Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Journal name:
Nature
Volume:
491,
Pages:
119–124
Date published:
DOI:
doi:10.1038/nature11582
Received
Accepted
Published online

Crohn’s disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations1. Genome-wide association studies and subsequent meta-analyses of these two diseases2, 3 as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy4, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases5. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

At a glance

Figures

  1. The IBD genome.
    Figure 1: The IBD genome.

    a, Variance explained by the 163 IBD loci. Each bar, ordered by genomic position, represents an independent locus. The width of the bar is proportional to the variance explained by that locus in Crohn’s disease (CD) and ulcerative colitis (UC). Bars are connected together if they are identified as being associated with both phenotypes, and loci are labelled if they explain more than 1% of the total variance explained by all loci for that phenotype. Labels are either the best-supported candidate gene in Table 1, or the chromosome and position of the locus if either no, or multiple, well-supported candidates exist. b, The 193 independent signals, plotted by total IBD odds ratio and phenotype specificity (measured by the odds ratio of Crohn’s disease relative to ulcerative colitis), and coloured by their IBD phenotype classification from Table 1. Note that many loci (for example, IL23R) show very different effects in Crohn’s disease and ulcerative colitis despite being strongly associated to both. c, GRAIL network for all genes with GRAIL P<0.05. Genes included in our previous GRAIL networks in both phenotypes are shown in light blue, newly connected genes in previously identified loci in dark blue, and genes from newly associated loci in gold. The gold genes reinforce the previous network (light blue) and expand it to include dark blue genes.

  2. Dissecting the biology of IBD.
    Figure 2: Dissecting the biology of IBD.

    a, Number of overlapping IBD loci with other immune-mediated diseases (IMD), leprosy and Mendelian PIDs. Within PID, we highlight MSMD. b, Signals of selection at IBD SNPs, from strongest balancing on the left to strongest directional on the right. The grey curve shows the 95% confidence interval for randomly chosen frequency-matched SNPs, illustrating our overall enrichment (P = 5.5×10−6), and the dashed line represents the Bonferroni significance threshold. SNPs highlighted in red are annotated as being involved in the regulation of IL-17 production, a key IBD functional term related to bacterial defence, and are enriched for balancing selection. c, Evidence of enrichment in IBD loci of differentially expressed genes from various immune tissues. Each bar represents the empirical P value in a single tissue, and the colours represent different cell type groupings. The dashed line is Bonferroni-corrected significance for the number of tissues tested. d, NOD2-focused cluster of the IBD causal sub-network. Pink genes are in IBD-associated loci, blue are not. Arrows indicate inferred causal direction of regulation of expression.

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Author information

  1. These authors contributed equally to this work.

    • Luke Jostins,
    • Stephan Ripke,
    • Jeffrey C. Barrett &
    • Judy H Cho

Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.

    • Luke Jostins,
    • Carl A. Anderson &
    • Jeffrey C. Barrett
  2. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

    • Stephan Ripke &
    • Mark J. Daly
  3. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Stephan Ripke &
    • Mark J. Daly
  4. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen 9700 RB, The Netherlands.

    • Rinse K. Weersma &
    • Dirk De Jong
  5. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.

    • Richard H. Duerr,
    • Leonard Baidoo,
    • Karin Fransen &
    • Miguel Regueiro
  6. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA.

    • Richard H. Duerr
  7. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California 90048, USA.

    • Dermot P. McGovern,
    • Stephan R. Targan &
    • Kent D. Taylor
  8. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

    • Dermot P. McGovern,
    • Talin Haritunians,
    • Jerome I. Rotter &
    • Kent D. Taylor
  9. Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06520, USA.

    • Ken Y. Hui &
    • Judy H Cho
  10. Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK.

    • James C. Lee &
    • Miles Parkes
  11. Department of Health Studies, University of Chicago, Chicago, Illinois 60637, USA.

    • L. Philip Schumm
  12. Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut 06520, USA.

    • Yashoda Sharma,
    • Kaida Ning,
    • Clara Abraham,
    • Matija Hedl &
    • Judy H Cho
  13. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

    • Jonah Essers
  14. University of Maribor, Faculty of Medicine, Center for Human Molecular Genetics and Pharmacogenomics, Maribor 2000, Slovenia.

