FAQ - Freqently Asked Questions about Mycobacterium paratuberculosis.

WARNING - The information presented on this page has not been written by a medical professional, and is in no way a subsitute for the advice of a qualified medical professional. The information presented here is for educational purposes only, and is intended to aid the patient in understanding discussions they may have with qualified medical professionals.

A lot of people email me to ask me questions about Mycobacterium paratuberculosis and Crohn's, and I'm sorry to say that complete answers to many of these questions do not exist. But rather than leaving people in an information vacuum, I have tried to at least provide enlightenment about the technical and medical knowledge involved in this complex issue.

• How can I get tested for M paratuberculosis infection?
• I have Crohn's disease and wish to be treated with antibiotics. How can I obtain this treatment?
• I have been treated with antibiotics before, such as Flagyl (metronidazole) or ciprofloxacin, and they did not bring my Crohn's disease into remission. Why is this?
• I have been diagnosed as having Crohn's disease. How can I be sure that I do not have intestinal tuberculosis?
• Is there a connection between Ulcerative Colitis and Mycobacterium paratuberculosis?
• Is Mycobacterium paratuberculosis transmissible (contagious) between humans?
• If cattle with paratuberculosis shed Mycobacterium paratuberculosis in their milk, do humans with Crohn's disease shed it in their milk as well?
• If Mycobacterium paratuberculosis is in milk, beef and water, then why doesn't everyone have Crohn's disease?

Question:

Answer:

There are three main ways to be tested for bacterial infection, and each has its complications in relation to testing for Mycobacterium paratuberculosis.

1. By testing for an immune reaction to the bacterium.

   Normally, if a bacterium causes infection in the body, the immune system reacts by producing antibodies to that bacterium. By testing for the presence of antibodies to the bacterium, it is possible to determine whether or not the bacterium is present. When testing for antibodies to a bacterium, the usual procedure is to identify one small piece of the bacterium, an antigen of that bacterium, and see if the patients body reacts to that antigen. It is important to choose the correct antigen for the bacterium, and two criteria must be fulfilled when choosing the antigen.

   1. The antigen must be immunogenic, i.e. it must cause a reaction in the human body. Not all antigens are immunogenic, since the human immune system, although highly efficient, is not 100% effective, and sometimes cannot recognize the antigens of invading bacteria.
   2. The antigen must be unique to the bacterium. Many species of bacteria share genes, and thus share antigens, with other species of bacteria. If the antigen tested is not unique to the bacterium to be tested for, then it will be uncertain to which bacterium the test results apply. For example, Mycobacterium paratuberculosis shares a large percentage of its genes, and thus a large percentage of its antigens, with its cousin Mycobacterium tuberculosis. If an immunology test tests for an antigen that is common to both Mycobacterium paratuberculosis and Mycobacterium tuberculosis, and the tests shows a positive reaction, then it is unknown whether the reaction was caused by a Mycobacterium paratuberculosis infection or a Mycobacterium tuberculosis infection.

   To date, an antigen that is both 1) unique to Mycobacterium paratuberculosis and 2) is immunogenic has not been discovered. Extensive research into the genetics of Mycobacterium paratuberculosis must be conducted before such an antigen can be found.

2. By testing for presence of the bacterium in pieces of tissue taken from the body (biopsy).

   A common technique for testing for bacterial infection is to take a biopsy from the patient. This involves placing an instrument inside the patients body, and removing a sample of the patients tissue for testing, either by laboratory culture (see below) or by genetic testing techniques.

   The immune system reaction to Mycobacterium paratuberculosis is to "seal it inside" an impenetrable wall of immune cells, called a granuloma, so that it cannot escape to cause damage to the body. Standard biopsy techniques are not accurate enough to retrieve a sample from inside a granuloma. The only method which is guaranteed to deliver material from inside a granuloma is to surgically remove a section of the intestines. Since avoiding surgery is the goal of testing and treatment, to carry out this test would be excessively invasive. Such a test can only be conducted if the patient is already undergoing surgery.

   This sample can then be tested for Mycobacterium paratuberculosis, by culture (see below for problems with this) or by PCR (Polymerase Chain Reaction) genetic testing. Very few laboratories have the necessary expertise to conduct PCR testing, and as far as I am aware, there are none that will conduct such tests on a commercial basis.

