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Crohn Disease: HELP
Articles by Georgina Louise Hold
Based on 14 articles published since 2010
(Why 14 articles?)

Between 2010 and 2020, G. Hold wrote the following 14 articles about Crohn Disease.
+ Citations + Abstracts
1 Review Review article: the gut microbiome in inflammatory bowel disease-avenues for microbial management. 2018

McIlroy, J / Ianiro, G / Mukhopadhya, I / Hansen, R / Hold, G L. ·School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK. · Internal Medicine, Gastroenterology and Liver Unit, Gastroenterology Area, Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy. · Royal Hospital for Children, Glasgow, UK. ·Aliment Pharmacol Ther · Pubmed #29034981.

ABSTRACT: BACKGROUND: The concept of an altered collective gut microbiota rather than identification of a single culprit is possibly the most significant development in inflammatory bowel disease research. We have entered the "omics" era, which now allows us to undertake large-scale/high-throughput microbiota analysis which may well define how we approach diagnosis and treatment of inflammatory bowel disease (IBD) in the future, with a strong steer towards personalised therapeutics. AIM: To assess current epidemiological, experimental and clinical evidence of the current status of knowledge relating to the gut microbiome, and its role in IBD, with emphasis on reviewing the evidence relating to microbial therapeutics and future microbiome modulating therapeutics. METHODS: A Medline search including items 'intestinal microbiota/microbiome', 'inflammatory bowel disease', 'ulcerative colitis', 'Crohn's disease', 'faecal microbial transplantation', 'dietary manipulation' was performed. RESULTS: Disease remission and relapse are associated with microbial changes in both mucosal and luminal samples. In particular, a loss of species richness in Crohn's disease has been widely observed. Existing therapeutic approaches broadly fall into 3 categories, namely: accession, reduction or indirect modulation of the microbiome. In terms of microbial therapeutics, faecal microbial transplantation appears to hold the most promise; however, differences in study design/methodology mean it is currently challenging to elegantly translate results into clinical practice. CONCLUSIONS: Existing approaches to modulate the gut microbiome are relatively unrefined. Looking forward, the future of microbiome-modulating therapeutics looks bright with several novel strategies/technologies on the horizon. Taken collectively, it is clear that ignoring the microbiome in IBD is not an option.

2 Review The gut microbiota and host health: a new clinical frontier. 2016

Marchesi, Julian R / Adams, David H / Fava, Francesca / Hermes, Gerben D A / Hirschfield, Gideon M / Hold, Georgina / Quraishi, Mohammed Nabil / Kinross, James / Smidt, Hauke / Tuohy, Kieran M / Thomas, Linda V / Zoetendal, Erwin G / Hart, Ailsa. ·School of Biosciences, Museum Avenue, Cardiff University, Cardiff, UK Centre for Digestive and Gut Health, Imperial College London, London, UK. · NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, Birmingham, UK. · Nutrition and Nutrigenomics Group, Department of Food Quality and Nutrition, Research and Innovation Centre, Trento, Italy. · Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands Top Institute Food and Nutrition (TIFN), Wageningen, The Netherlands. · Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK. · Section of Computational and Systems Medicine, Faculty of Medicine, Imperial College London, London, UK. · Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands. · Yakult UK Limited, Middlesex, UK. · IBD Unit, St Mark's Hospital and Imperial College London, London, UK. ·Gut · Pubmed #26338727.

ABSTRACT: Over the last 10-15 years, our understanding of the composition and functions of the human gut microbiota has increased exponentially. To a large extent, this has been due to new 'omic' technologies that have facilitated large-scale analysis of the genetic and metabolic profile of this microbial community, revealing it to be comparable in influence to a new organ in the body and offering the possibility of a new route for therapeutic intervention. Moreover, it might be more accurate to think of it like an immune system: a collection of cells that work in unison with the host and that can promote health but sometimes initiate disease. This review gives an update on the current knowledge in the area of gut disorders, in particular metabolic syndrome and obesity-related disease, liver disease, IBD and colorectal cancer. The potential of manipulating the gut microbiota in these disorders is assessed, with an examination of the latest and most relevant evidence relating to antibiotics, probiotics, prebiotics, polyphenols and faecal microbiota transplantation.

