on the study of the molecular mechanisms mediating the interaction between gut bacteria and the mucus layer. We are especially interested in the role played by bacterial adhesins (e.g. mucus binding proteins) and enzymes (e.g. carbohydrate–active enzymes, CAZymes) from major gut symbionts. Our project aims to define the nature and specificity of the interaction and characterize bacterial effectors and mucus receptors (e.g. mucin glycans) at the molecular and structural level. The experimental approaches include functional and comparative genomics, transciptomics, metabolomics, complemented by detailed molecular enzymology and structural studies of bacterial adhesins and CAZymes. Another aspect of our core-research is to define what constitutes a functional mucus layer and how it influences/is influenced by the host mucosal immune system and the microbiota. Here we rely on the use of specific mouse models (with alterations in immune and epithelium cells, microbiota composition) and the development of ex vivo intestinal cell models to assess the impact of bacteria interaction to mucus on the host, using histoimmunochemistry, confocal microscopy, gene expression studies and complemented by glycomics approach to analyse changes in mucin structure and function.

Publications

10 25 50

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Etzold S (2014) Structural insights into bacterial recognition of intestinal mucins. in Current opinion in structural biology

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Flint H (2015) The role of microbes in carbohydrate digestion in Food Science & Technology

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Gunning AP (2013) Mining the "glycocode"--exploring the spatial distribution of glycans in gastrointestinal mucin using force spectroscopy. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

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Jeffers F (2010) Mucin-lectin interactions assessed by flow cytometry. in Carbohydrate research

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Juge N (2019) Special Issue: Gut Bacteria-Mucus Interaction. in Microorganisms

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Juge N (2012) Microbial adhesins to gastrointestinal mucus. in Trends in microbiology

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Juge N (2016) Sialidases from gut bacteria: a mini-review. in Biochemical Society transactions

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Kober OI (2014) ?d T-cell-deficient mice show alterations in mucin expression, glycosylation, and goblet cells but maintain an intact mucus layer. in American journal of physiology. Gastrointestinal and liver physiology

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Latousakis D (2018) How Sweet Are Our Gut Beneficial Bacteria? A Focus on Protein Glycosylation in Lactobacillus. in International journal of molecular sciences

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Leclaire C (2018) Molecular basis for intestinal mucin recognition by galectin-3 and C-type lectins. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

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Monaco S (2017) Differential Epitope Mapping by STD NMR Spectroscopy To Reveal the Nature of Protein-Ligand Contacts. in Angewandte Chemie (International ed. in English)

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Nielsen MM (2011) Substrate and metal ion promiscuity in mannosylglycerate synthase. in The Journal of biological chemistry

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Rodríguez JM (2015) The composition of the gut microbiota throughout life, with an emphasis on early life. in Microbial ecology in health and disease

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Sequeira S (2018) Structural basis for the role of serine-rich repeat proteins from in gut microbe-host interactions. in Proceedings of the National Academy of Sciences of the United States of America

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Tailford LE (2015) Mucin glycan foraging in the human gut microbiome. in Frontiers in genetics

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Thursby E (2017) Introduction to the human gut microbiota. in The Biochemical journal

 
Description This research identified important enzymes and proteins involved in carbohydrate metabolism in the human gut. These include glycoenzymes from gut bacteria and bacterial adhesins shown to be important for the ability of gut bacteria to interact with the host. We have notably discovered a novel enzyme activity in our gut bacteria which may help beneficial bacteria to colonise our gut at the expense of pathogenic microbes. We also showed the importance of specific cell-surface proteins present on beneficial bacteria in the adhesion to the gut wall, biofilm formation, host adaptation, and communication with the host immune system.
Exploitation Route Specific carbohydrate-active enzymes from gut bacteria could be used as potential biomarkers of health and diseases and therapeutics.

Specific carbohydrate-active enzymes from gut bacteria could be used as a tool to modulate the gut microbial community.

Specific carbohydrate-active enzymes from gut bacteria could be developed as anti-infective strategies against pathogens .

Specific carbohydrate-active enzymes from gut bacteria could be used as a tool for glycan analysis and synthesis.

