Does Mycobacterium paratuberculosis cause Crohn's Disease?

Update: Please read this Important notice

For up-to-date news and information, visit the Paratuberculosis Awareness & Research Association

Introduction.

Since Crohn's disease was first recognised in the early part of the twentieth century, it has been theorised that the disease is caused by a bacterial infection, with the principal suspect being mycobacteria, and more specifically in recent times, Mycobacterium paratuberculosis. Recently, research is making advances in understanding this organism, and is indicating more and more that at least some cases of Crohn's disease, if not all, are caused by paratuberculosis infection. Most importantly, the majority of Crohn's patients treated with antibiotic treatment which has activity against Mycobacterium paratuberculosis go into clinical remission.

This is important information for sufferers of Crohn's disease, because Mycobacterium paratuberculosis is endemic in foods derived from cattle in most areas of the western world. Mycobacterium paratuberculosis causes a chronic Inflammatory Bowel Disease in cattle, and many other species, which is similar to Crohn's disease. In some countries, the percentage of cattle herds infected with Mycobacterium paratuberculosis is extemely high. In the United States, 40% of large dairy herds are infected with Mycobacterium paratuberculosis.

Mycobacterium paratuberculosis is present in the milk, faeces and meat of infected cattle. There is a large body of evidence which indicates that Mycobacterium paratuberculosis is not killed by the standard food processing techniques that we rely on to protect us from disease-causing bacteria, such as pasteurization and cooking. Mycobacterium paratuberculosis may also be present in water supplies in areas where the faeces of infected cattle wash into the water supply, and standard water treatment methods do not kill it.

Up to now, the beef and dairy industries have preferred to defer action on removing Mycobacterium paratuberculosis from herds of food animals until it is proven that Mycobacterium paratuberculosis causes disease in humans. That proof has now arrived. In February 1998, a paper was published in the British Medical Journal which documented the first proven case of M. paratuberculosis causing disease in a human being. The patient, a seven year old boy, developed a M. paratuberculosis infection in the lymph nodes of his neck. This was followed, after a five year incubation period, by an intestinal disease that was indistinguishable from Crohn's disease. See Mycobacterium paratuberculosis Cervical Lymphadenitis followed five years later by terminal ileitis similar to Crohn's Disease for more details.

In order to facilitate self-education about this important subject, I have put together this web site, which contains either the full-text or abstracts of most of the relevant medical research. The information is broken down into various sections, as listed in "Contents", along the left hand side of this screen. All of the medical references have been taken from the Medline database. There is also an Index of the research papers which are available in full-text.

For information about the methods/author of this web site, see site information. For a summary of the contents of the site, see the page "Summary of main points". For a list of links to important sites for Crohn's disease sufferers and for medical professionals, see the page "Links to other information resources on the Web". For a list of changes/updates that have been made to this site, see the page "Changes".

For a description of Crohn's disease, see the page What is Crohn's disease?.

For further information about the situation with Crohn's disease and Mycobacterium paratuberculosis in the United States, please visit the Paratuberculosis Awareness & Research Association, an organization of sufferers of Crohn's disease that has been formed to address important questions about research into the connection between Mycobacterium paratuberculosis and Crohn's disease and the presence of Mycobacterium paratuberculosis in food derived from cattle.

What are mycobacteria?

Mycobacteria are a genus of bacteria. There are many different species of mycobacteria, widely spread throughout the environment. They are broken into three main groups.

• non-pathogenic mycobacteria, are usually harmless to humans, and exist in the global environment without human interaction.
• obligate pathogenic mycobacteria (i.e. known to cause disease) mycobacteria, cause disease in humans and other animals. Also, they require the benign environment of a host animal to multiply. Well known examples of pathogenic mycobacterial disease in humans are tuberculosis and leprosy. Disease caused by these obligate pathogen organisms is always chronic (long-lasting), since they take long periods of time to multiply, and are difficult to eradicate. Not all humans mount a successful immune response to these mycobacteria, and they can be fatal in those people if untreated.
• potential pathogenic mycobacteria, can exist in the environment independent of humans but can also cause disease if the immune defences of the host they infect are impaired or suppressed. These potential pathogens are often referred to as opportunistic pathogens, because they become pathogenic when presented with the right opportunity.

Follow this link for more information about mycobacteria.

Mycobacterium paratuberculosis.