3 Review Role of the gut microbiota in inflammatory bowel disease pathogenesis: what have we learnt in the past 10 years? 2014

Hold, Georgina L / Smith, Megan / Grange, Charlie / Watt, Euan Robert / El-Omar, Emad M / Mukhopadhya, Indrani. ·Georgina L Hold, Megan Smith, Charlie Grange, Euan Robert Watt, Emad M El-Omar, Indrani Mukhopadhya, Gastrointestinal Research Group, Division of Applied Medicine, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, United Kingdom. ·World J Gastroenterol · Pubmed #24574795.

ABSTRACT: Our understanding of the microbial involvement in inflammatory bowel disease (IBD) pathogenesis has increased exponentially over the past decade. The development of newer molecular tools for the global assessment of the gut microbiome and the identification of nucleotide-binding oligomerization domain-containing protein 2 in 2001 and other susceptibility genes for Crohn's disease in particular has led to better understanding of the aetiopathogenesis of IBD. The microbial studies have elaborated the normal composition of the gut microbiome and its perturbations in the setting of IBD. This altered microbiome or "dysbiosis" is a key player in the protracted course of inflammation in IBD. Numerous genome-wide association studies have identified further genes involved in gastrointestinal innate immunity (including polymorphisms in genes involved in autophagy: ATG16L1 and IGRM), which have helped elucidate the relationship of the local innate immunity with the adjacent luminal bacteria. These developments have also spurred the search for specific pathogens which may have a role in the metamorphosis of the gut microbiome from a symbiotic entity to a putative pathogenic one. Here we review advances in our understanding of microbial involvement in IBD pathogenesis over the past 10 years and offer insight into how this will shape our therapeutic management of the disease in the coming years.

4 Review The role of infection in the aetiology of inflammatory bowel disease. 2010

Hansen, Richard / Thomson, John M / El-Omar, Emad M / Hold, Georgina L. ·Gastrointestinal Research Group, Division of Applied Medicine, Institute of Medical Sciences, Aberdeen University, Foresterhill, Aberdeen AB25 2ZD, UK. ·J Gastroenterol · Pubmed #20076977.

ABSTRACT: We have greatly increased our understanding of the genetics of inflammatory bowel disease (IBD) in the last decade; however, migrant studies highlight the importance of environment in disease risk. The possibility that IBD is an infection has been debated since the first description of Crohn's disease. Mycobacterium avium paratuberculosis was the first organism to be suggested as an IBD pathogen, and it has been argued that it fulfils Koch's postulates and could be designated the cause of Crohn's disease. Other organisms have been postulated as possible IBD pathogens, including various Helicobacter species, one of which has been identified in primate colitis;others are widely used in animal models of IBD. Adherent invasive Escherichia coli appear specific to ileal Crohn's disease and have been shown to induce the release of TNF-alpha, a key cytokine in IBD inflammation. The aim of this article is to give a concise overview of the infections postulated as being relevant to the onset of IBD. We will also briefly cover the immunology underpinning IBD, in addition to reviewing current knowledge regarding other microorganisms that are associated with modifying the risk of developing IBD. It may be that infectious organisms have an orchestrator role in the development of dysbiosis and subsequently IBD.

5 Article Propionic Acid Promotes the Virulent Phenotype of Crohn's Disease-Associated Adherent-Invasive Escherichia coli. 2020

Ormsby, Michael J / Johnson, Síle A / Carpena, Nuria / Meikle, Lynsey M / Goldstone, Robert J / McIntosh, Anne / Wessel, Hannah M / Hulme, Heather E / McConnachie, Ceilidh C / Connolly, James P R / Roe, Andrew J / Hasson, Conor / Boyd, Joseph / Fitzgerald, Eamonn / Gerasimidis, Konstantinos / Morrison, Douglas / Hold, Georgina L / Hansen, Richard / Walker, Daniel / Smith, David G E / Wall, Daniel M. ·Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow G12 8TA, UK. · Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh EH14 4AS, UK. · Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow G12 8TA, UK; Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK. · Human Nutrition, School of Medicine, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · Scottish Universities Environmental Research Centre, University of Glasgow, Glasgow G75 0QF, UK. · Microbiome Research Centre, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia. · Department of Paediatric Gastroenterology, Hepatology and Nutrition, Royal Hospital for Children, 1345 Govan Road, Glasgow G51 4TF, UK. · Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: donal.wall@glasgow.ac.uk. ·Cell Rep · Pubmed #32075765.

