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Epidemiological evidence for Mycobacterium avium subspecies paratuberculosis as a cause of Crohn's disease

  • J. C. UZOIGWE (a1), M. L. KHAITSA (a2) and P. S. GIBBS (a2)
  • DOI:
  • Published online: 01 October 2007

Mycobacterium avium subspecies paratuberculosis is the causative agent of Johne's disease, a chronic enteritis in ruminants including cattle, sheep, goats, and farmed deer. Recently, this bacterium has received an increasingly wide interest because of a rapidly growing body of scientific evidence which suggests that human infection with this microorganism may be causing some, and possibly all, cases of Crohn's disease. Recent studies have shown that a high percentage of people with Crohn's disease are infected with M. avium subsp. paratuberculosis; whether the association of this bacterium and Crohn's disease is causal or coincidental is not known. Crohn's disease is a gastrointestinal disease in humans with similar histopathological findings to those observed in the paucibacillary form of Johne's disease in cattle. The search for risk factors in Crohn's disease has been frustrating. However, epidemiologists have gathered enough information that points to an association between M. avium subsp. paratuberculosis and Crohn's disease. This paper reviews epidemiological models of disease causation, the major philosophical doctrines about causation, the established epidemiological criteria for causation, and the currently known epidemiological evidence of M. avium subsp. paratuberculosis as a possible cause of Crohn's disease.

Corresponding author
*Author for correspondence: Dr P. S. Gibbs, Department of Veterinary and Microbiological Sciences, North Dakota State University, Fargo, ND58105, USA. (Email:
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This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

CD Buergelt , PE Ginn . The histopathologic diagnosis of subclinical Johne's disease in North American bison (Bison bison). Veterinary Microbiology 2000; 77: 325331.

WE Cook , Radiometric culture of Mycobacterium avium subsp. paratuberculosis from the faeces of tule elk. Journal of Wildlife Diseases 1997; 33: 635637.

EJB Manning , Testing for Mycobacterium avium subsp. paratuberculosis infection in asymptomatic free-ranging tule elk from an infected herd. Journal of Wildlife Diseases 2003; 39: 323328.

A Greig , Paratuberculosis in wild rabbits (Oryctolagus cuniculus). Veterinary Record 1997; 140: 141143.

PM Beared , Natural paratuberculosis infection in rabbits in Scotland. Journal of Comparative Pathology 2001; 124: 290299.

PM Beard , Paratuberculosis infection of nonruminant wildlife in Scotland. Journal of Clinical Microbiology 2001; 39: 15171521.

HM McClure , Mycobacterium paratuberculosis infection in a colony of stumptail macaques (Macaca arctoides). Journal of Infectious Diseases 1987; 155: 10111019.

LS Zwick , Paratuberculosis in a mandrill (Papio sphinx). Journal of Veterinary Diagnostic Investigation 2000; 14: 326328.

FA El Zaatari , MS Osato , DY Graham . Aetiology of Crohn's disease: the role of Mycobacterium avium paratuberculosis. Trends in Molecular Medicine 2001; 7: 247252.

K Hulten , Identification of cell wall deficient forms of M. avium subsp. paratuberculosis in paraffin embedded tissues from animals with Johne's disease by in situ hybridization. Journal of Microbiological Methods 2000; 42: 185195.

P Quirke . Antagonist. Mycobacterium avium subspecies paratuberculosis is a cause of Crohn's disease. Gut 2001; 49: 757760.

CJ Clarke . The pathology and pathogenesis of paratuberculosis in ruminants and other species. Journal of Comparative Pathology 1997; 116: 217261.

RJ Greenstein . Is Crohn's disease caused by a mycobacterium? Comparison with leprosy, tuberculosis, and Johne's disease. Lancet Infectious Diseases 2003; 3: 507514.

MT Moss , Polymerase chain reaction detection of Mycobacterium paratuberculosis and Mycobacterium avium subsp. silvaticum in long term cultures from Crohn's disease and control tissues. Gut 1992; 33: 12091213.