Mycobacterium paratuberculosis is an obligate pathogen, i.e. it cannot multiply outside the cells of animals. It is known to cause disease in a wide variety of animals, including primates and humans. See the page "Mycobacterium Paratuberculosis in Animals" for more information. In common with other obligate pathogens, the environment required by Mycobacterium paratuberculosis for multiplying is the environment found inside mammals and other animals. In animals, the most common site for infection by Mycobacterium paratuberculosis is the gastrointestinal tract, where it tends to cause a chronic inflammatory disease. The most well studied animal paratuberculosis is BJD (Bovine Johne's Disease), the name given to the disease as seen in cattle. Mycobacterium paratuberculosis occurs in two forms, the bacillary form and the spheroplast form. Many paratuberculosis bacteria of the bacillary form may be required to cause clinical disease. In contrast, only a few paratuberculosis bacteria of the spheroplast form will cause disease. This difference between diseases caused by the two forms of paratuberculosis is a result of the infected hosts immune reaction.

Whether Mycobacterium paratuberculosis causes disease in humans has been a question for researchers for over a hundred years, since the organism was first discovered in 1895, causing disease in a german cow. Since that time, paratuberculosis has been recognised in many species of animals, in both its bacillary and spheroplast forms. The bacillary form is easily detected in animals, since it grows in large numbers and is identifiable by a simple chemical test. In contrast, the spheroplast form, since it comes in only very small numbers and cannot be easily be identified, was not detected until the advent of modern genetic testing techniques.

This question of disease causing ability was finally answered in a paper published in the British Medical Journal in February 1998. This paper describes the case of a young boy who developed a M. paratuberculosis infection in the lymph nodes of his neck and, after a five year incubation period, developed an intestinal disease which was indistinguishable from Crohn's disease.

Information about Mycobacterium paratuberculosis, its environment, etc, are available in the paper "Mycobacteria and the aetiology of Crohn's disease". This paper also refers to Mycobacterium avium. At the "Johnes Disease Information Center", there is

• an electron micrograph of some bacillary form paratuberculosis bacteria.
• A history of research into Mycobacterium paratuberculosis.
• Information on the biology, environment, host range, etc, of Mycobacterium paratuberculosis.

Mycobacterium avium.

Mycobacterium avium is an opportunistic pathogen, and comes in two forms, the bacillary and spheroplast form. Both of these forms can cause disease in animals. The spheroplast form also causes disease in humans. The people who most often contract disease from Mycobacterium avium are sufferers from AIDS, whose immune systems have been suppressed by the HIV virus. In immunocompromised people, Mycobacterium avium invades the white blood cells of the infected person, and uses them as sites to multiply.

What is Crohn's disease?

Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract. Its affects hundreds of thousands of people around the world. Its cause is unknown. The disease is autoimmune in nature, i.e. it causes the immune system to attack and inflame the bodies own tissues, most often in the gastrointestinal tract, but also in other parts of the body. When the disease is active in a patient, treatments include long term administration of immunosuppressive drugs and surgery, involving removal of segments of the damaged bowel, and sometimes the fitting of ostomy bags. Two of the main drug treatments are steroids, often in high doses, which have an immunosuppressive anti-inflammatory effect and "6-MP" based drugs, which suppress the action of the immune system, and are used after organ transplant surgery to prevent rejection of transplanted organs.

For a detailed description of the wide range of symptoms experienced by sufferers of Crohn's disease, including a discussion of fatality and Crohn's disease, see the page What is Crohn's disease?.

The epidemiology of Crohn's disease.

Epidemiology studies of Crohn's disease have been conducted in many countries. They yield some important insights into the disease. These include

• There is strong evidence that Crohn's disease is caused by an environmental agent.
• Incidence of Crohn's disease is increasing in most parts of Europe and North America.
• Crohn's disease is beginning to make an appearance in parts of the world that have not experienced it before.

For more information on these topics, see the page "The epidemiology of Crohn's disease".

Crohn's disease costs billions of dollars across the world.

In the United States, in 1990, Crohn's disease cost between 1.0 and 1.2 billion dollars. Other countries with a high prevalence of Crohn's disease are:- Canada, Sweden, Norway, Germany, United Kingdom, Netherlands, Belgium, France, Switzerland, Austria, Spain, Portugal, Greece, Italy, Ireland, Australia, New Zealand, and many countries of Eastern and Central Europe. For a brief discussion of the worldwide cost of Crohn's disease, see the page "The financial cost of Crohn's disease."