ABSTRACT: Propionic acid (PA) is a bacterium-derived intestinal antimicrobial and immune modulator used widely in food production and agriculture. Passage of Crohn's disease-associated adherent-invasive Escherichia coli (AIEC) through a murine model, in which intestinal PA levels are increased to mimic the human intestine, leads to the recovery of AIEC with significantly increased virulence. Similar phenotypic changes are observed outside the murine model when AIEC is grown in culture with PA as the sole carbon source; such PA exposure also results in AIEC that persists at 20-fold higher levels in vivo. RNA sequencing identifies an upregulation of genes involved in biofilm formation, stress response, metabolism, membrane integrity, and alternative carbon source utilization. PA exposure also increases virulence in a number of E. coli isolates from Crohn's disease patients. Removal of PA is sufficient to reverse these phenotypic changes. Our data indicate that exposure to PA results in AIEC resistance and increased virulence in its presence.

6 Article Comparative genomics and genome biology of 2019

Hsu, Tiffany / Gemmell, Matthew R / Franzosa, Eric A / Berry, Susan / Mukhopadhya, Indrani / Hansen, Richard / Michaud, Monia / Nielsen, Hans / Miller, William G / Nielsen, Henrik / Bajaj-Elliott, Mona / Huttenhower, Curtis / Garrett, Wendy S / Hold, Georgina L. ·a Department of Biostatistics , Harvard T. H. Chan School of Public Health , Boston , USA. · b School of Medicine, Medical Sciences and Nutrition , Centre for Genome Enabled Biology and Medicine, University of Aberdeen , Aberdeen , UK. · c School of Medicine, Medical Sciences and Nutrition , GI Research Group, University of Aberdeen , Aberdeen , UK. · d Department of Paediatric Gastroenterology , Royal Hospital for Children , Glasgow , UK. · e Departments of Genetics and Complex Diseases and Immunology and Infectious Diseases , Harvard T. H. Chan School of Public Health , Boston , USA. · f Department of Clinical Microbiology , Aalborg University Hospital , Aalborg , Denmark. · g Produce Safety and Microbiology Research Unit, U.S. Department of Agriculture , Agricultural Research Service , Albany , USA. · h Department of Infectious Diseases , Aalborg University Hospital Aalborg , Denmark. · i Infection, Immunity, Inflammation Programme , UCL Great Ormond Street Institute of Child Health , London , UK. · j St George and Sutherland Clinical School , Microbiome Research Centre, University of New South Wales , Sydney , Australia. ·Emerg Microbes Infect · Pubmed #31169073.


7 Article Inflammation associated ethanolamine facilitates infection by Crohn's disease-linked adherent-invasive Escherichia coli. 2019

Ormsby, Michael J / Logan, Michael / Johnson, Síle A / McIntosh, Anne / Fallata, Ghaith / Papadopoulou, Rodanthi / Papachristou, Eleftheria / Hold, Georgina L / Hansen, Richard / Ijaz, Umer Z / Russell, Richard K / Gerasimidis, Konstantinos / Wall, Daniel M. ·Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow G12 8TA, United Kingdom. · School of Engineering, University of Glasgow, Glasgow, Rankine Building, 79-85 Oakfield Ave, Glasgow G12 8LT, United Kingdom. · Human Nutrition, School of Medicine, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G31 2ER, United Kingdom. · Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Australia. · Department of Pediatric Gastroenterology, Hepatology and Nutrition, Royal Hospital for Children, 1345 Govan Road, Glasgow G51 4TF, United Kingdom. · Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow G12 8TA, United Kingdom. Electronic address: Donal.Wall@glasgow.ac.uk. ·EBioMedicine · Pubmed #31036531.