3. By testing for the bacterium in secretions/excretions of the body, by laboratory culture.

   When someone suffers from a pulmonary tuberculosis infection, the bacterium Mycobacterium tuberculosis grows in large numbers in the lungs of the infected patient. The patient often "expectorates" (coughs-up) sputum, which contains Mycobacterium tuberculosis bacteria. This sputum is placed in a laboratory culture dish, which contains an environment which encourages Mycobacterium tuberculosis bacteria to grow. The culture dish is left alone for a number of weeks, ranging from 8 up to 16 weeks. The culture dish is then visually inspected to see if a colony of bacteria has grown. If not, then the test is deemed to be negative. If a colony is present, that colony must be chemically tested to see if the bacteria are Mycobacteria. This chemical test is known as the Ziehl-Neelsen stain test. When subjected to the Ziehl-Neelsen stain test, all Mycobacteria turn red. Note that it is not possible to differentiate between species of Mycobacteria using the Ziehl-Neelsen stain test.

   However, there is a further complication. Ziehl-Neelsen staining only works for the most common form of Mycobacteria, which is the bacillary form. It is not capable of detecting other forms. When Mycobacterium paratuberculosis infects the human body, it does not exist in this bacillary form. Mycobacterium paratuberculosis has only been found to infect the human body in the spheroplast form. The spheroplast form is not detectable by the Ziehl-Neelsen stain test. Since the Ziehl-Neelsen stain test is the only test used to detect Mycobacterial infection in many modern hospitals, this type of testing will deliver incorrect results for Mycobacterium paratuberculosis infection.

   Also, Mycobacterium paratuberculosis is one of the slowest-growing bacteria known. It has precise nutritional and temperature requirements, and to culture it in a laboratory requires many years laboratory experience on the part of the laboratory technician. Lastly, it is even more difficult to get spheroplast form Mycobacteria to "revert" to bacillary form Mycobacteria, so that it can be detected by the standard Ziehl-Neelsen stain test. Only a handful of researchers in the world have succeeded in making Mycobacterium paratuberculosis undergo this reversion.

In summary, not enough is known about Mycobacterium paratuberculosis for testing to be 100% certain, and what testing is currently is possible requires extensive experience and specialised equipment. Such testing is not commercially available. Current hospital tests for mycobacterial infection do not work for Mycobacterium paratuberculosis.

Question:

Answer:

• Drug toxicity.

  The drugs described in the paper, clarithromycin/azithromycin and rifabutin, can be toxic, particularly if administered for long periods of time. This treatment requires that the drugs be administered for a period of at least six months, and possibly up to three years. Possible side-effects include Uveitis, diarrhoea, and flu-like symptoms. In some cases, these symptoms are severe enough to warrant withdrawal from treatment, as happened to 6 out of the 52 patients in the study described above.

• Antibiotic resistance.

  If a patient is treated with these antibiotics, and withdrawn from the treatment, this may provide an opportunity for the infecting bacteria to develop resistance to the antibiotics used. Since very few antibiotics are effective against Mycobacterium paratuberculosis, whatever antibiotics exist should be used with extreme caution.

• Treatment failure.

  In the study described above, 3 out of 46 patients who continued on the treatment experienced no change in their state of health, i.e. the treatment was ineffective for them.

• The risk of surgery.

  In the above study, fifteen of the patients treated required surgery during the course of the treatment, ten of them because they had formed "healing strictures". Healing of inflamed tissue often involves scarring, and scarring in Crohn's disease usually means tightening of intestinal strictures. This increase in stricturing is an unavoidable consequence of the healing process. However, an inexperienced doctor might interpret the increase of intestinal stricturing as a treatment failure, and stop treatment, thus risking antibiotic resistance.

  However, it is important to note that when surgery is conducted on patients undergoing antibiotic treatment, it is necessary only to remove small sections of intestine immediately surrounding strictures, perhaps 5 cms (2 inches) or less. In surgery where antibiotic treatment is not being administered, it is usually necessary to remove large sections of intestine (often measured in meters or feet), because the intestines of the patient are not only strictured but also uncontrollably inflamed.