J Hermon-Taylor . Protagonist. Mycobacterium avium subspecies paratuberculosis is a cause of Crohn's disease. Gut 2001; 49: 755756.

TP Primm , CA Lucero , JO Falkinham . Health impacts of environmental mycobacteria. Clinical Microbiology Reviews 2004; 17: 98106.

C Cocito , Paratuberculosis. Clinical Microbiology Reviews 1994; 7: 328345.

ND Harris , RG Barletta . Mycobacterium avium subsp. paratuberculosis in veterinary medicine. Clinical Microbiology Reviews 2001; 14: 489512.

SL Ott , SJ Wells , BA Wagner . Herd-level economic losses associated with Johne's disease on US dairy operations. Preventive Veterinary Medicine 1999; 40: 179192.

JR Stabel . Johne's disease: a hidden trait. Journal of Dairy Science 1998; 81: 283288.

C Reed , Environmental risk factors for infection with Mycobacterium avium complex. American Journal of Epidemiology 2006; 164: 3240.

IR Grant , HJ Ball , MT Rowe . Incidence of Mycobacterium paratuberculosis in bulk raw and commercially pasteurized cows' milk from approved dairy processing establishments in the United Kingdom. Applied and Environmental Microbiology 2002; 68: 24282435.

WY Ayele , Mycobacterium avium subspecies paratuberculosis cultured from locally and commercially pasteurized cow's milk in the Czech Republic. Applied and Environmental Microbiology 2005; 71: 12101214.

CN Bernstein , The epidemiology of inflammatory bowel disease in Canada: A population-based study. American Journal of Gastroenterology 2006; 101: 15591568.

EV Loftus , P Schoenfeld , WJ Sandborn . The epidemiology and natural history of Crohn's disease in population-based patient cohorts from North America: a systematic review. Alimentary Pharmacology and Therapeutics 2002; 16: 5160.

B Moum , Incidence of Crohn's disease in four counties in southeastern Norway, 1990–1993. A prospective population-based study. The Inflammatory Bowel South-Eastern Norway (IBSEN) Study Group of Gastroenterologists. Scandinavian Journal of Gastroenterology 1996; 31: 355361.

EV Loftus Jr., Crohn's Disease in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival. Gastroenterology 1998; 114: 11611168.

E Armitage , Increasing incidence of both juvenile-onset Crohn's disease and ulcerative colitis in Scotland. European Journal of Gastroenterology and Hepatology 2001; 13: 14391447.

Y Niv , G Abuksis , GM Fraser . Epidemiology of Crohn's disease in Israel: a survey of Israeli kibbutz settlements. American Journal of Gastroenterology 1999; 94: 29612965.

EV Loftus Jr.. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 2004; 126: 15041517.

T Card , R Hubbard , RFA Logan . Mortality in inflammatory bowel disease: a population-based cohort study. Gastroenterology 2003; 125: 15831590.

SJ Shivananda , Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut 1996; 39: 690697.

A Lapidus , Incidence of Crohn's disease in Stockholm county 1955–1989. Gut 1997; 41: 480486.

J Satsangi , DP Jewell , JI Bell . The genetics of inflammatory bowel disease. Gut 1997; 40: 572574.

C Tysk , Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 1988; 29: 990996.

NP Thompson , Genetics versus environment in inflammatory bowel disease: results of a British twin study. British Medical Journal 1996; 312: 9596.

Y Ogura , Frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001; 411: 603606.

JF Fielding . The relative risk of inflammatory bowel disease among parents and siblings of Crohn's disease patients. Journal of Clinical Gastroenterology 1986; 8: 655657.

DA van Heel , Inflammatory bowel disease: Progress toward a gene. Canadian Journal of Gastroenterology 2000; 14: 207218.

AP Cuthbert , The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology 2002; 122: 867874.

N Inoue , Lack of common NOD2 variants in Japanese patients with Crohn's disease. Gastroenterology 2002; 123: 8691.

