Bile acid modification by the human gut microbiota and its role in pathogenesis of colorectal cancer

Lead Research Organisation: University of Brighton
Department Name: Sch of Pharmacy & Biomolecular Sciences

Abstract

The human gut is home to a wide range of bacteria, and every adult harbours around 100 trillion microbial cells in their intestines belonging to hundreds of bacterial species. This population of bacteria is referred to as the gut microbiota, and these bacteria are thought to undertake numerous beneficial activities. However some of the activities undertaken by the gut microbiota may be involved in the development of colorectal cancer (CRC).
Diet, and in particular a high intake of animal fat and red meat, has been identified as a major risk factor for CRC, but it is not yet clear how these dietary factors lead to the development of CRC. It is important for us to understand the causes of diseases like CRC, in order to develop effective treatments or identify ways in which the disease could be prevented altogether.
Recent studies have indicated that the gut microbiota may be an important factor in the influence of diet on CRC risk, and in particular the ability of gut microbes to modify components of bile, called bile acids. Bile acids are naturally produced by our bodies to help us digest the fat contained within the food we eat, and a diet rich in fat results in a increased level of bile acid in the intestine. Bile acids are readily converted to different forms by the gut microbiota, and some of these altered bile acids may be carcinogenic and affect the expression of genes thought to be important in the development of CRC.
The purpose of this study is to investigate the relationship between the modification of bile acids by gut bacteria and development of CRC, to determine how these microbes may cause this disease. By comparing the gut bacteria of individuals with CRC and those who are healthy, we will be able to identify any association between activities of these microbes and risk of disease. Subsequently we will be able to look at the effect of these bacteria on specific human genes known to be associated with CRC, which will allow us to identify the how gut bacteria may trigger development of CRC.

Technical Summary

CRC is the third most common malignancy worldwide and it is estimated that more than 100 new cases are diagnosed daily in the UK. The incidence of this disease worldwide has risen from ~500,000 new cases in 1975 to over a million new cases in 2002. Acquisition and pathogenesis of sporadic CRC is complex and multifactorial. While diet has consistently been associated with an increased risk of CRC, the underlying mechanisns which result in genetic damage and carcinogenesis are poorly understood. There is increasing evidence that the indigenous gut microbial population is a significant factor in the pathogenesis of CRC, and that this community mediates the effects of diet on colonic health.
In particular microbial bile acid modification is emerging as a key activity through which the gut microbial population and dietary factors interact to initiate CRC or enhance its progression. The products of microbial bile acid metabolism have been proposed to act as carcinogens and activate pro-inflammatory regulators such as NF-kB and COX-2 which result in the inhibition of apoptosis and the survival of malignant cells. Recent studies have also indicated that the capacity for bile acid modification may vary between the gut microbial populations of different individuals, and if so this could relate to overall risk of CRC acquisition.
The overall aim of this project is to identify any relationship between the capacity for bile acid modification in the human gut microbiota and acquisition of colorectal cancer. The capacity for bile acid metabolism in the gut microbiomes of healthy individuals, and those with CRC and pre-cancerous polyps will be determined and compared. The contribution of microbial bile salt hydrolase (BSH) upon activation of key host encoded genes (NF-kB and COX-2) involved in inflammation, inhibition of apoptosis, and acquisition of CRC will be established. Ultimately this will clarify the relationship between microbial bile acid metabolism and CRC, and elucidate underlying mechanisms of disease.

Publications

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Buelow E (2014) Effects of selective digestive decontamination (SDD) on the gut resistome. in The Journal of antimicrobial chemotherapy

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Jones Brian (2011) Bacterial bile acid modification and potential pharmaceutical applications in Journal fo Applied Therpeutic Research

 
Description Alternatives 2 antibiotics Wellcome Trust and DoH commissioned policy document
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description SfAM HoC Select S&T common ABR
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description Dunhill Medical Trust Proof of Concept award
Amount £71,914 (GBP)
Funding ID R394/1114 
Organisation The Dunhill Medical Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2015 
End 11/2017
 
Description Internal PhD studentship
Amount £55,000 (GBP)
Organisation University of Brighton 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 10/2014
 
Description MRC Developmental Pathways Funding Scheme (Biomedical Catalyst)
Amount £443,000 (GBP)
Funding ID MR/N006496/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2015 
End 10/2019
 