    • Mitja Mitrovic &
    • Uros Potocnik
  15. University Medical Center Groningen, Department of Genetics, Groningen 9700 RB, The Netherlands.

    • Mitja Mitrovic
  16. Department of Clinical and Experimental Medicine, Gastroenterology section, KU Leuven, Leuven 3000, Belgium.

    • Isabelle Cleynen &
    • Severine Vermeire
  17. Unit of Animal Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) and Faculty of Veterinary Medicine, University of Liège, Liège 4000, Belgium.

    • Emilie Theatre &
    • Michel Georges
  18. Division of Gastroenterology, Centre Hospitalier Universitaire, Université de Liège, Liège 4000, Belgium.

    • Emilie Theatre &
    • Edouard Louis
  19. Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King’s College London School of Medicine, Guy’s Hospital, London SE1 9RT, UK.

    • Sarah L. Spain,
    • Natalie J. Prescott &
    • Christopher G. Mathew
  20. Division of Rheumatology Immunology and Allergy, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA.

    • Soumya Raychaudhuri &
    • Xinli Hu
  21. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.

    • Soumya Raychaudhuri
  22. Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA.

    • Soumya Raychaudhuri
  23. Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec H1T 1C8, Canada.

    • Philippe Goyette,
    • Gabrielle Boucher &
    • John D. Rioux
  24. Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey 07102, USA.

    • Zhi Wei
  25. Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.

    • Jean-Paul Achkar
  26. Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.

    • Jean-Paul Achkar
  27. Peninsula College of Medicine and Dentistry, Exeter EX1 2LU, UK.

    • Tariq Ahmad
  28. Erasmus Hospital, Free University of Brussels, Department of Gastroenterology, Brussels, 1070 Belgium.

    • Leila Amininejad &
    • Denis Franchimont
  29. Massachusetts General Hospital, Harvard Medical School, Gastroenterology Unit, Boston, Massachusetts 02114, USA.

    • Ashwin N. Ananthakrishnan,
    • Kathy L. Devaney &
    • Ramnik J. Xavier
  30. Viborg Regional Hospital, Medical Department, Viborg 8800, Denmark.

    • Vibeke Andersen
  31. Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and School of Medicine, University of Adelaide, Adelaide 5000, Australia.

    • Jane M. Andrews
  32. Institute of Clinical Chemistry, Christian-Albrechts-University, Kiel 24105, Germany.

    • Tobias Balschun,
    • David Ellinghaus,
    • Stefan Schreiber &
    • Andre Franke
  33. Department of Gastroenterology and Hepatology, Flinders Medical Centre and School of Medicine, Flinders University, Adelaide 5000, Australia.

    • Peter A. Bampton
  34. Division of Gastroenterology, McGill University Health Centre, Royal Victoria Hospital, Montréal, Québec H3A 1A1, Canada.

    • Alain Bitton &
    • Jürgen Glas
  35. Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich 80336, Germany.

    • Stephan Brand
  36. Department of Gastroenterology, Charité, Campus Mitte, Universitätsmedizin Berlin, Berlin 10117, Germany.

    • Carsten Büning
  37. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York City, New York 10029, USA.

    • Ariella Cohain,
    • Bin Zhang &
    • Eric E. Schadt
  38. Department of Genomics, Life & Brain Center, University Hospital Bonn, Bonn 53012, Germany.

    • Sven Cichon
  39. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm 14 183, Sweden.

    • Mauro D’Amato
  40. Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, California 90048, USA.

    • Marla Dubinsky
  41. Torbay Hospital, Department of Gastroenterology, Torbay, Devon TQ2 7AA, UK.

    • Cathryn Edwards
  42. School of Medical Sciences, Faculty of Medical & Health Sciences, The University of Auckland, Auckland 1142, New Zealand.

    • Lynnette R. Ferguson &
    • Angharad R. Morgan
  43. University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen T9700 RB, The Netherlands.

    • Karin Fransen &
    • Cisca Wijmenga
  44. Department of Medicine, University of Otago, Christchurch 8140, New Zealand.

