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Mycobacterium avium subspecies paratuberculosis is a cause of Crohn's disease
  1. J Hermon-Taylor
  1. Department of Surgery, St George's Hospital Medical School, London SW17 0RE, UK
  1. Dr J Hermon-Taylor.jhermon{at}sghms.ac.uk

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Mycobacterium avium subspeciesparatuberculosis(MAP) belongs to theM avium complex (MAC). MAC occur widely in the environment and inhabit normal animal and human intestine. MAC do not usually cause disease unless the host is debilitated.MAP is a pathogen and causes chronic inflammation of the intestine in many animals, including primates.MAP is closely related genetically to other MAC but possesses additional DNA such as IS900, the hspX region, and the low %GC genetic element “GS”, which are associated with its pathogenic phenotype. Further genetic elements related to pathogenicity may be revealed by the whole genome sequencing ofMAP currently underway at the University of Minnesota. A recent review and extensive bibliography is available.1

MAP can colonise animals for years without causing disease. Chronic inflammation of the intestine (Johne's disease) may emerge after a long latent period, particularly when animals are stressed. Regional lymph nodes, liver, and lung are also involved. Histopathological features vary between animals and between different organs in the same animal.2 MAP disease in animals ranges from pluribacillary to paucimicrobial, like leprosy in humans.3Terminal ileum and adjacent colon are commonly affected but segmental lesions in the small gut as well as colonic and rectal involvement also occur. Animals usually die of their infection and although perforation, stricture, and fistulation are not usually found in Johne's disease, these features occur in regional ileitis and colitis in dogs and pigs.4 5 In experimental infection,MAP demonstrates a distinct tissue tropism and will cause chronic inflammation of the intestine if given intravenously or subcutaneously.6 7

With the opportunity to amplify in intensely farmed domestic livestock for over a century, MAP may have undergone an adaptive diversification. Genotyping ofMAP has so far revealed 28 different strains, including those favouring a particular host such as sheep or cattle.8 The herd prevalence ofMAP infection in Western Europe and North America is in the range 21–70%.9 10 Reinfection of new generations of young animals comes by passage ofMAP from parent to offspring in milk, and from contaminated farm environments. Wildlife reservoirs contribute to environmental contamination.11 Subclinically infected cows secrete MAP in their milk.MAP is more robust thanM tuberculosis and can survive commercial pasteurisation conditions, commonly 72°C for 15 seconds.1 MAP is present in retail pasteurised milk in Britain.12 MAP survives in the environment and is probably conveyed to humans in water supplies.1Colonisation of the human intestine is cumulative. As with other mycobacteria, MAP may remain in a state of dormancy for years. Inflammatory disease develops in those who have an inherited or acquired susceptibility. Clinical disease may be triggered by intercurrent infection and by physical or psychological trauma.

In conventional media, MAP ranges from very slow growing to unculturable. MAP is more resistant to chemical and enzymatic lysis than other organisms.1 It is present in the intestine of a proportion of normal subjects and can be detected in a majority of full thickness surgical samples of Crohn's disease gut if the correct culture and IS900 polymerase chain reaction (PCR) methods are used.13 14 MAP in Crohn's disease is present in low abundance and in a tough ZN negative form putatively coated with methylated and acetylated fucose.1 MAP in humans can minimise immune recognition, and tests of antibody or cell mediated immunity using crude lysates of laboratory culturedMAP or other MAC, with some exceptions, have not distinguished general immune reactivity to MAC in Crohn's disease from that in normal subjects.1 Highly significant immune recognition in Crohn's disease can be detected if molecules bearingMAP specific epitopes or those shared with other mycobacteria are used.1 15

MAP in Crohn's disease does not have a conventional mycobacterial cell wall. Pathogenic mechanisms and drug susceptibilities are not like tuberculosis. IntracellularMAP probably causes an immune dysregulation with transmural inflammation resulting from a perturbed immune response to leakage of enteric organisms and food residues into the gut wall. Without killing MAP, improvements following immune suppression or modulation, elemental diets, and antibiotics active against enteric bacteria are seldom lasting.MAP infection in animals is not eradicated by anti-tuberculosis drugs.1 The failure of a lengthy controlled trial of rifampicin, isoniazid, and ethambutol to confer benefit16 is consistent with what has long been known of the resistance of MAC to such agents in vitro and in vivo, and the non-bacillary phenotype of MAP in Crohn's disease. Crohn's disease is not healed by rifampicin and streptomycin which have broad activity against enteric organisms. Four outcome analyses have all shown that a substantial proportion of people with Crohn's disease improve with tissue healing when treated with a combination of rifabutin and clarithromycin.17-20 These drugs also have a broad antibacterial action but are more active against MAC and MAP. A controlled trial of rifabutin, clarithromycin, and clofazimine began in Australia in September 1999. Therapeutic MAP vaccines for immune mediated microbial clearance are needed.

Summary

  • Mycobacterium avium subspecies paratuberculosis (MAP) is a member of the M avium complex (MAC). Unlike other MAC, MAP is a specific cause of chronic inflammation of the intestine of a broad range of histopathological types, affecting many species of animals including subhuman primates.

  • MAP can colonise animals for years without causing clinical disease. Such subclinically infected animals shed MAP in their milk and onto pastures. The herd prevalence of subclinical MAP infection in Europe and North America is reported to be in the range 21–70%.

  • MAP is present in retail pasteurised milk in Britain and is probably also conveyed in water supplies.

  • MAP is harboured in the ileocolonic mucosa of a proportion of normal subjects and can be demonstrated in full thickness samples of gut wall in the majority of patients with Crohn's disease if the correct culture and PCR methods are used.

  • As with other MAC, MAP infections are difficult to eradicate and the organisms are resistant to most standard anti-tuberculosis drugs. Rifabutin and clarithromycin are more active against MAP and about two thirds of patients with active Crohn's disease will go into remission with healing of the intestine when treated with a combination of these agents.

References

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