ABSTRACT: BACKGROUND: The predominance of specific bacteria such as adherent-invasive Escherichia coli (AIEC) within the Crohn's disease (CD) intestine remains poorly understood with little evidence uncovered to support a selective pressure underlying their presence. Intestinal ethanolamine is however readily accessible during periods of intestinal inflammation, and enables pathogens to outcompete the host microbiota under such circumstances. METHODS: Quantitative RT-PCR (qRT-PCR) to determine expression of genes central to ethanolamine metabolism; transmission electron microscopy to detect presence of bacterial microcompartments (MCPs); in vitro infections of both murine and human macrophage cell lines examining intracellular replication of the AIEC-type strain LF82 and clinical E. coli isolates in the presence of ethanolamine; determination of E. coli ethanolamine utilization (eut) operon transcription in faecal samples from healthy patients, patients with active CD and the same patients in remission following treatment. RESULTS: Growth on the intestinal short chain fatty acid propionic acid (PA) stimulates significantly increased transcription of the eut operon (fold change relative to glucose: >16.9; p-value <.01). Additionally ethanolamine was accessible to intra-macrophage AIEC and stimulated significant increases in growth intracellularly when it was added extracellularly at concentrations comparable to those in the human intestine. Finally, qRT-PCR indicated that expression of the E. coli eut operon was increased in children with active CD compared to healthy controls (fold change increase: >4.72; P < .02). After clinical remission post-exclusive enteral nutrition treatment, the same CD patients exhibited significantly reduced eut expression (Pre vs Post fold change decrease: >15.64; P < .01). INTERPRETATION: Our data indicates a role for ethanolamine metabolism in selecting for AIEC that are consistently overrepresented in the CD intestine. The increased E. coli metabolism of ethanolamine seen in the intestine during active CD, and its decrease during remission, indicates ethanolamine use may be a key factor in shaping the intestinal microbiome in CD patients, particularly during times of inflammation. FUND: This work was funded by Biotechnology and Biological Sciences Research Council (BBSRC) grants BB/K008005/1 & BB/P003281/1 to DMW; by a Tenovus Scotland grant to MJO; by Glasgow Children's Hospital Charity, Nestle Health Sciences, Engineering and Physical Sciences Research Council (EPSRC) and Catherine McEwan Foundation grants awarded to KG; and by a Natural Environment Research Council (NERC) fellowship (NE/L011956/1) to UZI. The IBD team at the Royal Hospital for Children, Glasgow are supported by the Catherine McEwan Foundation and Yorkhill IBD fund. RKR and RH are supported by NHS Research Scotland Senior fellowship awards.

8 Article Faecal microbiota transplantation as a treatment for inflammatory bowel disease: a national survey of adult and paediatric gastroenterologists in the UK. 2018

Mcilroy, James Roger / Nalagatla, Niharika / Hansen, Richard / Hart, Ailsa / Hold, Georgina Louise. ·School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK. · EnteroBiotix Limited, Aberdeen, UK. · Royal Hospital for Children, Glasgow, UK. · IBD Unit, St Mark's Hospital, Harrow, UK. · Department of Medicine, University of New South Wales, Sydney, New South Wales, Australia. ·Frontline Gastroenterol · Pubmed #30245786.

ABSTRACT: Background: Interest in the use of faecal microbiota transplantation (FMT) in inflammatory bowel disease (IBD) has increased following outcomes in patients with Objective: To assess the perceptions of gastroenterologists and current practice relating to FMT as a treatment for IBD in the UK. Design: A web-based survey (Snap Survey software) was distributed through the British Society of Gastroenterology (BSG) and British Society of Paediatric Gastroenterology, Hepatology and Nutrition e-newsletters, and at the BSG Conference in June 2017. Results: 61 respondents completed the survey including presubspecialty trainees, gastroenterology specialists, associate specialists and consultants. Most (95%; n=58) respondents stated that they had heard of FMT being used as a treatment for IBD prior to participating in the survey. Based on current evidence, 34% (n=21) of respondents would consider using FMT in patients with IBD, 26% (n=16) would not and 39% (n=24) were undecided. When asked to rank routes of delivery in terms of preference, nasogastric tube was the least preferred route (39%; n=24) and oral capsule was the most preferred route (34%; n=21). Conclusions: A clear majority of UK gastroenterologists recognise FMT as a potential treatment for IBD; however, uptake is limited. A proportion of clinicians would consider FMT in IBD and the majority would consider entering patients into clinical trials. Future work should explore the utility and efficacy of oral FMT capsules in IBD.

