Crohn’s Disease and Johne’s Disease
– Is There a Connection?

Johne’s disease, caused by Mycobacterium avium subspecies paratuberculosis (MAP), manifests itself as a chronic diarrheal disease marked by wasting and eventual death . It occurs in wild and domesticated animals essentially worldwide, with the possible exception of Sweden and parts of Australia.

USDA officials view Johne’s disease with some concern, as it is costly to manage and results in the early cull of infected animals and loss of production in dairy herds. Endemically infected herds worsen over time as the disease spreads. Johne’s disease affects all ruminants, and cross-species infection has occurred. Johne’s can be transmitted through feces, though milk, and via the womb. Young animals are especially susceptible. Although the cause of the disease was discovered in the early 20th century, many US beef and dairy producers are not familiar with it’s full implications. There are increasing concerns that the disease may pose a threat to public, as well as ruminant health.1

In contrast, Australia has a very proactive stance on Johne’s disease, including testing programs, zone reporting, and abbatoir monitoring.2 Crohn’s disease (CD) occurs in humans, and has symptoms very similar to Johne’s disease. It affects mainly people between the ages of 20 to 40 years. Many of them endure multiple surgical bowel resections and other serious sequelae. The suffering endured by the patient, family and friends of these patients is enormous, as is the cost. Current CDC estimates for the USA are that approximately 500,000 people have Crohn’s disease. Formerly, CD was thought to be an autoimmune disease influenced by diet and stress. An infectious cause of this disease is now under investigation.

Evidence is growing that the same microorganism, MAP, plays a role in both diseases. In 1999, the CDC acknowledged a probable link between Crohn’s and Johne’s diseases. In its “Infectious Causes of Chronic Diseases” monograph, it cited the theory that MAP may cause both diseases and set goals for further action.3

Mycobacteria are notoriously difficult to culture as they are very slow growing and fastidious, drawing attention to our ignorance concerning microbial growth requirements. Staining methods used to characterize different types of bacteria, for example the “Gram” stain, are ineffective if the bacteria in question don’t have cell walls. Hence the Ziehl-Neelsen (“acid-fast”) method of staining, which helps to identify most mycobacteria, can’t be used to identify the prevalent strain of MAP involved in CD, as it is cell-wall deficient, or a spheroplast, form. This makes applying Koch’s Postulates rather difficult. Briefly, these postulates maintain that to prove an organism causes a disease, you must remove it from a diseased organism, grow it in pure culture, inject it into a healthy organism, and produce the same disease. Until recently, this was the gold standard proof of pathology. Mycobacteria in general make this difficult because the disease may take years to manifest itself or the animal may be a carrier of the disease without ever showing any symptoms. It should be noted that Koch’s postulates have never been met in the case of Mycobacterium leprae and leprosy, although this organism is widely held to be the cause. Thus the inability of researchers to consistently produce Johne’s disease in animals from people infected with Crohn’s disease is not surprising but has nevertheless led to a lot of controversy. However, there are documented cases in which Mycobacterium from Crohn’s patients inoculated into an animal host have produced Johne’s disease.4

Enter biotechnology, genome sequencing and polymerase chain reaction techniques (PCR). It turns out that there are fragments of the genetic code in organisms, specifically in the small subunit ribosomal RNA and DNA, that reliably provide the ancestral “fingerprint” of a microbe, even when its in the soup of infected host tissue. Over the past 20 years, quite a library of specific “fingerprints “has been identified, thus increasing the usefulness of this technique. Many previously uncharacterized microbes have been identified in this way.

Another method of identifying the etiology of CD involves the use of known antigens. Antibodies are part of a host’s immune system and form in response to the presence of a specific invading organism or “antigen”. A recent study tested two antigens from the MAP genomic library, identified as p35 and p36, and found the following results: 75% of 53 CD patients and 14% of 35 normal patients reacted to the p35 antigen, and 89% of 89 CD patients and 14% of 50 normal patients reacted to the p36 antigen, only the Crohn’s disease patients reacted to both antigens. For anyone fond of statistics, this resulted in a 98% positive predictive value with 98% specificity. Thus the reactivity of CD patients to these two antigens suggests a causal role for MAP in the disease.5

Mycobacteria produce what is called “protean” disease. This means the disease is not specific to one organ, but may occur any place in the body. For example, people usually associate tuberculosis, caused by M. tuberculosis, as a disease of the lungs, but it can appear in other forms, notably an intestinal one, as well. It is very difficult for diagnosticians to distinguish intestinal tuberculosis from CD. This may be because the causative organisms are very similar. To extend this analogy, tuberculosis and CD both show a mild and a severe forms. This too is typical of diseases caused by Mycobacteria. At the beginning of the 20th century, another species of Mycobacterium, M. bovis, caused tuberculosis in humans. This organism was mainly spread by drinking cow’s milk instead of droplet infection, as with M. tuberculosis. All of these bacteria can remain alive in cool, moist conditions for protracted periods of time. M. bovis survives in cow dung for about 5 months. MAP can survive in pond water for up to a year. Since they are intracellular organisms which reside inside the macrophages of their host’s cells (the very organelle that is responsible for digesting and eliminating bacteria), they resist normal immune intervention and evade destruction. They are indeed very robust and versatile organisms!