    • Richard Gearry
  45. Department of Gastroenterology, Christchurch Hospital, Christchurch 8011, New Zealand.

    • Richard Gearry
  46. Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.

    • Christian Gieger
  47. St Mark’s Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK.

    • Ailsa Hart
  48. Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham NG7 1AW, UK.

    • Chris Hawkey
  49. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo 0424, Norway.

    • Tom H. Karlsen
  50. Kaunas University of Medicine, Department of Gastroenterology, Kaunas 44307, Lithuania.

    • Limas Kupcinskas &
    • Jurgita Sventoraityte
  51. Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

    • Subra Kugathasan
  52. Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo 71013, Italy.

    • Anna Latiano,
    • Orazio Palmieri &
    • Vito Annese
  53. Ghent University Hospital, Department of Gastroenterology and Hepatology, Ghent 9000, Belgium.

    • Debby Laukens &
    • Martine De Vos
  54. School of Medicine and Pharmacology, The University of Western Australia, Fremantle, Western Australia 6009, Australia.

    • Ian C. Lawrance
  55. Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.

    • Charlie W. Lees &
    • Jack Satsangi
  56. Department of Gastroenterology, The Townsville Hospital, Townsville, Queensland 4810, Australia.

    • Gillian Mahy
  57. Institute of Human Genetics, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.

    • John Mansfield
  58. Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.

    • Craig Mowat
  59. Genetic Medicine, MAHSC, University of Manchester, Manchester M13 9PL, UK.

    • William Newman
  60. Academic Medical Center, Department of Gastroenterology, Amsterdam 1105 AZ, The Netherlands.

    • Cyriel Y. Ponsioen
  61. University of Maribor, Faculty for Chemistry and Chemical Engineering, Maribor 2000, Slovenia.

    • Uros Potocnik
  62. Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow G3 8SJ, UK.

    • Richard K. Russell &
    • David C. Wilson
  63. Guy’s & St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, Department of Gastroenterology, London SE1 7EH, UK.

    • Jeremy D. Sanderson
  64. Department of Gastroenterology, Hospital Clinic/Institut d’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

    • Miquel Sans
  65. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EHD), Barcelona 08036, Spain.

    • Miquel Sans
  66. Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Kiel 24118, Germany.

    • Stefan Schreiber &
    • Sebastian Zeissig
  67. Inflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane 4029, Australia.

    • Lisa A. Simms &
    • Graham Radford-Smith
  68. Norfolk and Norwich University Hospital, Norwich NR4 7UY, UK.

    • Mark Tremelling
  69. Department of Gastroenterology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.

    • Hein W. Verspaget
  70. Child Life and Health, University of Edinburgh, Edinburgh, Scotland EH9 1UW, UK.

    • David C. Wilson
  71. Institute of Human Genetics and Department of Neurology, Technische Universität München, Munich 80336, Germany.

    • Juliane Winkelmann
  72. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Ramnik J. Xavier
  73. Department of Biostatistics, School of Public Health, Yale University, New Haven, Connecticut 06520, USA.

    • Clarence K. Zhang &
    • Hongyu Zhao
  74. Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario M5G 1X5, Canada.

    • Mark S. Silverberg
  75. Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence 50134, Italy.

    • Vito Annese
  76. Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

    • Hakon Hakonarson
  77. Department of Pediatrics, Center for Pediatric Inflammatory Bowel Disease, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

    • Hakon Hakonarson
  78. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, and Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.

    • Steven R. Brant
  79. Department of Gastroenterology, Royal Brisbane and Women’s Hospital, and School of Medicine, University of Queensland, Brisbane 4029, Australia.

    • Graham Radford-Smith
  80. Department of Gastroenterology, University Hospital Leuven, Leuven 3000, Belgium

    • Severine Vermeire
  81. Lists of participants and their affiliations appear in the Supplementary Information.

