The Crohn's Group

Johne’s Disease and Crohn’s Disease:

Are They Related?

A report from the National Academies recommends a closer look at the connection between Johne’s

disease (pronounced Yo-knees), an intestinal disease found in cattle and other animals, and Crohn’s disease,

an intestinal inflammatory disorder that affects humans. Crohn’s disease is a devastating illness of unknown

cause that is lifelong and currently has no cure. Certain similarities between the two diseases have fueled

increasing concern of a possible link.

The report, Diagnosis and Control of Johne’s Disease, is primarily focused on the effective diagnosis

and control of Johne’s disease, but also addresses the possible connection to Crohn’s disease. If evidence of

a link were found, it would transform Johne’s disease into a serious public health problem. The report breaks

new ground in suggesting that scientists looking at the relationship of the diseases have been asking the

wrong set of questions and should significantly shift the focus of their research.

The Potential Link

To understand the human health implications of Johne’s disease,

researchers must resolve a central question: Is the underlying bacterial

agent of Johne’s disease, referred to as Map (Myobacterium avium

subsp. paratuberculosis), a significant cause of disease in humans? More

specifically, is Map a cause of Crohn’s disease, or is it an incidental

bystander? Despite intense interest in Map, there is not enough evidence

to prove or disprove that Map is a cause of Crohn’s disease or a significant

human pathogen.

There have been, however, two well-documented cases of Map infections

in humans. One is a young boy with scrofula (a bacterial infection

affecting the lymph nodes) who subsequently developed Crohn’s

disease. This case that has been cited as supporting evidence for a causal

(etiologic) role of Map in at least some cases of Crohn’s disease. The

second case is an adult male with AIDS with Map bacteria widely spread

throughout his body. Because Map infection will be diagnosed only if it is

specifically considered and if appropriate laboratory tests are performed,

it is possible that Map has passed unrecognized in similar cases.

There are many similarities between Crohn’s and Johne’s disease.

Both are diseases of the intestines that primarily affect the ileum (the

portion of the intestines just above the colon), and both cause chronic

diarrhea and weight loss. However, when they are compared clinically

(symptoms) and pathologically (lesion sites and specific damage),

several significant differences can be seen. Experts have interpreted

these similarities and differences both in favor of and in opposition to

the view that Map is a cause of Crohn’s disease.

The Search for Evidence

There have been several human studies aimed at finding the cause of Crohn’s disease. Researchers have

examined cultures of bacteria from Crohn’s tissues, looked at the blood’s antibody responses to Map, and

charted patient response to therapeutic treatments directed at Map infections Unfortunately, these studies

Epidemiology of Crohn’s Disease

The occurrence of Crohn’s disease is not

uniform throughout the world or even in the United

States. The highest rates in Europe are found

in Sweden and the United Kingdom, specifically

Scotland, with much lower rates in the Mediterranean

countries. Studies of incidence in Europe

show a variation of 0.9 to 9.5 per 100,000 population.

Rates as high as 133 per 100,000 have been

observed in Olmstead County, Minnesota.

In the U.S., there is as much as a threefold

variation in incidence rates from state to

state. A 1991 study of patients in the Veterans

Administration hospital system showed the highest

rates in Oregon, Idaho, Nebraska, Wisconsin,

West Virginia, Maine New Hampshire, Massachusetts,

Connecticut and Rhode Island. It has

been suggested that there is a gradient of prevalence

from north to south in both the U.S. and

Europe, though the significance of this observation

is not clear.

Incidence in both the United States and

Sweden has increased over the last sixty years,

and the disease is much more common in urban

areas than rural areas. It is more common in

white Americans than in blacks, Jews compared

to other ethnic groups, and in smokers versus

nonsmokers. The disease can affect more than

one member of a family and rare family clusters

have been reported.

have produced highly variable and conflicting results. Most of the studies have been small and there has been no standardized

patient selection criteria or laboratory methods. A large-scale therapeutic trial is now underway in Australia that, if properly

designed and large enough, could help provide an answer to the question of therapeutic response.

What evidence would establish Map as a human pathogen? The generally accepted standard for establishing a specific infectious

agent as the cause of a human disease has been the fulfillment of Koch’s postulates. Based on current evidence for Map in

Crohn’s disease, Koch’s postulates have been only partially fulfilled as follows:

The microorganism must be found in all cases of the disease. – Partially fulfilled. Found in some cases, but not all.

It must be isolated from the host and grown in pure culture. – Fulfilled.

It must reproduce the original disease when introduced into a susceptible host. – Partially fulfilled. Experimental

animals have been infected with human isolates but do not reproduce the syndrome.

It must be found in the experimental host so infected – Fulfilled.

Partial fulfillment of Koch’s postulates support an association with disease but may or may not support causation. Different

pathogens can be responsible for a single clinical syndrome. For example, Koch’s postulates are not fulfilled for a single organism

in the general clinical syndromes of pneumonia, meningitis, hepatitis, and urinary tract infections, among other diseases. Koch’s

postulates can be difficult or impossible to apply to many chronic diseases of complex origin. A notorious recent example was

the claim that HIV did not cause AIDS because the human virus did not produce the disease in animal models. Only the tragic

infection and disease of laboratory workers and recent responses to effective therapy has settled this controversy.

The Right Research Questions

The report recommends a new approach to resolving the question of whether Map is a cause of some cases of Crohn’s

disease. A shift is needed from Koch’s postulates to fulfilling the Hills-Evans criteria, which are better suited to establishing the

cause of complex chronic diseases like Crohn’s disease. The report also recommends convening an independent panel to establish

standardized protocols and laboratory methods for the critical studies required to confirm or refute a causal role for Map in

Crohn’s disease. This would allow direct comparison of results from different laboratories and facilitate attempts to repeat key

experiments.

Epidemiologic evidence is an important element of the Hills-Evans criteria. Gathering such evidence for a causal connection

will be difficult, however, because it is possible that exposure to Map is occurring in infancy but disease does not manifest itself

for several decades. While fulfillment of all 10 of the Hill-Evans criteria would strongly incriminate Map, a lack of data makes

this unlikely as illustrated by the following partial list of Hill-Evans postulates and an evaluation of currently available data:

Prevalence of Crohn’s disease should be significantly higher in those exposed than those not. No systematic studies

correlating exposure to Map to incidence of Crohn’s have been performed.

Exposure to Map should be more frequent among those with Crohn’s than without. No studies specifically evaluate

the exposure of patients with Crohn’s disease to Map.

Modifying or preventing the response should decrease or eliminate the disease. Various therapeutic trials have

been performed but the data are inconclusive.

All findings should make biologic and epidemiological sense. Johne’s and Crohn’s diseases have many clinical and

pathological similarities, but there are significant differences as well. It seems biologically plausible that Map could

cause at least a subset of Crohn’s disease.

In addition to recommending a new research approach to the question of Crohn’s disease, the main body of the report outlines

the steps that should be taken to control Johne’s disease, reduce the spread of Map, and minimize effects of the disease in

animals. Johne’s disease is a significant animal-health problem that warrants the creation of control programs tailored both to

specific animal species and segments of the agricultural industry. The report recommends an integrated, bottom-up approach to

on-farm disease control that meets the needs of the livestock producers and motivates behavioral change, with support at industry,

state and federal levels.

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Diagnosis and Control of Johne’s Disease is available from the National Academies Press, 500 5th Street,

Washington, DC, 20001; (800) 624-6242 or http://www.nap.edu. This study was conducted under the auspices of

the National Academies’ Board on Agriculture and Natural Resources.

© 2003 by the National Academies

Permission granted to reproduce this report brief in its entirety, with no additions or alterations