Question:

Answer:

• Intracellular bacteria. When mycobacteria infect the human body, the most common site for them to infect are Macrophages, a particular type of white blood cell. Disease-causing bacteria that survive/multiply inside cells are known as intracellular pathogens. To eradicate mycobacteria that are inside cells, antibiotics must intracellular activity, i.e. they must make their way inside cells, so that they can work against the target mycobacteria. Very few antibiotics have intracellular activity. Antibiotics that do not have intracellular activity are completely ineffective against mycobacterial infections.
• Slow growing bacteria. Mycobacteria are the slowest growing bacteria known to science. Whereas most other bacteria take an hour or less to grow and divide, mycobacteria can take an entire day. Many antibiotics are only effective against bacteria at the moment when they are dividing, when the bacterial cell-wall "defenses" are down, and the antibiotic can get inside the bacterial cell. Since mycobacteria divide very seldom, it can take months or years of antibiotic treatment to eradicate a mycobacterial infection. For example, successful antibiotic treatment of a Mycobacterium tuberculosis infection takes a minimum of nine months, and sometimes well over a year. Successful treatment of a Mycobacterium leprae infection can take up to two and a half years.

  Often, when people are given antibiotic treatments for a non-mycobacterial illness, such as a chest infection, the duration of the treatment is less than one month. This is far too short to have any noticeable effect against mycobacterial infections.

• Antibiotic resistance. Mycobacteria mutate often, and are very adept at developing resistance to antibiotics. If an antibiotic is administered alone, then there is a high risk that the infecting mycobacteria will develop resistance to that antibiotic, rendering further treatment with that antibiotic useless. For this reason, mycobacterial infections are almost always treated with a combination of at least two antibiotics, and often with three, four or even five antibiotics. For example, a Mycobacterium tuberculosis infection is often treated with a combination of four or more antibiotics, to ensure that antibiotic resistance does not develop.

  When patients are treated with antibiotics for non-mycobacterial infection, treatment is most often administered in a single drug regime. For example, a common treatment for chest infections is to administer clarithromycin (aka Biaxin, aka Klacid, aka Klaricid) for seven to ten days. Although clarithromycin is active against mycobacteria, and indeed is one of the very few antibiotics active against Mycobacterium paratuberculosis, 7 to 10 days is far too short to have any noticeable effect against a mycobacterial infection. In fact, if Mycobacterium paratuberculosis is indeed a cause of Crohn's disease, then it is highly dangerous for patients with Crohn's disease to be treated with clarithromycin as a single drug regime for a short period of time, since this would give an opportunity to the infecting Mycobacterium paratuberculosis bacteria to develop resistance to clarithromycin. Without clarithromycin as part of an anti-paratuberculosis regime, it is unlikely that that regime would be able to eradicate a Mycobacterium paratuberculosis infection.

In summary, to successfully treat a mycobacterial infection requires that

1. The treatment regime must include at least two, and preferably more, antibiotics
2. Treatment time must be at least nine to twelve months
3. Each one of the drugs used must be active against mycobacteria.

If all three of these criteria are not met, antibiotic treatment of a Mycobacterium paratuberculosis infection will fail.

Question:

Answer:

The standard way to test for intestinal tuberculosis is to take a biopsy sample from the intestines, and culture it to see if bacteria grow from the sample. If bacteria do grow, they are then subjected to the "Ziehl-Neelsen acid-fast stain test". If this test identifies "acid-fast" bacteria, then it is assumed that those bacteria are Mycobacterium tuberculosis bacteria. If no "acid-fast" bacteria are found, the diagnosis becomes Crohn's disease.

When you were diagnosed with Crohn's disease, it is most likely that this "Ziehl-Neelsen" test will have been conducted. However, you will not have been told the results, since the test was negative and thus you were diagnosed with Crohn's disease.

If you think that you were not tested for tuberculosis at the time of diagnosis, you can go back to the hospital, and ask them to test you for tuberculosis. However, there are some important points to note

• If you actually did have intestinal tuberculosis, and were given standard Crohn's disease treatment, such as steroids or immunosuppressives, then your symptoms would very likely have gotten much worse. A fully active immune system is necessary for the eradication of a tuberculosis infection, and often a lengthy course of antibiotics is necessary.
• There is a form of tuberculosis where the disease is caused by the "spheroplast" form of Mycobacterium tuberculosis. Since the "Ziehl-Neelsen acid fast stain test" is not capable of detecting spheroplast forms of mycobacteria, the test will not show up any bacteria, and hence a diagnosis of Crohn's disease will be the most likely outcome.
• There are other ways to test for tuberculosis infection, such as the PPD ("Purified Protein Derivative") tuberculin skin test.

