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Mycobacterium Avium Subspecies Paratuberculosis Is a Cause of Crohn’S Disease

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Mycobacterium Avium Subspecies Paratuberculosis Is a Cause of Crohn’S Disease Gut 2001;49:755–760 755 ................................ PROTAGONIST Debate Gut: first published as 10.1136/gut.49.6.755 on 1 December 2001. Downloaded from Mycobacterium avium subspecies paratuberculosis is a cause of Crohn’s disease J Hermon-Taylor Mycobacterium avium subspecies paratuberculosis pasteurised milk in Britain.12 MAP survives in the (MAP) belongs to the M avium complex (MAC). environment and is probably conveyed to humans MAC occur widely in the environment and in water supplies.1 Colonisation of the human inhabit normal animal and human intestine. intestine is cumulative. As with other mycobacte- MAC do not usually cause disease unless the host ria, MAP may remain in a state of dormancy for is debilitated. MAP is a pathogen and causes years. Inflammatory disease develops in those chronic inflammation of the intestine in many who have an inherited or acquired susceptibility. animals, including primates. MAP is closely Clinical disease may be triggered by intercurrent related genetically to other MAC but possesses infection and by physical or psychological trauma. additional DNA such as IS900, the hspX region, In conventional media, MAP ranges from very and the low %GC genetic element “GS”, which slow growing to unculturable. MAP is more are associated with its pathogenic phenotype. resistant to chemical and enzymatic lysis than Further genetic elements related to pathogenicity other organisms.1 It is present in the intestine of a may be revealed by the whole genome sequencing proportion of normal subjects and can be of MAP currently underway at the University of detected in a majority of full thickness surgical Minnesota. A recent review and extensive bibliog- samples of Crohn’s disease gut if the correct cul- raphy is available.1 ture and IS900 polymerase chain reaction (PCR) MAP can colonise animals for years without methods are used.13 14 MAP in Crohn’s disease is causing disease. Chronic inflammation of the present in low abundance and in a tough ZN intestine (Johne’s disease) may emerge after a negative form putatively coated with methylated long latent period, particularly when animals are and acetylated fucose.1 MAP in humans can stressed. Regional lymph nodes, liver, and lung minimise immune recognition, and tests of are also involved. Histopathological features vary antibody or cell mediated immunity using crude between animals and between diVerent organs in lysates of laboratory cultured MAP or other http://gut.bmj.com/ the same animal.2 MAP disease in animals ranges MAC, with some exceptions, have not dis- from pluribacillary to paucimicrobial, like leprosy tinguished general immune reactivity to MAC in in humans.3 Terminal ileum and adjacent colon Crohn’s disease from that in normal subjects.1 are commonly aVected but segmental lesions in Highly significant immune recognition in Crohn’s the small gut as well as colonic and rectal involve- disease can be detected if molecules bearing MAP ment also occur. Animals usually die of their specific epitopes or those shared with other 115 infection and although perforation, stricture, and mycobacteria are used. on September 28, 2021 by guest. Protected copyright. fistulation are not usually found in Johne’s MAP in Crohn’s disease does not have a disease, these features occur in regional ileitis and conventional mycobacterial cell wall. Pathogenic colitis in dogs and pigs.45 In experimental mechanisms and drug susceptibilities are not like infection, MAP demonstrates a distinct tissue tuberculosis. Intracellular MAP probably causes tropism and will cause chronic inflammation of an immune dysregulation with transmural inflam- the intestine if given intravenously or subcutane- mation resulting from a perturbed immune ously.67 response to leakage of enteric organisms and food With the opportunity to amplify in intensely residues into the gut wall. Without killing MAP, farmed domestic livestock for over a century, improvements following immune suppression or MAP may have undergone an adaptive diversifi- modulation, elemental diets, and antibiotics cation. Genotyping of MAP has so far revealed 28 active against enteric bacteria are seldom lasting. diVerent strains, including those favouring a par- MAP infection in animals is not eradicated by ticular host such as sheep or cattle.8 The herd anti-tuberculosis drugs.1 The failure of a lengthy prevalence of MAP infection in Western Europe controlled trial of rifampicin, isoniazid, and and North America is in the range 21–70%.910 ethambutol to confer benefit16 is consistent with Department of Surgery, ................................ Reinfection of new generations of young animals what has long been known of the resistance of St George’s Hospital comes by passage of MAP from parent to MAC to such agents in vitro and in vivo, and the Medical School, London oVspring in milk, and from contaminated farm non-bacillary phenotype of MAP in Crohn’s dis- SW17 0RE, UK environments. Wildlife reservoirs contribute to ease. Crohn’s disease is not healed by rifampicin J Hermon-Taylor 11 environmental contamination. Subclinically in- and streptomycin which have broad activity Correspondence to: fected cows secrete MAP in their milk. MAP is against enteric organisms. Four outcome analyses Dr J Hermon-Taylor. more robust than M tuberculosis and can survive have all shown that a substantial proportion of [email protected] commercial pasteurisation conditions, commonly people with Crohn’s disease improve with tissue Accepted for publication 72°C for 15 seconds.1 MAP is present in retail healing when treated with a combination of 21 July 2000 www.gutjnl.com 756 Hermon-Taylor ................................ 6 Twort FW, Ingram GLY. A Monograph on Johne’s Disease. Debate Summary London: Bailliere, Tindall and Cox, 1913. • Mycobacterium avium subspecies paratuber- 7 Larsen AB, Miller JM, Kermal RS. Subcutaneous Gut: first published as 10.1136/gut.49.6.755 on 1 December 2001. Downloaded from culosis (MAP) is a member of the M avium exposure of calves to Mycobacterium paratuberculosis complex (MAC). Unlike other MAC, MAP is a compared with intravenous and oral exposures.AmJVet specific cause of chronic inflammation of the Res 1977;38:1669–71. intestine of a broad range of histopathological 8 Pavlik I, Horvathova A, Dvorska L, et al. Standardisation of types, affecting many species of animals restriction fragment length polymorphism analysis for including subhuman primates. Mycobacterium avium subspecies paratuberculosis. J Microbiol Methods 1999;38:155–67. • MAP can colonise animals for years without 9 Wells SJ, Ott SL, Garber LP, et al. Johne’s disease on US causing clinical disease. Such subclinically dairy operations: results from the NAHMS dairy 96 study. infected animals shed MAP in their milk and In: Chiodini RJ, Hines ME, Collins MT, eds. Proceedings onto pastures. The herd prevalence of sub- of the Fifth International Colloquium on Paratuberculosis clinical MAP infection in Europe and North 1996. Rehoboth, MA, USA: International Association for America is reported to be in the range Paratuberculosis, 1996:140–2. 21–70%. 10 Nielsen SS, Thamsborg SM, Houe H, et al. Bulk-tank milk • MAP is present in retail pasteurised milk in ELISA antibodies for estimating the prevalence of paratu- Britain and is probably also conveyed in water berculosis in Danish dairy herds. Prev Vet Med 2000;44: supplies. 1–7. • MAP is harboured in the ileocolonic mucosa of 11 Beard PM, Henderson D, Daniels MJ, et al. Evidence of a proportion of normal subjects and can be paratuberculosis in fox (Vulpes vulpes) and stoat demonstrated in full thickness samples of gut (Mustela erminea). Vet Rec 1999;145:612–13. wall in the majority of patients with Crohn’s 12 Report of the Scientific Committee on Animal Health and disease if the correct culture and PCR meth- Animal Welfare, European Commission. Possible links ods are used. between Crohn’s disease and paratuberculosis. http:// • As with other MAC, MAP infections are diffi- europa.eu.int/comm/dg24/health/sc/scah/ cult to eradicate and the organisms are resist- outcome_en.html ant to most standard anti-tuberculosis drugs. 13 Sanderson JD, Moss MT, Tizard MLV, et al. Mycobacte- Rifabutin and clarithromycin are more active rium paratuberculosis DNA in Crohn’s disease tissue. Gut against MAP and about two thirds of patients 1992;33:890–6. with active Crohn’s disease will go into remis- 14 Schwartz D, Shafran I, Romero C, et al. Use of short-term sion with healing of the intestine when treated culture for identification of Mycobacterium avium subsp with a combination of these agents. paratuberculosis in tissue from Crohn’s disease patients. Clin Microbiol Infect 2000;6:303–7. 15 Cohavy O, Harth G, Horwitz M, et al. Identification of a 17–20 rifabutin and clarithromycin. These drugs also novel mycobacterial histone H1 homologue (HupB) as an have a broad antibacterial action but are more antigenic target of panca monoclonal antibody and serum active against MAC and MAP. A controlled trial immunoglobulin a from patients with Crohn’s disease. of rifabutin, clarithromycin, and clofazimine Infect Immun 1999;67:6510–17. http://gut.bmj.com/ began in Australia in September 1999. Therapeu- 16 Thomas GAO, Swift GL, Green JT, et al. Controlled trial of tic MAP vaccines for immune mediated microbial antituberculous chemotherapy in Crohn’s disease: a five year follow up study. Gut 1998;42:497–500. clearance are needed. 17 Gui GPH, Thomas PRS, Tizard MLV, et al. Two-year- outcomes analysis of Crohn’s disease treated with rifabu- 1 Hermon-Taylor J, Bull TJ, Sheridan JM, et al. Causation of tin and macrolide antibiotics. J Antimicrob Chemother Crohn’s disease by Mycobacterium avium subspecies 1997;39:393–400. paratuberculosis. Can J Gastroenterol 2000;14:521–39. 18 Borody TJ, Pearce L, Bampton PA, et al. Treatment of 2 Buergelt CD, Hall C, McEntee K, et al. Pathological evalu- on September 28, 2021 by guest. Protected copyright. severe Crohn’s disease (CD) using rifabutin-macrolide- ation of paratuberculosis in naturally infected cattle.Vet clofazimine combination: interim report.
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