The similarity of Crohn's disease to mycobacterial diseases.

The symptoms of Crohn's disease are extremely similar to symptoms of diseases caused by known pathogenic mycobacteria, particularly intestinal tuberculosis, caused by the obligate pathogen, Mycobacterium tuberculosis. So much so, that intestinal tuberculosis is often misdiagnosed as Crohn's disease. This confusion is contributed to by the fact that there a degree of commonality of treatments between the two diseases. For a comparison of the symptoms of known mycobacterial diseases and Crohn's disease, and discussion of the known commonalities between the two diseases in terms of diagnosis and treatment, see the page "Similarities between Crohn's disease and mycobacterial disease.".

Also, there is evidence that Crohn's disease presents in two main forms, the aggressive "perforating" form and the contained "nonperforating" form. This is a feature that Crohn's disease shares with the mycobacterial disease leprosy, which also presents in two forms, the aggressive "lepromatous" form and the contained "tuberculoid" form. See the page "The polar manifestations of mycobacterial diseases and of Crohn's disease" for more details.

History of Crohn's/Paratuberculosis Research.

Crohn's disease was first recognised by a Glasgow surgeon, Dalziel, in 1913. He recognised that it was a different disease from intestinal tuberculosis, but believed that it was so similar to that disease, and to paratuberculosis in cows, that it must have a mycobacterial cause. He failed to prove this connection, because of the inability to demonstrate visible bacteria from tissue samples. In 1932, Crohn et al., on the basis of this same inability to demonstrate visible bacteria, classified the disease as not having a mycobacterial origin. Nonetheless, this classification was not universally accepted, and research into whether Crohn's disease is involved with Mycobacterium paratuberculosis has been carried out since then. See the page "History of early research on Crohn's disease" for a description of early research and the work of Crohn et al.

Milestones of Crohn's/Paratuberculosis Research.

An important milestone in paratuberculosis research in recent years was the discovery in 1985 of a genetic code (the IS900 insertion sequence) that is unique to Mycobacterium paratuberculosis. The sequence is found in both the bacillary and spheroplast forms of Mycobacterium paratuberculosis. Polymerase Chain Reaction (PCR) techniques make it possible to detect small numbers of Mycobacterium paratuberculosis against the background of other DNA signals present in the human body. Knowledge of this sequence permits researchers to state with certainty (depending on the care with which this highly complex test is conducted) whether the organism is present in any given sample. It also permits them to rule out the presence of other forms of mycobacteria.

In December 1994, attention was drawn to the fact that Crohn's disease, in common with known mycobacterial diseases, is not a uniform disease and may present in two main forms, the "perforating" and "nonperforating" forms. See the page "The polar manifestations of mycobacterial diseases and of Crohn's disease", for a detailed discussion of this. No research to date has considered this division.

A vital piece of research in the paratuberculosis puzzle was very recently uncovered. As described in the paper Mycobacterium paratuberculosis Cervical Lymphadenitis followed five years later by terminal ileitis similar to Crohn's Disease, M. paratuberculosis has been proven to cause disease in humans. This paper describes the worlds first documented case of bacillary form M. paratuberculosis being isolated from a human being. The patient involved was a seven year old boy, who developed a M. paratuberculosis infection in the lymph nodes of his neck. Due to the proximity of the infection site to the mouth, it is most likely that the boy contracted M. paratuberculosis from consuming M. paratuberculosis contaminated food. The boy went on to develop, after an incubation period of five years, an intestinal disease which was indistinguishable from Crohn's disease.

Overview of Medical research.

I have tried to organise the medical research here, by breaking it down into six main areas, as listed below. Each item in the list is a link to a page that contains a brief explanation of what the research is trying to achieve, and contains links to abstracts from the actual medical research papers. In order to aid you in understanding what questions are being addressed in the medical research, I have written a basic primer of infectious disease that explains some of the terms that you will need to understand.

• Animals affected by mycobacterium paratuberculosis.
• The search for Mycobacterium paratuberculosis in Crohn's disease.
• The search for a human immune reaction to Mycobacterium paratuberculosis.
• Treatment of Crohn's disease with antibiotics.
• The prevalence of BJD (Bovine Johne's disease).

Source: http://archive.crohn.ie/welcome.htm
This is the top level page.