Question:

Answer:

Although Mycobacterium paratuberculosis is not yet transmissible between humans, it is guaranteed that Mycobacterium paratuberculosis will eventually "follow in the footsteps" of its cousins, Mycobacterium tuberculosis, Mycobacterium leprae and Mycobacterium avium, to become transmissible between humans.

Mycobacterium paratuberculosis is transmissible between animals. Infected animals can shed up to 5 trillion "bacillary form" Mycobacterium paratuberculosis bacteria per day, in their faeces and their milk. Bacillary form Mycobacterium paratuberculosis, also known as the "cell-wall-intact" form, multiply readily, once a day, and quickly infect other animals that are exposed to them.

However, there is another form of Mycobacterium paratuberculosis, called the "spheroplast" form, also known as the "cell-wall-deficient" form. This form of the bacterium does not multiply quickly, and is notoriously difficult to culture in the laboratory. It can take months or even years to grow into a recognisable colony in a culture dish.

Animals that are infected with the "spheroplast" form of Mycobacterium paratuberculosis do not shed the bacterium in their feces. Up to one eighth of cases of Johne's disease in sheep are caused by spheroplasts, and the bacterium can not be identified in those animals, by any means. The only way to know that those animals have Johne's disease is by the clinical symptoms they present, and by the fact that other animals in the herd shed bacillary form Mycobacterium paratuberculosis.

Animals infected with the spheroplast form of Mycobacterium paratuberculosis do not transmit the disease to other animals through their faeces. It is unknown whether they transmit it to their young, through milk.

Bacillary form Mycobacterium paratuberculosis have never been observed in humans with Crohn's disease. Only the spheroplast form has been observed in humans with Crohn's disease.

However, Mycobacterium paratuberculosis is not a static organism. Like all other species of bacteria, it is a mutating organism, and is constantly trying to adapt to new environments. If Mycobacterium paratuberculosis is permitted to continue infecting humans, through the ingestion of Mycobacterium paratuberculosis contaminated food and water, then it is inevitable that it will eventually mutate to be able to infect more and more humans in its bacillary form. This has already happened once: see Mycobacterium paratuberculosis cervical lymphadenitis followed five years later by terminal ileitis similar to Crohn's disease. It is only a matter of time before Mycobacterium paratuberculosis mutates further to infect the human intestine in bacillary form, and thus become transmissible between humans, through contaminated faeces.

It is important to note that this "mutation event", that allows Mycobacterium paratuberculosis to infect the human intestine in bacillary form, and develop into a full "human strain", may already have happened.

The standard tests used in hospitals to detect mycobacterial infection are incapable of distinguishing between different species of mycobacteria. The "Ziehl-Neelsen acid-fast stain test" can only determine whether or not mycobacteria are present. It cannot distinguish between Mycobacterium tuberculosis, Mycobacterium paratuberculosis or Mycobacterium avium, for example. Clinical doctors (mistakenly) assume that a positive result from a Ziehl-Neelsen stain test means that the patient is infected with Mycobacterium tuberculosis or Mycobacterium avium.

Therefore, if human strain Mycobacterium paratuberculosis does already exist in bacillary form, it most likely that such an infection would mis-diagnosed as Mycobacterium tuberculosis or Mycobacterium avium infection.

Question:

Answer:

However, if you are trying to decide whether or not it is safe to breast-feed your child, it is important to take a few things into consderation.

• Low likelihood of transmission: In contrast to cattle, who can shed up to five trillion (5,000,000,000,000) Mycobacterium paratuberculosis bacteria per day, Mycobacterium paratuberculosis is only present in humans in extremely low numbers. It is so difficult to find in humans that finding it requires precise genetic fingerprinting techniques that are capable of finding paratuberculosis DNA against a background signal that is up to one million times stronger. The Mycobacterium paratuberculosis cell contains one thousandth the amount of DNA that a human cell does, and in Crohn's disease there is as few as one Mycobacterium paratuberculosis cell per thousand human cells.
  
  
• Breast milk protects against Crohn's disease: There is a substantial amount of (statistical) research which shows that there is correlation between breast-feeding and not developing Crohn's disease, i.e. people with Crohn's disease are less likely to have been breast-fed as children. The milk of humans, as with all other mammals, contains immune cells from the mother that help to protect the baby against infections which its immature immune system might not be able to fight off by itself. Immune cells from the mother are a vital part of a babies immune defences.
  
