Review
Is Crohn's disease caused by a mycobacterium? Comparisons with leprosy, tuberculosis, and Johne's disease

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Summary

Although Crohn's disease is considered to be autoimmune in origin, there is increasing evidence that it may have an infectious cause. The most plausible candidate is Mycobacterium avium subspecies paratuberculosis (MAP). Intriguingly, Koch's postulates may have been fulfilled for MAP and Crohn's disease, even though they still have not been met for Mycobacterium leprae and leprosy. In animals MAP causes Johne's disease, a chronic wasting intestinal diarrhoeal disease evocative of Crohn's disease. Johne's disease occurs in wild and domesticated animals, including dairy herds. Viable MAP is found in human and cow milk, and is not reliably killed by standard pasteurisation. MAP is ubiquitous in the environment including in potable water. Since cell-wall-deficient MAP usually cannot be identified by Ziehl-Neelsen staining, identification of MAP in human beings requires culture or detection of MAP DNA or RNA. If infectious in origin, Crohn's disease should be curable with appropriate antibiotics. Many studies that argue against a causative role for MAP in Crohn's disease have used antibiotics that are inactive against MAP. However, trials that include macrolide antibiotics indicate that a cure for Crohn's disease is possible. The necessary length of therapy remains to be determined. Mycobacterial diseases have protean clinical manifestations, as does Crohn's disease. The necessity of stratifying Crohn's disease into two clinical manifestations (perforating and non-perforating) when interpreting the results of antibiotic therapy is discussed. Rational studies to evaluate appropriate therapies to cure Crohn's disease are proposed.

Section snippets

Mycobacteria are effective pathogens

Mycobacterium tuberculosis infects about one-third of humankind today.20 However, only an estimated 5–10% of those exposed have a lifetime risk of developing active tuberculosis.21 An even smaller minority of those who are infected are killed by the disease.22 Nevertheless, M tuberculosis has killed about one billion people over the past two centuries.23 I suggest that MAP is an equally effective and even more insidious pathogen than M tuberculosis. It infects many species and yet, in human

MAP in the environment and in animals

MAP is found in the potable water supply of large cities in industrialised nations.24 Mycobacteria are at least two orders of magnitude more resistant to chlorine purification than Escherichia coli.25 MAP survives higher concentrations of chlorine (two parts per million) than the 1·1 parts per million routinely achieved with first-use municipal water in the USA.26 Additionally, mycobacteria are more resistant to chlorine purification at the low-nutrient, low-temperature, and increased-pH

MAP in milk

MAP in milk from domestic animals is well described,40, 41, 42, 43, 44 and it is not reproducibly eradicated by pasteurisation at the parameters routinely used in the USA.15, 45, 46, 47, 48, 49 There are concerns that using pasteurisation standards effective against MAP may adversely effect the taste and, therefore, consumer acceptance of milk products.15

MAP has been cultured from the milk of two women with active Crohn's disease who were breast feeding.50 Identification was confirmed by the

Pathogenicity of MAP in human beings

The dogma that MAP is not a zoonotic organism—ie, that it is not pathogenic in human beings—is challenged by two case reports. A 36-year-old patient with haemophilia, AIDS, and a CD4+ lymphocyte count of 29 × 106/mL developed vicious diarrhoea. Acid-fast bacilli were seen in biopsy samples from his colon, liver, and bone marrow. Uniquely in human beings, these cell-wall-containing mycobacteria were identified as MAP by both culture (requiring mycobactin containing medium) and IS900 DNA analysis.

Ziehl-Neelsen staining for MAP

Both of the publications that identified Crohn's disease1, 2 commented on a major difference between the disease they were describing and intestinal tuberculosis: a lack of identifiable acid-alcohol-fast-staining bacteria by the technique described by Ziehl and Neelsen in 1886.55 This staining method identifies the complex and characteristic cell wall of intact mycobacteria. The major difference between Crohn's disease and Johne's disease is that the causative organism can be seen in some

Growing MAP in vitro

Part of the problem in diagnosing MAP infections in human beings may be due to the difficulty of growing MAP in vitro.60, 71 In part the culture problem is due to the fact that MAP lacks the iron-chelating agent mycobactin. As a consequence, either the infected host or the culture medium must provide the MAP with iron for it to grow. Achieving growth may be even more difficult when the organism is initially in its cell-wall-deficient form.56, 57 Although culturing MAP is difficult, it is not