For those who ascribe to the theory that CD is indeed caused by MAP, the source of the infection would appear to be drinking milk or eating meat from herds with endemic Johne’s disease. This is certainly a plausible assumption, since as of 1996, the USDA estimated its prevalence in dairy herds at 22%.6 With very little testing or control in place, the percentage could by now be higher. This begs the question: how safe is the milk supply?Studies have been undertaken to address this concern. In 1996,samples of pasteurized milk were collected from shops in various locations in England and Wales throughout the year. The prevalence of MAP organisms found averaged 7%. Curiously, the prevalence was seasonal. It rose to 25% in the autumn and winter months, and was non-existent in the late spring and summer.7 A 2002 study in Canada on the effects of pasteurization on the viability of MAP found that out of 7 batches at regular pasteurization temperatures, (63 degrees C. for 30 minutes), no surviving organisms were found after 15 minutes. Yet out of 11 high-temperature short-term (HTST) batches at 72 degrees C. for 15 seconds, MAP was detected in 2 batches. This indicates that MAP may survive HTST pasteurization when present in sufficient quantity.8 Other studies indicate that MAP is less susceptible to heat-killing than other food-borne bacterial pathogens.9 A “smoking gun” was found in 1988 when MAP cervical lymphadenitis (swollen neck glands) occurred in a 7-year old boy inEngland. These nodes were removed and found to contain an abundant quantity of MAP organisms. Five years later, the patient developed achronic inflammation of the intestine indistinguishable from Crohn’s disease. After being treated with antibiotics for MAP, he went into complete remission.10 His initial presentation was similar to the pre-pasteurization era presentations of M. bovis infection, i.e. Swollen lymph glands nearest the avenue of infection – in this case, the mouth. Since then, many Crohn’s patients have responded to antibiotic treatment regimens tailored to Mycobacteria. The advent of macrolide antibiotics such as clarithromycin have provided much hope for those suffering from CD.

There seems little room for doubt that MAP can cause CD in humans, but many questions remain. Why doesn’t it present as its cousin, M. bovisdoes, with swollen cervical lymph glands? Why is it we see thes pheroplast (un-walled) form in CD rather than the bacillary (walled) form as we do in animal infection? This may have to do with the level of host resistance, the quantity of organisms present upon initial infection, or something completely different. In any case, the subject is an interesting one, and warrants concerted and earnest attention from livestock farmers, medical professionals, and the informed consumer if we are to protect both human and animal health.

Some things have to be believed in to be seen.

-Ralph Hodgson

1 USDAAPHIS Info Sheet. What do I Need to Know about Johne’s Disease in Beef Cattle? August 1999.

2 JDNews, Animal Health Australia. Winter 2002.

3 Centersfor Disease Control and Prevention report, as viewed January 2004 atthe PARA website http://www.crohns.org/research/cdc.htm#report

4 Greenstein,RJ. 2003. Is Crohn’s disease caused by a mycobacterium? Comparisonswith leprosy, tuberculosis, and Johne’s disease. Lancet Infect. Dis.2003 Aug; 3(8): 507-14.

5 Naser SA, Hulten, K et al. 2000. Specific seroreactivity of Crohn’sdisease patients against p35 and p36 antigens of M. avium subsp.paratuberculosis. Vet. Microbiol. 2000 Dec 20: 77(3-4): 497-504.

6 Stabel JR. 2000. Johne’s disease and milk: do consumers need to worry? JDairy Sci. 2000 Jul; 83(7): 1659-63.

7 MillarD, Ford J, Sanderson J, et al. 1996. IS900 PCR to detectMycobacterium paratuberculosis in retail supplies of wholepasteurized cows milk in England and Wales. Applied andEnvironmental Microbiology 62, 3446-52.

8 GaoA, Mutharia L et al. 2002. Effect of pasteurization on survival ofMycobacterium paratuberculosis in milk. J Dairy Sci. 2002 Dec;85(12): 3198-205.

9 Collins,MT. 1997. Mycobacterium paratuberculosis: a potential food-bornepathogen? J Dairy Sci. 1997 Dec; 80(12): 3445-8.

10 Hermon-TaylorJ, Barnes, N., et al. Grand Round: Mycobacterium paratuberculosiscervical lymphadenitis followed five years later by terminal ileitissimilar to Crohn’s Disease. BMJ Feb 7,1998; 316:449-453

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