L Zouten-Mekki , Card15/NOD2 in a Tunisian population with Crohn's disease. Digestive Diseases Sciences 2005; 50: 130135.

FA Uyar , Distribution of common CARD15 variants in patients with sporadic Crohn's disease: Cases from Turkey, 2006. Digestive Disease Science 2006; 51: 706710.

JP Hugot , Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411: 599603.

Y Kojima , Inflammatory bowel disease is associated with a novel promoter polymorphism of natural resistance-associated macrophage protein 1 (NRAMP1) gene. Tissue Antigens 2001; 58: 379384.

M Parascandola , DL Weed . Causation in epidemiology. Journal of Epidemiology and Community Health 2001; 55: 905912.

KJ Rothman , S Greenland . Causation and causal inference in epidemiology. American Journal of Public Health 2005; 95: S144S150.

N Krieger . Epidemiology and the web of causation: has anyone seen the spider? Social Science and Medicine 1994; 39: 887903.

P Jantchou , E Monnet , F Carbonnel . Environmental risk factors in Crohn's Disease and ulcerative colitis (excluding tobacco and appendicectomy). Gastroenterologie Clinique et Biologique 2006; 30: 859867.

B Sicilia , Environmental risk factors and Crohn's Disease: a population based, case-control study in Spain. Digestive and Liver Disease 2001; 33: 762–727.

JM Dumonceau , No Mycobacterium paratuberculosis found in Crohn's Disease using polymerase chain reaction. Digestive Diseases and Sciences 1996; 41: 421426.

KJ Rothman , S Greenland . Modern Epidemiology, 2nd edn. Philadelphia: Lippincott-Raven, 1998.

M Jeyenathan , Evaluation of in situ methods used to detect Mycobacterium avium subsp. paratuberculosis in samples from patients with Crohn's disease. Journal of Clinical Microbiology 2006; 44: 29422950.

BA Forbes . Critical Assessment of gene amplification approaches on the diagnosis of tuberculosis. Immunology Investigations 1997; 26: 105116.

GT Noordhoek , Multicenter quality control study for detection of Mycobacterium tuberculosis in clinical samples by nucleic amplification methods. Clinical Microbiology and Infection 2004; 10: 295301.

L Rychetnik , A glossary for evidence based public health. Journal of Epidemiology and Community Health 2004; 58: 538545.

N Pearce , D Crawford-Brown . Critical discussion in epidemiology: problems with the Popperian approach. Journal of Clinical Epidemiology 1989; 42: 177184.

C Buck . Popper's philosophy for epidemiologists. International Journal of Epidemiology 1975; 4: 159168.

GP Page , Are we there yet?: deciding when one has demonstrated specific genetic causation in complex diseases and quantitative traits. American Journal of Human Genetics 2003; 73: 711719.

P Vineis , D Kriebel . Causal models in epidemiology: past inheritance and genetic future. Environmental Health 2006; 5: 21.

M Kundi . Causality and the interpretation of epidemiological evidence. Environmental Health Perspectives 2006; 114: 969974.

M Höfler . The Bradford Hill considerations on causality: a counterfactual perspective. Emerging Themes in Epidemiology 2005; 2: 11.

M Susser . Rules of inference in epidemiology. Regulatory Toxicology and Pharmacology 1986; 6: 116128.

RH Fletcher , SW Fletcher , EH Wagner . Clinical Epidemiology: the Essentials, 3rd edn. Baltimore: Williams and Wilkins, 1996.

W Chamberlin , Review article: Mycobacterium avium subsp. paratuberculosis as one cause of Crohn's disease. Alimentary Pharmacology and Therapeutics 2001; 15: 337346.

SA Naser , Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn's disease. Lancet 2004; 364: 10391044.

D Mishina , On the aetiology of Crohn disease. Proceedings of the National Academy of Sciences USA 1996; 93: 98169820.