Specific bacterial adhesins could be used to target different sites of the gastrointestinal tract to enhance drug delivery systems.
Sectors Agriculture, Food and Drink,Pharmaceuticals and Medical Biotechnology

 
Description We have published a patent application and are actively engaged with QIB Business Team to take our technology forward. The patent has now entered International phase.
Sector Healthcare
 
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 10/2015 
End 05/2016
 
Description Evaluation of HMOs on gut barrier function
Amount £200,000 (GBP)
Organisation Glycom A/S 
Start 01/2017 
End 07/2019
 
Description Glycoenzymes for Bioindustries
Amount £1,243,310 (GBP)
Funding ID BB/M029034/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2015 
End 09/2020
 
Description Investigating the mechanisms of Fusobacterium nucleatum adaption to the colorectal cancer tumour microenvironment
Amount £130,000 (GBP)
Organisation Big C Cancer Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2019 
End 12/2019
 
Description Mucin-derived sialic acid metabolism in gut bacteria
Amount £549,580 (GBP)
Funding ID BB/P008895/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2017 
End 04/2020
 
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 10/2016 
End 09/2020
 
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 10/2015 
End 09/2019
 
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 09/2016 
End 10/2020
 
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 09/2017 
End 10/2021
 
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 09/2018 
End 10/2022
 
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 Uncovering the molecular strategies that allow human gut symbionts to degrade insoluble dietary and host glycans
Amount £391,303 (GBP)
Funding ID BB/L008602/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 03/2014 
End 09/2017
 
Title DEEP-STD NMR 
Description Our collaboration with Jesus Angulo at UEA led to the development of a new way of analysing how drugs interact with molecules throough adaptation of a technique known as ligand-based Nuclear Magnetic Resonance (NMR) spectroscopy 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? Yes  
Impact This method could to lead to stronger and more selective drug candidates. 
URL https://quadram.ac.uk/completing-drug-design-jigsaw/
 
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 Charity/Non Profit 
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 Collabration with Industry 
Organisation Glycom A/S
PI Contribution Expertise on mucus biology and gut barrier function
Collaborator Contribution Provision of human milk oligosaccharides for testing
Impact Confidential
Start Year 2017
 
Description Glycoimmunology 
Organisation University of Dundee
Department Division of Cell Signalling and Immunology
Country United Kingdom 
Sector Academic/University 
PI Contribution Exchange of ideas and findings
Collaborator Contribution Exchange of ideas and materials/member of Supervisory PhD Commiteee
Impact Joint abstracts to Conferences (posters and oral presentations)
Start Year 2018
 
Description IVOC 
Organisation University of East Anglia
Department School of Medicine UEA
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided expertise/knowledge in mucus biology and gut symbionts. Provided material to study bacteria-mucus interaction using IVOC (including bacterial strains and antibodies).
Collaborator Contribution Provided expertise/knowledge in cell biology in particular in vitro organ culture to study bacterial pathogen interactions.
Impact Joint PhD studentships. Joint publications: Cell Microbiol. 2017 Jun;19(6). doi: 10.1111/cmi.12717; Front Microbiol. 2016 Mar 1;7:244. doi: 10.3389/fmicb.2016.00244
Start Year 2012
 
Description Iceni 
Organisation Iceni Diagnostics
PI Contribution Supervision of research project
Collaborator Contribution Provided industry placement to post-doctoral scientists working on the project
Impact Carbohydr Res. 2017 Nov 8;451:110-117. doi: 10.1016/j.carres.2017.08.008.
Start Year 2016
 
Description Lactobacillus 
Organisation University of Alberta
Country Canada 
Sector Academic/University 
PI Contribution Supervision of projects on molecular/structural mechanisms of Lactobacillus reuteri adaptation/adhesion to the gut . .
Collaborator Contribution Supervision of projects on ecology of Lactobacillus reuteri adaptation to the host.
Impact BMC Genomics. 2015 Dec 1;16:1023. doi: 10.1186/s12864-015-2216-7;PLoS Genet. 2013;9(12):e1004057. doi: 10.1371/journal.pgen.1004057; PLoS Genet. 2011 Feb;7(2):e1001314. doi: 10.1371/journal.pgen.1001314; Microbiology. 2010 Nov;156(Pt 11):3368-78. doi: 10.1099/mic.0.043265-0.
Start Year 2009
 