9 Article The Impact of NOD2 Variants on Fecal Microbiota in Crohn's Disease and Controls Without Gastrointestinal Disease. 2018

Kennedy, Nicholas A / Lamb, Christopher A / Berry, Susan H / Walker, Alan W / Mansfield, John / Parkes, Miles / Simpkins, Rachel / Tremelling, Mark / Nutland, Sarah / Anonymous1501112 / Parkhill, Julian / Probert, Chris / Hold, Georgina L / Lees, Charlie W. ·GI Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. · IBD Pharmacogenetics Group, University of Exeter, UK. · Institute of Cellular Medicine, Newcastle University, UK. · Gastrointestinal Research Group, University of Aberdeen, Aberdeen, UK. · Pathogen Genomics Group, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. · Microbiology Group, The Rowett Institute, University of Aberdeen, Aberdeen, UK. · Dept of Gastroenterology, Royal Victoria Infirmary, Newcastle, UK. · Dept of Gastroenterology, Addenbrookes Hospital, Cambridge, UK. · Cambridge BioResource, Cambridge. · Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, UK. · Institute of Translational Medicine, University of Liverpool, UK. ·Inflamm Bowel Dis · Pubmed #29462388.

ABSTRACT: Background/Aims: Current models of Crohn's disease (CD) describe an inappropriate immune response to gut microbiota in genetically susceptible individuals. NOD2 variants are strongly associated with development of CD, and NOD2 is part of the innate immune response to bacteria. This study aimed to identify differences in fecal microbiota in CD patients and non-IBD controls stratified by NOD2 genotype. Methods: Patients with CD and non-IBD controls of known NOD2 genotype were identified from patients in previous UK IBD genetics studies and the Cambridge bioresource (genotyped/phenotyped volunteers). Individuals with known CD-associated NOD2 mutations were matched to those with wild-type genotype. We obtained fecal samples from patients in clinical remission with low fecal calprotectin (<250 µg/g) and controls without gastrointestinal disease. After extracting DNA, the V1-2 region of 16S rRNA genes were polymerase chain reaction (PCR)-amplified and sequenced. Analysis was undertaken using the mothur package. Volatile organic compounds (VOC) were also measured. Results: Ninety-one individuals were in the primary analysis (37 CD, 30 bioresource controls, and 24 household controls). Comparing CD with nonIBD controls, there were reductions in bacterial diversity, Ruminococcaceae, Rikenellaceae, and Christensenellaceae and an increase in Enterobacteriaceae. No significant differences could be identified in microbiota by NOD2 genotype, but fecal butanoic acid was higher in Crohn's patients carrying NOD2 mutations. Conclusions: In this well-controlled study of NOD2 genotype and fecal microbiota, we identified no significant genotype-microbiota associations. This suggests that the changes associated with NOD2 genotype might only be seen at the mucosal level, or that environmental factors and prior inflammation are the predominant determinant of the observed dysbiosis in gut microbiota.

