Mycobacterium avium subsp paratuberculosis (Map) is the causative agent of Johne's disease (JD), a chronic and progressive intestinal disease in ruminants, which imposes large direct and indirect productivity losses on affected farms. Crohn's disease (CD) in humans has been characterized as a chronic, relapsing, and remitting inflammatory process of the digestive tract with protein losing enteropathy,general malabsorption and steatorrhea. Numerous studies have shown that genetic and environmental factors are the basis for the pathogenesis of CD. Twin studies and familial aggregation have provided compelling evidence for the heritable nature of CD, and strong familial pattern has been observed in CD patients. It has been reported that the lifetime risk for developing CD in the sibling of an affected person is approximately 30-40 times greater than that in the general population. To date, several human genes and loci have been identified that may contribute to CD such as the IBD1.

There are several histopathological and clinical similarities between JD and CD. Because of these similarities, a mycobacterial cause of CD has been sought for more than 90 years! Although early studies did not detect Map in tissues from patients with CD by conventional stating and culturing techniques, in the late 80's researchers could isolate Map from tissue samples from patients with CD after many months of incubation, leading to renewed interest in a mycobacterial origin of CD. Recent serologic studies have demonstrated that up to 83% of CD patientsshowed evidence of serum antibodies to Map. However, molecular mimicry that can serve as target for cross-reactive immunity in CD has been recently described. To date, several antibodies have been identified in the serum from CD patients such as for Pseudomonas fluorescens, and E. coli. These antibodies are regarded as signals of abnormal responses to innate or foreign proteins, because they do not usually exist in the healthy population.

The frequent use of the DNA insertion element IS900 as a tool for accurate identification, in addition to bacterial culture, has yield provocative but inconsistent results, probably because PCR cannot differentiate between viable Map and Map DNA. In these studies, 13%-100% of CD patients tested positive to Map. Other studies, however, have beenunable to demonstrate Map DNA in CD tissue. One potential problem withthese results is that some primers designed from IS900 can cross-react with closely related IS901 and IS902. Nevertheless, in addition to CD patients, studies have detected Map also in control subjects. It is possible that low incidence rates in CD patients' tissues may be moreof a reflection of the widespread and ubiquitous occurrence of mycobacterialorganisms, than an indication that Mapis a causative agent in CD. It has been also demonstrated that lactating mothers withCD shed Map in theirbreast milk. Unlike in JD, where Map can be detected in almost any clinical case, reports are mixed as to the presence or absence of Map at the site of the intestinal lesions.

There is no sound epidemiological evidence that links exposureto Map to an increased incidence ofCD disease, even though cows with clinical paratuberculosisdo shed viable organisms in their milk at low levels (50 CFU/50ml milk), and the consumption of inadequately pasteurized dairy products has been a major source of concern for the potential spread of Map to humans. Standard temperatures and times for heat pasteurization of milk, especially eithervia standard holder methods (63.5°C for 30 minutes) or high-temperature,short-time methods (71.7°C for 15 seconds), have been shownto be insufficient to kill all Map in milk. In Great Britain it has been demonstrated that Map DNA is present in milk samples obtainedfrom retail markets. On the other hand, some studies indicate that through adequately pasteurized dairy products (72°C for 15 seconds), the transmission of viable Map from animals to humansvia can be made even less likely, thus minimizing any remaining potential concern thatit may act as a zoonotic agent in CD. The culture, however, of viable Map from pasteurized retail milk samples, raised the concern that milk may become contaminated post pasteurization. Nevertheless, the detection of Map DNA in retailed milk raised the obvious question whether people with lifetime or childhood intense exposure to dairy cows are more susceptible or more resistant to CD?

In cattle, Map infection occurs in a very early age but clinical signs do not develop until at least 2 years of age. If Map were to behave in a similar manner in humans, it would be extremely difficult to associate exposure events occurring during childhood with the subsequent development of CD, perhaps many years later. No clinical evidence has shown an increased incidence of CD in farmers oragricultural workers associated with dairy herds with a highincidence of JD. Nor has eating organs ortissues from infected animals been documented to cause infectionof humans with Map. Two studies one from England and another from Israel find no association between exposure to dairy or even to JD cows and CD. Another case-control study from the UK, found that the consumption of pasteurized milk was associated with reduced risk for CD (OR=0.82). Finally a recent study in Ontario, Canada performed a systematic review of the literature on the subject, weighing in on the current evidence for or against a causal relationship. So far, despite the volume of research conducted to address this issue, the evidence for an association between JD and CD has not been strong. Because CD is a rare disease the appropriate epidemiological approach would be a large-population case-control study, looking for potential risk factors with strong association.

These and other study results, even when supporting the presence of Map in CD patients, require us to reflect on two basic concepts in epidemiology: association and causality. An apparent association between Map and Chron's does not imply casual relationship. The issue of causality can only be addressed by examining disease onset in relation to exposure to the putative pathogen. Temporal association, one of the important criteria for causality, makes us wonder what came first? The egg or the hen i.e. Map or CD? Is it possible that Map is only an opportunistic bacteria?

In the absence of suitable animal models, epidemiological studies are the most effective means of determining whether Map plays a causative role in the etiology of CD. As a conclusion it is suggested that although solid evidence insinuate an association between CD and Map, the proclamation of Map as the causal agent of CD and therefore JD as a zoonotic disease requires not only time, but large population epidemiological studies.

Reference available from the author upon request.