Description Microneedles: Bypassing the Gastrointestinal Microbiota to Circumvent Antibiotic Resistance
Amount £908,272 (GBP)
Funding ID 206854/Z/17/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2018 
End 05/2022
 
Description Research Challenges
Amount £50,000 (GBP)
Organisation University of Brighton 
Sector Academic/University
Country United Kingdom
Start 11/2012 
End 11/2013
 
Description SfAM Presidents Fund
Amount £1,200 (GBP)
Organisation Society for Applied Microbiology 
Sector Learned Society
Country United Kingdom
Start 09/2011 
End 11/2011
 
Description University of Brighton Doctoral Training Scholarships
Amount £55,000 (GBP)
Organisation University of Brighton 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 10/2015
 
Title Genome Signtnature analysis for metagenomes 
Description Developed new approaches for analysis metagenomic datasets which will be and have already been highly beneficial in our research. This was developed in response the the large number of sequence that are of unknown phylogenetic affiliation in any give metagenomic dataset, impeding analysis. Our new approach proves a strategy which can help classify metagenomic sequences and was validated by dissection of viral sequences from existing gut metagenomes, and provided an indication of their bacterial host range. This also revealed the potential existence of "viral enterotypes" in the gut microbiome. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This has allowed us to initiate work aimed at understanding relatively unexplored facets of the human gut microbiome and how this may related to risk/progression/diagnosis of disease such as CRC. 
URL http://www.nature.com/ncomms/2013/130916/ncomms3420/full/ncomms3420.html
 
Title Human faecal samples collection 
Description We have begun devleoping a collection fo stool samples from patients with colorectal cancer, polyposis and healthy controls, along with information of generla diet and weight. Furthermore, we have also formed a collaboration with research groups in Czech republic to aquire siilar samples from this country also. 
Type Of Material Biological samples 
Provided To Others? No  
Impact Work usng these smaples is currently ongoign and impacts will not be apparent until later int he project. However these material allow a wide range of research project to be pursed in our lab, and the aquisition of samples from countries outsde the UK in particular will faciliate more effective comparisions of gut microbiomes related to colorectal cancer, between countries. 
 
Description 16S pyro sequencing and shotgun metagenomes - Paul Cotter 
Organisation Teagasc
Department Teagasc Food Research Centre
Country Ireland 
Sector Academic/University 
PI Contribution This collaboration will afford a considerably more detailed and in depth survey of gut microbiome composition in health and disease, than originally intended.
Collaborator Contribution My team will undertake sample processing and preparation, with collaborators providing access to pyro-sequencing facilities to provide 16S sequences. We now also have the opportunity ti generate shotgun metagenomes of a subset of samples. Both groups will participate in data analysis.
Impact This collaboration has so far allowed us to optimise methods for metagenomic DNA extraction and 16S rRNA gene amplification from stool samples. We have now generated in depth 16S sequence data from 61 stool samples and are presently analysing the data. We are also in the process of generating full shotgun metagenomes fro 15 samples (5 per group).
Start Year 2011
 
Description Genome signatures - UWE 
Organisation University of the West of England
Country United Kingdom 
Sector Academic/University 
PI Contribution We are working with colleague at UWE to further develop and apply genome signature based tools of analysis of metagenomes.
Collaborator Contribution Expertise in bioinformatics.
Impact no outputs yet
Start Year 2015
 
Description Metabolomics, Liz Hill, Sussex 
Organisation University of Sussex
Department School of Life Sciences Sussex
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration facilitates analysis of the capacity for bile acid metabolism in the human gut microbiome. My team is coordinating the collection and preparation of human stool samples, and will undertake analysis of the microbiome. Collaborators at UoS will analyse the faecal metabolome.
Collaborator Contribution Collaborators will help us to realise a key element of the project directed towards analysis of bile acid species present in stool samples. When combined with data regarding the microbiome this will permit us to better understand changes in capacity for bile acid modification in health and disease. However, collaborators will also be able to expand this analysis to the metabolome as a whole provide significant more insight and potentially allowing us to identify other disease biomarkers.
Impact Methods for metabolite extraction have been optimised and processing of stool samples is ongoing. This involves a multi-disceplinary collaboration between microbiologist, molecular biologists, and chemists. We have now submitted a paper for publication on the faecal metabolome and methods to analyse this.
Start Year 2011
 
