Does Mycobacterium Avium Subspecies Paratuberculosis
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896 COMMENTARIES Crohn’s disease this observation has not been replicated ....................................................................................... by other investigators, and there is no evidence of increased frequency of Crohn’s disease in the offspring of Gut: first published as 10.1136/gut.2004.055889 on 10 June 2005. Downloaded from Does Mycobacterium avium subspecies mothers versus fathers with Crohn’s disease. Even if transmission of viable paratuberculosis cause Crohn’s MAP occurs, a plausible mechanism of tissue injury and induction of chronic disease? intestinal inflammation has not been proposed. Even advocates of the theory R Balfour Sartor that MAP causes Crohn’s disease con- cede that infection, if present, consists ................................................................................... of a low bacterial load and that no histochemical evidence of acid fast Reassessing this persistent theory in light of advances in molecular staining in Crohn’s disease tissues is microbial detection and genetic pathogenesis of disease seen. This could be explained by a paucibacillary infection with an obligate imilarities between chronic idio- Data from this study help address intracellular, cell wall deficient bacterial 19 pathic granulomatous ileocolitis some of the controversies that have form. In this setting, inflammation Sand mycobacterial infections have fuelled the vigorous debate between and tissue injury must be mediated by been noted since the original descrip- committed advocates and confirmed a cell mediated immune response. tions of the clinical syndrome now sceptics that is receiving increasing However, a cellular immune response called Crohn’s disease.1–4 Interest in a attention in the scientific literature, lay to MAP has not been documented in 20 possible infectious origin of this disorder press, and internet chat rooms. The Crohn’s disease patients, despite was renewed in 1989 when Chiodini arguments in favour or opposed to this increased serological responses to MAP et al cultured apparently identical theory (table 1) have some merit but antigens in the same patients. Another Mycobacterium avium subspecies paratu- many are flawed by incomplete data and serious flaw in the MAP pathogenesis of berculosis (MAP) from three patients lack of rigorous reflection. There is no Crohn’s disease theory is the observa- with Crohn’s disease.5 This controversy doubt that a potential source of zoonotic tion that these patients respond to 21 increased in intensity following the infection exists, with widespread MAP chronic immunosuppressive therapies detection of the specific DNA insertion infections in the dairy herds of Europe, and acquired immunosuppressive infec- sequence, IS900, of MAP in relatively North America, and Australia,13 14 excre- tions decrease disease activity as CD4 T 22 high numbers of patients with Crohn’s tion of MAP in milk from infected cell counts fall. In contrast, M tubercu- disease relative to ulcerative colitis and cows,15 relative resistance of intracellu- losis massively proliferates with anti- normal controls,6 and is now raging as lar MAP to widely used pasteurisation tumour necrosis factor or steroid treat- several different groups have detected techniques,16 and recovery of viable ment and M avium intracellulare thrives this organism in the food chain7 and MAP from the water supplying Los in the intestine as CD4 counts fall in water supply,8 proposed maternal-fetal Angeles.8 Moreover, the vast majority human immunodeficiency virus http://gut.bmj.com/ transmission in human milk,9 reported of studies using diverse techniques have infected patients. It is possible that long term responses to antimycobacter- detected MAP DNA or cultured this intracellular cell wall deficient MAP ial antibiotic combinations,10 and even organism in higher frequency from may not replicate well despite immuno- cultured viable M paratuberculosis in tissues of patients with Crohn’s disease suppression, but this issue has never blood samples of Crohn’s disease than from those with ulcerative colitis been studied by in vitro investigation or patients.11 and other disorders, although the in animals with Johne’s disease. In the Additional data to support an associa- reported frequency of recovery in both study by Autschbach et al, corticosteroid on October 1, 2021 by guest. Protected copyright. tion of MAP with Crohn’s disease is Crohn’s disease and ulcerative colitis therapy was associated with lower MAP provided by Autschbach and collea- have ranged from 0% to 100%.17 These detection rates.12 gues12 in this issue of Gut (see page results are consistent with two possibil- The most irrefutable evidence that a 944). This carefully