10 Article Multi-omics differentially classify disease state and treatment outcome in pediatric Crohn's disease. 2018

Douglas, Gavin M / Hansen, Richard / Jones, Casey M A / Dunn, Katherine A / Comeau, André M / Bielawski, Joseph P / Tayler, Rachel / El-Omar, Emad M / Russell, Richard K / Hold, Georgina L / Langille, Morgan G I / Van Limbergen, Johan. ·Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada. · Department of Paediatric Gastroenterology, Royal Hospital for Children, Glasgow, UK. · Department of Pharmacology, Dalhousie University, Halifax, NS, Canada. · Department of Biology, Dalhousie University, Halifax, NS, Canada. · CGEB-Integrated Microbiome Resource (IMR), Dalhousie University, Halifax, NS, Canada. · Department of Medicine, St George and Sutherland Clinical School, UNSW, Sydney, NSW, Australia. · Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada. morgan.g.i.langille@dal.ca. · Department of Pharmacology, Dalhousie University, Halifax, NS, Canada. morgan.g.i.langille@dal.ca. · CGEB-Integrated Microbiome Resource (IMR), Dalhousie University, Halifax, NS, Canada. morgan.g.i.langille@dal.ca. · Department of Pediatrics, Dalhousie University, Halifax, NS, Canada. ·Microbiome · Pubmed #29335008.

ABSTRACT: BACKGROUND: Crohn's disease (CD) has an unclear etiology, but there is growing evidence of a direct link with a dysbiotic microbiome. Many gut microbes have previously been associated with CD, but these have mainly been confounded with patients' ongoing treatments. Additionally, most analyses of CD patients' microbiomes have focused on microbes in stool samples, which yield different insights than profiling biopsy samples. RESULTS: We sequenced the 16S rRNA gene (16S) and carried out shotgun metagenomics (MGS) from the intestinal biopsies of 20 treatment-naïve CD and 20 control pediatric patients. We identified the abundances of microbial taxa and inferred functional categories within each dataset. We also identified known human genetic variants from the MGS data. We then used a machine learning approach to determine the classification accuracy when these datasets, collapsed to different hierarchical groupings, were used independently to classify patients by disease state and by CD patients' response to treatment. We found that 16S-identified microbes could classify patients with higher accuracy in both cases. Based on follow-ups with these patients, we identified which microbes and functions were best for predicting disease state and response to treatment, including several previously identified markers. By combining the top features from all significant models into a single model, we could compare the relative importance of these predictive features. We found that 16S-identified microbes are the best predictors of CD state whereas MGS-identified markers perform best for classifying treatment response. CONCLUSIONS: We demonstrate for the first time that useful predictors of CD treatment response can be produced from shotgun MGS sequencing of biopsy samples despite the complications related to large proportions of host DNA. The top predictive features that we identified in this study could be useful for building an improved classifier for CD and treatment response based on sufferers' microbiome in the future. The BISCUIT project is funded by a Clinical Academic Fellowship from the Chief Scientist Office (Scotland)-CAF/08/01.

11 Article Two-stage genome-wide methylation profiling in childhood-onset Crohn's Disease implicates epigenetic alterations at the VMP1/MIR21 and HLA loci. 2014

Adams, Alex T / Kennedy, Nicholas A / Hansen, Richard / Ventham, Nicholas T / OʼLeary, Kate R / Drummond, Hazel E / Noble, Colin L / El-Omar, Emad / Russell, Richard K / Wilson, David C / Nimmo, Elaine R / Hold, Georgina L / Satsangi, Jack. ·*Gastrointestinal Unit, Centre for Genetics and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom; †Gastrointestinal Research Group, Division of Applied Medicine, University of Aberdeen, Aberdeen, United Kingdom; ‡Department of Paediatric Gastroenterology, Royal Hospital for Sick Children, Glasgow, United Kingdom; and §Paediatric Gastroenterology and Nutrition, Child Life and Health, University of Edinburgh, Royal Hospital for Sick Children, Edinburgh, United Kingdom. ·Inflamm Bowel Dis · Pubmed #25144570.