    • The International IBD Genetics Consortium

Consortia

  1. The International IBD Genetics Consortium (IIBDGC)

Contributions

R.K.W., R.H.D., D.P.M., C.G.M., J.D.R., E.E.S., M.J.D., A.F., M.P. and S.V. contributed equally to the manuscript. J.H.C., J.C.B., R.K.W., R.H.D., D.P.M., A.F., M.P., C.G.M., J.D.R., S.V., M.D.A. and V. Annese conceived, designed and managed the study and managed the funding. J.H.C., J.C.B., L.J., S. Ripke, R.K.W., R.H.D., D.P.M., M.J.D., M.P. and C.G.M. were involved in manuscript preparation. J.H.C., J.C.B., L.J., S. Ripke, R.K.W., K.Y.H., C.A.A., J.E., K.N., S.L.S., S. Raychaudhuri, Z.W., C.A., A.C., G.B., M.H., X.H., B.Z., C.K.Z., H.Z., J.D.R., E.E.S. and M.J.D. performed or supervised statistical and computational analyses. R.K.W., R.H.D., D.P.M., J.C.L., L.P.S., Y.S., P.G., J.-P.A., T.A., L.A., A.N.A., V. Andersen, J.M.A., L.B., P.A.B., A.B., S.B., C.B., S.C., M.D.A., D.D.J., K.L.D., M.D., C.E., L.R.F., D.F., M.G., C.G., R.G., J.G., A.H., C.H., T.H.K., L.K., S.K., A.L., D.L., E.L., I.C.L., C.W.L., A.R.M., C.M., G.M., J.M., W.N., O.P., C.Y.P., U.P., N.J.P., M.R., J.I.R., R.K.R., J.D.S., M.S., J. Satsangi, S.S., L.A.S., J. Sventoraityte, S.R.T., M.T., H.W.V., M.D.V., C.W., D.C.W., J.W., R.J.X., S.Z., M.S.S., V. Annese, H.H., IIBDGC, S.R.B., J.D.R., G.R.S., C.G.M., A.F., M.P., S.V. and J.H.C. were involved in study subject recruitment and assembling phenotypic data. R.K.W., R.H.D., D.P.M., L.P.S., Y.S., M.M., I.C., E.T., T.B., D.E., K.F., T.H., K.D.T., C.G.M., A.F., M.P. and J.H.C. established DNA collections, genotyping and data management. All authors read and approved the final manuscript before submission.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Data have been deposited in the NCBI database of Genotypes and Phenotypes under accession numbers phs000130.v1.p1 and phs000345.v1.p1. Summary statistics for imputed GWAS are available at http://www.broadinstitute.org/mpg/ricopili/. Summary statistics for the meta-analysis markers are available at http://www.ibdgenetics.org/. The 523 causal gene network Cytoscape file is available on request.

Author details

Supplementary information

PDF files

  1. Supplementary Information (10.3M)

    This file contains Supplementary Text, Supplementary Figures 1-12, full legends for Supplementary Tables 1-6, Supplementary References and a list of IBD Genetics Consortium members – see Supplementary Contents for details.

Zip files

  1. Supplementary Tables (357K)

    This zipped files contains Supplementary Tables 1-6 as follows: 1 shows the GWAS and Immunochip samples used in the study; 2 contains complete details of 163 IBD loci; 3 contains details of disease overlaps with IMD, PID and MSMD described in section 2 of the methods; 4 contains detailed enrichment statistics for all GO terms and canonical pathways; 5 contains the signals of selection at IBD loci; 6 shows enrichment scores for genes in IBD loci within co-expression modules. Supplementary Table 2, which is contained in this zipped file, has been replaced, as there was an error in the original file. In the ‘Detailed assoc stats’ tab, the ‘IC risk’ and ‘IC_nonrisk’ column labels were inadvertently switched. In addition, clarification of the cohort used to determine the odds ratio (OR) shown in the ‘Detailed assoc stats’ and ‘Main Table’ tabs has been included. This file was replaced online on 31 January 2013.

  2. Supplementary Data (722K)

    This zipped file is a Cytoscape file for the macrophage enriched, omental adipose Bayesian network.

Comments

  1. Report this comment #52232

    Luke Jostins said:

    Since this paper was published other scientists have pointed out that the interpretation of the selections signals on IBD loci may be more complex than the story that we present here. For instance, further analysis of the selection data suggests that the "balancing selection" signal could also be explained by recent local selection in Europeans.