Description UMC Utrecht metagenomic libraires 
Organisation University Medical Center
PI Contribution Provided knowledge, and triaing for the construction of large instert metagneomic libraries from the human gut microboota for a research group based at UMC Utrecht
Collaborator Contribution This collaboration will allow us to access new methods and techniques to explore the gut microboiome not currently avasilable through exisiting collaborations defined in the original proposal.
Impact Prelimianry data from screening of these libriares has been presented at the Human Microbiome Conference 2011, Vancouver, Canada. A manuscript resulting from this collaboration has now been published in The Journal of Antimicrobial Chemotherapy (Buelow et al 2014 PMID: 24710024)
Start Year 2011
 
Description University Hospital Motol, Prague, Czech Rep. 
Organisation University Hospital Motol
Department Surgery Department - 2nd Medical Faculty
Country Czech Republic 
Sector Hospitals 
PI Contribution Collaborators at UHM, Prague are currently collecting stool samples from individuals with intestinal polyps, colorectal cancer, and healthy controls. Documentation required for ethical approval was prepared by my team in consultation with Czech partners, and samples will be shipped to my laboratory for analysis of the gut microbiome.
Collaborator Contribution The provision of stool samples is vital to the element of the project concerned with analysis of the gut microbiome and capacity for bile acid modification in health and disease. Access to patient samples from Czech republic not only helps deliver original project aims, but also provides an added dimension in access to samples from a geographically distinct region.
Impact Initiated collection of stool human stool samples form Czech republic. Current 10 samples have been acquired comprising a mixture of healthy, poly and CRC samples. Collection is continuing at UHM. This collaboration is between clinical and academic partners. We have now submitted a paper for publication on the faecal metabolome and methods to analyse this.
Start Year 2011
 
Description Alternatives to Antibiotics working group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Member of the alternatives to antibiotics working party organised by the Wellcome Trust and Dept of Health to review status of alternatives portfolio and suggest priority areas for funding.
Year(s) Of Engagement Activity 2015,2016
URL http://www.wellcome.ac.uk/News/Media-office/Press-releases/2016/WTP060091.htm
 
Description Hospital visit and presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Gave a tlak to hospital staff regarding the gut microbiota and coclon cancer.

Staff indicated that they had gained an intertesing insiht to this field and were keen to participate in research of this nature.
Year(s) Of Engagement Activity 2011
 
Description NComms press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press release regarding work published in Ogilvie et al 2013 PMID 24036533. Results have still not been ascertained, but one invitation for interview was received shortly after.

Dissemination of research findings to a wide audience
Year(s) Of Engagement Activity 2013
URL http://www.brighton.ac.uk/news/2013/130918understanding_viruses.php?PageId=810&dm_i=1RM7,1V6AH,A8104...
 
Description News article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact News article describing research in local news paper

NA
Year(s) Of Engagement Activity 2010
 
Description Science Education Meeting fro Nursing staff (Royal Sussex County Hospital) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Local
Primary Audience Health professionals
Results and Impact Presented current understanding on the human gut microbiome, including preliminary data from our MRC funded research to nursing staff at the Royal Sussex Country Hospital. Run as inform presentation and discussion group covering what our work may mean, and wider work in the area of the human gut microbiome on the diagnosis, treatment and management of disease. Helped healthcare staff engage with and take onboard new scientific knowledge in this area and understand how this may eventually impact on their work - as well as discussing how they can become more involved in the research process.

Nursing staff indicated that this gave them a greater understanding and awareness of research in this area, and also increased interest in becoming involved in aspects of research in this area. Staff indicated this knowledge will also be useful in answering patient queries on related fields such as use of probiotics.
Year(s) Of Engagement Activity 2013
 
Description Science News Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interview with Journalist from Science News (Washington DC, USA) regarding human gut microbiome research and in particular the human gut virome.

International dissemination of our research to a a broad audience including the general public.
Year(s) Of Engagement Activity 2013
URL https://www.sciencenews.org
 
Description Yakut HCP study day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited to participate in the Yakult sponsored study day for healthcare practitioners, and cover the topic of probiotics and cancer. NB: invitation to participate has been accepted but the event is not scheduled to take place until 20th October 2016
Year(s) Of Engagement Activity 2016