ABSTRACT: BACKGROUND: As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene-environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease. METHODS: The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. Data were corrected for differential leukocyte proportions. Targeted replication was performed in adults using pyrosequencing. Methylation changes were correlated with gene expression in blood and intestinal mucosa. RESULTS: We identified 65 individual CpG sites with methylation alterations achieving epigenome-wide significance after Bonferroni correction (P < 1.1 × 10(-7)), and 19 differently methylated regions displaying unidirectional methylation change. There was a highly significant enrichment of methylation changes around GWAS single nucleotide polymorphisms (P = 3.7 × 10(-7)), notably the HLA region and MIR21. Two-locus discriminant analysis in the discovery cohort predicted disease in the pediatric replication cohort with high accuracy (area under the curve, 0.98). The findings strongly implicate the transcriptional start site of MIR21 as a region of extended epigenetic alteration, containing the most significant individual probes (P = 1.97 × 10(-15)) within a GWAS risk locus. In extension studies, we confirmed hypomethylation of MIR21 in adults (P = 6.6 × 10(-5), n = 172) and show increased mRNA expression in leukocytes (P < 0.005, n = 66) and in the inflamed intestine (P = 1.4 × 10(-6), n = 99). CONCLUSIONS: We demonstrate highly significant and replicable differences in DNA methylation in CD, defining the disease-associated epigenome. The data strongly implicate known GWAS loci, with compelling evidence implicating MIR21 and the HLA region.

12 Article Microbiota of de-novo pediatric IBD: increased Faecalibacterium prausnitzii and reduced bacterial diversity in Crohn's but not in ulcerative colitis. 2012

Hansen, Richard / Russell, Richard K / Reiff, Caroline / Louis, Petra / McIntosh, Freda / Berry, Susan H / Mukhopadhya, Indrani / Bisset, W Michael / Barclay, Andy R / Bishop, Jon / Flynn, Diana M / McGrogan, Paraic / Loganathan, Sabarinathan / Mahdi, Gamal / Flint, Harry J / El-Omar, Emad M / Hold, Georgina L. ·Gastrointestinal Research Group, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK. ·Am J Gastroenterol · Pubmed #23044767.

ABSTRACT: OBJECTIVES: The gastrointestinal microbiota is considered important in inflammatory bowel disease (IBD) pathogenesis. Discoveries from established disease cohorts report reduced bacterial diversity, changes in bacterial composition, and a protective role for Faecalibacterium prausnitzii in Crohn's disease (CD). The majority of studies to date are however potentially confounded by the effect of treatment and a reliance on established rather than de-novo disease. METHODS: Microbial changes at diagnosis were examined by biopsying the colonic mucosa of 37 children: 25 with newly presenting, untreated IBD with active colitis (13 CD and 12 ulcerative colitis (UC)), and 12 pediatric controls with a macroscopically and microscopically normal colon. We utilized a dual-methodology approach with pyrosequencing (threshold >10,000 reads) and confirmatory real-time PCR (RT-PCR). RESULTS: Threshold pyrosequencing output was obtained on 34 subjects (11 CD, 11 UC, 12 controls). No significant changes were noted at phylum level among the Bacteroidetes, Firmicutes, or Proteobacteria. A significant reduction in bacterial α-diversity was noted in CD vs. controls by three methods (Shannon, Simpson, and phylogenetic diversity) but not in UC vs. controls. An increase in Faecalibacterium was observed in CD compared with controls by pyrosequencing (mean 16.7% vs. 9.1% of reads, P=0.02) and replicated by specific F. prausnitzii RT-PCR (36.0% vs. 19.0% of total bacteria, P=0.02). No disease-specific clustering was evident on principal components analysis. CONCLUSIONS: Our results offer a comprehensive examination of the IBD mucosal microbiota at diagnosis, unaffected by therapeutic confounders or changes over time. Our results challenge the current model of a protective role for F. prausnitzii in CD, suggesting a more dynamic role for this organism than previously described.

13 Article Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans. 2012

Raju, Deepa / Hussey, Seamus / Ang, Michelle / Terebiznik, Mauricio R / Sibony, Michal / Galindo-Mata, Esther / Gupta, Vijay / Blanke, Steven R / Delgado, Alberto / Romero-Gallo, Judith / Ramjeet, Mahendra Singh / Mascarenhas, Heidi / Peek, Richard M / Correa, Pelayo / Streutker, Cathy / Hold, Georgina / Kunstmann, Erdmutte / Yoshimori, Tamotsu / Silverberg, Mark S / Girardin, Stephen E / Philpott, Dana J / El Omar, Emad / Jones, Nicola L. ·Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. ·Gastroenterology · Pubmed #22333951.