J Hermon-Taylor , Causation of Crohn's disease by Mycobacterium avium subsp. paratuberculosis. Canadian Journal of Gastroenterology 2000; 14: 521539.

K Hulten , Detection of Mycobacterium avium subsp. paratuberculosis in Crohn's diseased tissues by in situ hybridization. American Journal of Gastroenterology 2001; 96: 15291535.

JA Ikonomopoulos , Sensitive differential detection of genetically related mycobacterial pathogens in archival material. American Journal of Clinical Pathology 2000; 114: 940950.

LA Sechi , Detection and Isolation of Mycobacterium avium subsp. paratuberculosis from intestinal mucosal biopsies of patients with and without Crohn's disease in Sardinia. American Journal of Gastroenterology 2005; 100: 15291536.

LA Sechi , Identification of Mycobacterium avium subsp. paratuberculosis in biopsy specimens from patients with Crohn's disease identified by in situ hybridization. Journal of Clinical Microbiology 2001; 39: 45144517.

CY Turenne , Sequencing of hsp65 distinguishes among subsets of the Mycobacterium avium complex. Journal of Clinical Microbiology 2006; 44: 433440.

F Autschbach , High prevalence of Mycobacterium avium subsp. paratuberculosis 1S900 DNA in gut tissues from individuals with Crohn's disease. Gut 2005; 54: 944949.

TJ Bull , Characterization of IS900 loci in Mycobacterium avium subsp. paratuberculosis and development of muliplex PCR typing. Microbiology 2000; 146: 21852197.

TJ Bull , Detection and verification of Mycobacterium avium subsp. paratuberculosis in fresh ileocolonic mucosal biopsy specimens from individuals with and without Crohn's disease. Journal of Clinical Microbiology 2003; 41: 29152923.

J Hermon-Taylor , Molecular biology of Crohn's disease mycobacteria. Baillieres Clinical Gastroenterology 1990; 4: 2342.

MT Moss , Specific detection of Mycobacterium paratuberculosis by DNA hybridization with a fragment of the insertion element IS900. Gut 1991; 32: 395398.

F Ziehl . Zur Farbung des Tuberkelbacillus. Deutsche Medizinische Wochenschrift 1882; 8: 451.

C Fiocchi . Inflammatory bowel disease: aetiology and pathogenesis. Gastroenterology 1998; 115: 182205.

JD Sanderson , Mycobacterium paratuberculosis DNA in Crohn's disease tissue. Gut 1992; 33: 890896.

TT McDonald . The Hypothesised Link Between Dairy products, Mycobacterium paratuberculosis and Crohn's Disease. London: The Dairy Council (UK), 2001.

M Semret , Differentiating host-associated variants of Mycobacterium avium by PCR for detection of large sequence polymorphisms. Journal of Clinical Microbiology 2006; 44: 881887.

AL St. Amand , Use of specific rRNA oligonucleotide probes for microscopic detection of Mycobacterium avium complex organisms in tissue. Journal of Clinical Microbiology 2005; 43: 15051514.

MP Riggio , Search for Mycobacterium paratuberculosis DNA in orofacial granulomatosis and oral Crohn's disease tissue by polymerase chain reaction. Gut 1997; 41: 646650.

HJ Van Kruiningen , Experimental disease in infant goats induced by a mycobacterium isolated from a patient with Crohn's disease. A preliminary report. Digestive Diseases and Sciences 1986; 31: 13511360.

D Schwartz , Use of short-term culture for identification of Mycobacterium avium subsp. paratuberculosis in tissue from Crohn's disease patients. Clinical Microbiology and Infection 2000; 6: 303307.

PM Danze , Association of HLA class II genes with susceptibility to Crohn's disease. Gut 1996; 39: 6972.

HJ Hodgson . Keeping Crohn's disease quiet. New England Journal of Medicine 1998; 334: 15991600.

RA Van Hogezand , HW Verspaget . Selective immunomodulation in patients with inflammatory bowel disease-future therapy or reality. Netherlands Journal of Medicine 1996; 48: 6467.

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