Description Microbial polysaccharides 
Organisation Azienda Ospedaliera Universitaria Seconda Università di Napoli
PI Contribution Provided collaborator with bacterial samples to be analyses
Collaborator Contribution Purified bacterial cell surface polysaccharides and analysed glycosylation chemical structures
Impact Joint Abstract describing the collaborative work to Conference
Start Year 2018
 
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 Academic/University 
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 X-ray crystallography- UEA 
Organisation University of East Anglia
Country United Kingdom 
Sector Academic/University 
PI Contribution Supervision of projects investigating mechanisms of adhesions of gut bacteria with the host.
Collaborator Contribution X-ray crystallography of bacterial adhesins
Impact Proc Natl Acad Sci U S A. 2018 Mar 5. pii: 201715016. doi: 10.1073/pnas.1715016115; Mol Microbiol. 2014 May;92(3):543-56. doi: 10.1111/mmi.12574; Environ Microbiol. 2014 Mar;16(3):888-903. doi: 10.1111/1462-2920.12377;J Biol Chem. 2009 Nov 20;284(47):32444-53. doi: 10.1074/jbc.M109.040907.
Start Year 2007
 
Title Intramolecular trans-sialidase. 
Description The patent relates to the identification of an intramolecular trans-sialidase (ITsialidase) and to intramolecular trans-sialidase (IT-sialidase)-expressing bacteria. The invention further relates to compositions and uses of said intramolecular trans-sialidase enzyme and the enzyme expressing bacteria in medicine, in particular for the therapeutic and prophylactic treatment of infections and respiratory conditions. 
IP Reference WO2017134466 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact In progress
 
Description Genome Analysis of Lactobacillus reuteri ATCC53608 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The oral presentation (20 min) to the Friends of the JIC was under the TGAC banner and was followed by informal discussions with the attendees.
Year(s) Of Engagement Activity 2013
URL https://www.jic.ac.uk/whats-on/fojic/
 
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
 
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 CarboMet event (Barcelona) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Participation into CarboMet workshop with the view to:1.Establish a European Glycoscience User Group (EU-GUG)
2.Identify Common Scientific and Technical Challenges
3.Establish a Common Vision, Roadmap for 2030 and an Associated Implementation Plan
4.Through Knowledge Exchange Activities Facilitate the Formation of a Cross- Sectorial Glycoscience Metrology Platform
5.Establish Parallel Initiatives to Address Key Glycoscience Challenges
Year(s) Of Engagement Activity 2017
URL https://carbomet.eu/
 
Description Glycobiology Network Latin America 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Workshop on Glycobiology of host-microbe interactions in the gut. Biotechnology and glycobiology tools for human health, Guanajuato, Mexico, 9-11/10/2017
Year(s) Of Engagement Activity 2017
 
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 NNUH Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact Presentation of a poster describing our study on the influence of human milk oligosaccharides on gut barrier function in collaboration with gastroenterologists from NNUH and NRP biorepository
Year(s) Of Engagement Activity 2017
 
Description Nature café event 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Engagement with researchers and policy makers interested in the microbiome and/or probiotics and prebiotics, editors from relevant Nature journals and Yakult representatives.
Year(s) Of Engagement Activity 2017
 
Description School visit (Norwich) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk and Discussion about 'What is it like to be a Scientist?' from a female perspective
Year(s) Of Engagement Activity 2017
 
Description Science Festival Norwich 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presentation around 'Mucus and gut microbes: a sweet relationship to keep us healthy' stand and poster , interactive activities and discussions
Year(s) Of Engagement Activity 2017
URL http://norwichsciencefestival.co.uk/
 
Description Sugars and the maintenance of a healthy GI tract 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The oral presentation (20 min) on Carbohydrates "Sugars: more than just calories" was followed by lively informal discussions with attendees .
Year(s) Of Engagement Activity 2014
URL https://www.jic.ac.uk/whats-on/fojic/
 
Description What makes our gut bacteria stick? 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The oral presentation was followed by a Q&A session.
Year(s) Of Engagement Activity 2013