ABSTRACT: BACKGROUND & AIMS: The Helicobacter pylori toxin vacuolating cytotoxin (VacA) promotes gastric colonization, and its presence (VacA(+)) is associated with more-severe disease. The exact mechanisms by which VacA contributes to infection are unclear. We previously found that limited exposure to VacA induces autophagy of gastric cells, which eliminates the toxin; we investigated whether autophagy serves as a defense mechanism against H pylori infection. METHODS: We investigated the effect of VacA on autophagy in human gastric epithelial cells and primary gastric cells from mice. Expression of p62, a marker of autophagy, was also assessed in gastric tissues from patients infected with toxigenic (VacA(+)) or nontoxigenic strains. We analyzed the effect of VacA on autophagy in peripheral blood monocytes obtained from subjects with different genotypes of ATG16L1, which regulates autophagy. We performed genotyping for ATG16L1 in 2 cohorts of infected and uninfected subjects. RESULTS: Prolonged exposure of human gastric epithelial cells and mouse gastric cells to VacA disrupted induction of autophagy in response to the toxin, because the cells lacked cathepsin D in autophagosomes. Loss of autophagy resulted in the accumulation of p62 and reactive oxygen species. Gastric biopsy samples from patients infected with VacA(+), but not nontoxigenic strains of H pylori, had increased levels of p62. Peripheral blood monocytes isolated from individuals with polymorphisms in ATG16L1 that increase susceptibility to Crohn's disease had reduced induction of autophagy in response to VacA(+) compared to cells from individuals that did not have these polymorphisms. The presence of the ATG16L1 Crohn's disease risk variant increased susceptibility to H pylori infection in 2 separate cohorts. CONCLUSIONS: Autophagy protects against infection with H pylori; the toxin VacA disrupts autophagy to promote infection, which could contribute to inflammation and eventual carcinogenesis.

14 Article A comprehensive evaluation of colonic mucosal isolates of Sutterella wadsworthensis from inflammatory bowel disease. 2011

Mukhopadhya, Indrani / Hansen, Richard / Nicholl, Charlotte E / Alhaidan, Yazeid A / Thomson, John M / Berry, Susan H / Pattinson, Craig / Stead, David A / Russell, Richard K / El-Omar, Emad M / Hold, Georgina L. ·Gastrointestinal Research Group, Division of Applied Medicine, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom. ·PLoS One · Pubmed #22073125.

ABSTRACT: Inflammatory bowel disease (IBD) arises in genetically susceptible individuals as a result of an unidentified environmental trigger, possibly a hitherto unknown bacterial pathogen. Twenty-six clinical isolates of Sutterella wadsworthensis were obtained from 134 adults and 61 pediatric patients undergoing colonoscopy, of whom 69 and 29 respectively had IBD. S. wadsworthensis was initially more frequently isolated from IBD subjects, hence this comprehensive study was undertaken to elucidate its role in IBD. Utilizing these samples, a newly designed PCR was developed, to study the prevalence of this bacterium in adult patients with ulcerative colitis (UC). Sutterella wadsworthensis was detected in 83.8% of adult patients with UC as opposed to 86.1% of control subjects (p = 0.64). Selected strains from IBD cases and controls were studied to elicit morphological, proteomic, genotypic and pathogenic differences. This study reports Scanning Electron Microscopy (SEM) appearances and characteristic MALDI-TOF MS protein profiles of S. wadsworthensis for the very first time. SEM showed that the bacterium is pleomorphic, existing in predominantly two morphological forms, long rods and coccobacilli. No differences were noted in the MALDI-TOF mass spectrometry proteomic analysis. There was no distinct clustering of strains identified from cases and controls on sequence analysis. Cytokine response after monocyte challenge with strains from patients with IBD and controls did not yield any significant differences. Our studies indicate that S. wadsworthensis is unlikely to play a role in the pathogenesis of IBD. Strains from cases of IBD could not be distinguished from those identified from controls.