Isolating the DNA and RNA of MAP

The DNA sequence IS900, first identified in 1989,51 is considered the “gold standard” to differentiate MAP from other mycobacteria.41, 42, 43, 50, 51, 52, 54, 59, 64, 66, 67, 74, 75, 76, 77, 78, 79, 80 It must be emphasised that the mere presence of IS900 DNA is not pathognomonic of a causal relation between Crohn's disease and MAP. Importantly, the isolation of DNA of MAP from patients with Crohn's disease is not reproducible. In my laboratory, although we identified the RNA of MAP in 100% of

Koch's postulates may have been met for MAP and Crohn's disease

Although M leprae has not fulfilled the second, third, or fourth postulate of Koch as the cause of leprosy,73 because the organism cannot be grown in vitro, few would dispute the statement that leprosy is an infectious disease caused by M leprae.

Unlike M leprae, MAP can be grown in vitro, albeit with the considerable difficulty previously described.60, 71 I suggest that Koch's four postulates102 may already have been met for MAP and Crohn's disease.103 To accept this claim presupposes that

Clinical trials of antibiotics to treat Crohn's disease

Published material is replete with negative studies that have attempted to treat Crohn's disease with antibiotics.111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125 Importantly, in all these studies the antibiotics used were ineffective against the avium species of mycobacteria in general, and MAP in particular. I suggest that studies to treat Crohn's disease with antibiotics that have no activity against M avium and MAP are meaningless if the causative organism of

Comparisons among leprosy, tuberculosis, Johne's disease, and Crohn's disease

It is conceptually helpful to compare the clinical manifestations of three well-described mycobacterial diseases—leprosy, tuberculosis, and Johne's disease—with Crohn's disease. All four diseases under consideration have multiple clinical manifestations.

Possibly recognised in antiquity, leprosy has two distinct clinical manifestations (figure 2), which were designated by Hansen in 1874136 as the “tuberculoid” and “lepromatous” forms. M leprae is the organism that causes both the lepromatous and

Intestinal obstruction during antibiotic therapy for tuberculosis and Crohn's disease

Usually, during the course of a clinical trial involving medications, progression to surgery is interpreted as indicating a failure of therapy. To the contrary, I suggest that in tuberculosis as well as in Crohn's disease progression to intestinal obstruction may actually indicate a positive, albeit a paradoxical, clinical response.

One-third of patients with intestinal tuberculosis who receive appropriate anti-M tuberculosis therapy may require additional surgery to relieve intestinal

Crohn's and tuberculosis susceptibility to genetic defects

The presence of a gene that is associated with an increased susceptibility to develop a disease does not preclude the possibility that the disease may be infectious in aetiology. A genetic defect has been identified that suggests that black people are more susceptible to tuberculosis than other races.145 Similarly, an increased susceptibility to Crohn's disease, but not ulcerative colitis,132 is associated with a defect in the NOD2 gene132, 133, 134 It is of interest that the NOD2 gene

Immune modulation and the therapy of tuberculosis and Crohn's disease

Clinical responses to immune modulation have been reported in the therapy of Crohn's disease,146, 147 particularly the more aggressive perforating form.147 In the event that Crohn's disease is eventually accepted to be infectious in aetiology, this paradox of clinical improvement of an infectious disease by immune modulation will need to be fully explained. Again it is of use to compare Crohn's disease with tuberculosis. Although tuberculosis is incontrovertibly infectious, encouraging results

Conclusions and recommendations

There are increasingly compelling data that MAP, a major cause of disease in agricultural, domestic, and wild animals, may be responsible for much more disease in humans than has been recognised. Appropriate ethical, prospective, randomised studies, are indicated among patients with Crohn's disease. These studies should use multiple antibiotics that are active against the avium species of mycobacteria. The duration of therapy needs to be determined. Individuals with NOD2 defects may require

Search strategy and selection criteria

Searches were made using the National Library of Medicine Pubmed database. Search criteria were, individually and in combination: “Crohn”, “Crohn's”, “Johne's”, “paratuberculosis”, and “paratuberculosis and milk”. English language articles and English translations of abstracts in other languages were reviewed. Websites were identified using Google and the website of the International Paratuberculosis Association (http://www.paratuberculosis.org).

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      This seminal paper led to the coining of the Crohn´s disease eponym and its quick worldwide acceptance. After that, many studies and findings have been published along the years [30,31], of which the more relevant to this paper approach are included in Table 1 [7,24,25,27,28,32–51]. The incidence of human IBD has been increasing worldwide during the last century, but it seems to have stabilized now [2].

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