performed and well ities: either MAP infection could cause microbial agent causes a disease is long controlled study used nested polymerase Crohn’s disease in a subset of patients term remission of clinical manifesta- chain reaction (PCR) to detect the IS900 that are either selectively exposed to this tions and an altered natural history of insertion element of MAP in 52% of organism or who are genetically suscep- disease following clearance of the infec- Crohn’s disease resected tissues versus tible to infection or, alternatively, this tion. In vitro sensitivity analyses show 2% of ulcerative colitis and 5% of mostly relatively common dietary organism that clinical isolates of MAP are not non-inflammatory control tissues. This may selectively colonise (or a dead responsive to traditional anti-M tubercu- study provides novel data regarding the organism selectively lodge in) the ulcer- losis agents, and therefore lack of effi- prevalence of MAP in various pheno- ated mucosa of Crohn’s disease patients cacy with isoniazid, ethambutol, and types of Crohn’s disease by showing but not initiate or perpetuate intestinal rifampicin treatment for two years with slightly higher detection of IS900 DNA inflammation. Molecular fingerprints a three year follow up23 does not detract in colonic (66.7%) compared with distal show that genotypes of bovine and from this theory. However, reports of ileal (40.5%) tissues and decreased human isolates are not similar but efficacy of combinations of clarithromy- detection rates with corticosteroid use. instead indicate that human and ovine cin or azithromycin, rifabutin, and a In addition, these authors reported (sheep) strains are more closely variety of other agents in 58–82% of weak associations with perianal involve- related.18 Maternal/fetal transmission of Crohn’s disease patients10 24 are also not ment and a shorter duration of disease MAP has been proposed following cul- definitive due to the uncontrolled nat- but no correlation with patient sex, age ture of MAP from breast milk of two ure of these studies, the small number at diagnosis, stricturing versus penetrat- patients with Crohn’s disease.9 of patients treated, the variable treat- ing phenotype, or presence of granulo- However, the frequency of positive ment regimens, and the fact that these mas. cultures in human milk is uncertain, antibiotics, particularly clarithromycin, www.gutjnl.com COMMENTARIES 897 Table 1 Arguments for and against a Mycobacterium avium subspecies MAP analogous to Helicobacter pylori in paratuberculosis (MAP) causation of Crohn’s disease peptic ulcer disease, gastritis, and gastric cancer, where host genetics and micro- Pros bial virulence factors determine Gut: first published as 10.1136/gut.2004.055889 on 10 June 2005. Downloaded from (1) Clinical and pathological similarities between Johne’s and Crohn’s diseases34 immune responses that mediate clinical (2) Presence in food chain (milk, meat) and water supplies78 5633 disease in a small minority of patients (3) Increased detection of MAP in Crohn’s disease tissues by culture, PCR, FISH (4) Positive blood cultures of MAP in Crohn’s disease patients11 exposed to a widespread infectious (5) Increased serological responses to MAP in Crohn’s disease patients20 34 agent? Are we repeating the mistake of 9 (6) Detection of MAP in human breast milk by culture and PCR H pylori where the scientific establish- (7) Progression of cervical lymphadenopathy to distal ileitis in a patient with MAP infection35 (8) Therapeutic responses to combination antituberculosis therapy that include macrolide antibiotics10 24 ment resisted a new theory that chal- Cons lenged established paradigms of peptic (1) Differences in clinical and pathological responses in Johne’s and Crohn’s diseases4 ulcer disease until overwhelming clin- 36 (2) Lack of epidemiological support of transmissible infection ical evidence made such resistance (3) No evidence of transmission to humans in contact with animals infected with MAP (4) Genotypes of Crohn’s disease and bovine MAP isolates not similar18 untenable? Well designed clinical, (5) Variability in detection of MAP by PCR (0–100% in Crohn’s disease and ulcerative colitis tissues)8 microbiological, and mechanistic experi- and serological testing37 ments are urgently needed to defini- (6) No evidence of mycobacterial cell wall by histochemical staining tively settle this still unresolved debate. (7) No worsening of Crohn’s disease with immunosuppressive agents or HIV infection (8) No documented cell mediated immune responses to MAP in patients with Crohn’s disease20 To establish a causal relationship (9) No therapeutic response to traditional antimycobacterial antibiotics23 between MAP and Crohn’s disease, we need to determine if clearance of MAP MAP, Mycobacterium avium subspecies paratuberculosis;