    Read more here about this on the Genomes Unzipped blog: Looking closer at natural selection in inflammatory bowel disease

  2. Report this comment #52678

    Ramon Juste said:

    I have read with great interest this paper and I would like to add some evidence supporting the mycobacterial links pointed out in it, as well as comment on some the consequence of lack of a broader, more comparative, perspective on the etiology of these diseases.
    A relationship of human intestinal inflammatory disease with the mycobacterial counterpart in ruminants was already pointed out in 1913^6^, even before the index des cription of Crohn?s disease^5^, on the grounds of the pathological similarities between human regional intestinal inflammatory disease and ruminant paratuberculosis. This mycobacterial hypothesis, thus, linked the human form to the ruminant entity first reported in 1895^9^ and generally accepted to be caused by Mycobacterium avium subsp. paratuberculosis (MAP). This microorganism is a bacterial species characterized as slow and fastidious to grow even in specific isolation media. Since its first isolation from human patients by Chiodini et al in 1984^2^, this agent has been repeatedly linked to CD by immunologic^7,14^, epidemoiologic^1,10^, therapeutic^8^ and genetic^4^ approaches. The paper by Jostins et al. more strongly confirms that and brings out a rare disease (mendelian susceptibility to mycobacteria disease-MSMD) that was already postulated as a model for Crohn?s disease 4 years ago on the grounds of the significantly higher levels of circulating IFN-g in the blood of patients than in the blood of controls^13^. In that disease, a deficiency in the IFN-g receptors would disrupt normal transition from innate to adaptive immune response and cause higher levels of IFN-g in blood because of failure to metabolize it through its receptors.
    The mycobacterial etiology hypothesis for human inflammatory disease has faced generalized criticism and disinterest among the gastroenterology community and, in our closer Spanish medical community, has prevented testing the apparent effects of certain treatment patterns that in preliminary ?post hoc? analysis seemed to decrease both the blood MAP DNA levels and the disease activity indices^12^. Unfortunately this is coupled with reluctance of the veterinary authorities of most countries to allow the use of the most efficient control measure against paratuberculosis which is vaccination^11,3^. This is a radical approach grounded on a fundamentalist interpretation of interference with bovine tuberculosis tests results (even though bovine TB has become a highly compartmentalized, if increasingly concerning, animal infection and a nearly negligible zoonosis in the countries that have successfully run those schedules). This has caused a silencing of ongoing vaccination practice in cattle, and nearly so in other species except for the successfull recent introduction of vaccination for control of sheep paratuberculosis in Australia.
    All this has left the study of relationships of paratuberculosis and Crohn?s disease nearly orphan but for the efforts of a few researchers that cannot collect enough resources to conduct the right research and that generally also miss the deepening of the study of natural disease as a model of intestinal inflammatory disease. On the contrary vast amounts of public funding are devoted to the study of palliative treatments in humans and on paratuberculosis control programs that have repeatedly proven to fail to cure or to eradicate the infection, but that keep patients and farmers chained to long-term expensive programs. The combined result is that cattle production is less efficient and that human population remains exposed and unprotected in front of high environmental levels of the potential cause of such a common and devastating disease. I hope that the current paper will boost research in the trans-species inflammatory hypothesis and thus bring prompt relief to so many intestinal inflammatory patients currently sentenced to a life of symptomatic therapy.

    Reference List

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    9 Johne, H. A. and Frothingham, L., "Ein eigenthümlicher Fall von Tuberculose beim Rind," Deut Zeits Tiermed Vergl Pathol 21, 438 (1895).
    10 Juste, RA, "Crohn's disease and ruminant farming. Got lactase?," Medical Hyptoheses 75, 7 (2010).
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    12 Juste, RA, et al., "On the prevalence of M. avium subspecies paratuberculosis DNA in the blood of healthy individuals and patients with inflammatory bowel disease," PLoS. ONE. 3(7), e2537 (2008).
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    14 Juste, RA, et al., "Seroreactivity of Crohn's disease patients to mycobacterial antigens: original data and analytical review of the literature," An Vet (Murcia) 23, 91 (2007).

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