  
• What are the alternatives?: The only alternatives available are infant formula products which are derived from cows milk. There is a much higher risk that such products contain Mycobacterium paratuberculosis, therefore you are far more likely to infect the baby with Mycobacterium paratuberculosis by feeding it cows milk rather than human milk.

Question:

Answer:

• The majority of people infected with Mycobacterium tuberculosis don't develop clinical symptoms of tuberculosis.
• Of the huge number of people who harbor meningitis bacteria in their system, the great majority don't develop bacterial meningitis.
• Although a huge proportion of the population is infected with herpes simplex virus, very few people develop clinical herpes simplex from that infection.
• Less than half of people infected with Helicobacter pylori develop ulcers.

There are many factors involved in this question. Some of them are as follows.

• Mutation events: Like all other bacteria, Mycobacterium paratuberculosis is not a static organism. It is constantly mutating, trying to adapt to new environments. It has successfully adapted to the intestines of macaques (a type of monkey), gorillas, cattle, sheep, horses, goats, rabbits, dogs, cats, chickens, gerbils, llamas, deer, etc, etc. When it mutates to be able to infect a new species, it cannot infect all individuals of that species at once, since all individuals of that species are genetically different. It starts off with a small percentage of individuals of that species, and from there uses those individuals as a base to develop further mutations that allow it infect ever larger subsets of the population of individuals of that species. As more time passes, increasingly larger subsets of the population get infected. It has important to note however, that Mycobacterium paratuberculosis is not yet transmissible between humans, as it is between animals. However, if it is allowed to continue infecting us, through Mycobacterium paratuberculosis contaminated food and water, it will eventually adapt to humans. See the related question Is Mycobacterium paratuberculosis transmissible (contagious) between humans?

  When an organism first adapts to a new species, the organism is said to have "crossed the species barrier". Mycobacterium paratuberculosis has been proven to cross the species barrier to cause disease in humans. See the paper Mycobacterium paratuberculosis cervical lymphadenitis followed five years later by terminal ileitis similar to Crohn's disease.

  It is most important to note we, human beings, are probably accelerating the mutation of Mycobacterium paratuberculosis, through inadequate milk pasteurization.

  There is a wealth of research which shows that if you put any bacterial species under physical stress, e.g. by starving it, freezing it, boiling it, the bacterium drastically increases its mutation rate, to try to adapt to it's new environment. For example: A group of researchers developed a species of E. coli that could only digest the left-handed form of a certain sugar, but not the right-handed form of the sugar. They then put these bacteria into a culture dish that contained only the right-handed form of the sugar. Most of the individual E. coli starved to death, but at least one of them developed a mutation that allowed it to digest the right-handed form of the sugar. That individual bacterium then went on to recolonize the dish, and a substantial colony of the mutated bacteria developed.

  Mycobacterium paratuberculosis is not killed by pasteurization. It is almost killed by pasteurization, but it is not completely killed. Whatever bacteria are not killed vastly increase their mutation rate, to ensure survival. So we unsuspecting humans drink milk that contains rapidly mutating Mycobacterium paratuberculosis, and deliver them into an environment which is highly conducive to their survival:- the human intestine. They have just come from cattle intestines, and they are in a highly mutative state. Little surprise, then, that they learn to adapt to our intestines. They won't successfully mutate in all humans, but they will succeed regularly.
  
  

• Age Dependence: In animals, the age at which an individual is infected with Mycobacterium paratuberculosis determines whether or not it will develop clinical disease. Cattle infected when under 30 days old will almost certainly develop clinical disease, whereas animals that are mature are most likely to be able control the infection.
  
  A discussion of this can be read at Ruminant paratuberculosis:- Susceptibility and Resistance.

Question:

Answer:

Supporting evidence

In the paper "On the Etiology of Crohn Disease", researchers describe searching for Mycobacterium paratuberculosis RNA in 8 patients with Crohn's disease, 2 patients with Ulcerative Colitis, and 2 patients with non-IBD intestinal disease. The results were that Mycobacterium paratuberculosis RNA was found, implying that the bacterium was alive, in 8 out of 8 (100%) Crohn's patients, 2 out of 2 (100%) Ulcerative Colitis patients and 0 out of 2 (0%) control patients. However, as the researchers themselves note:- "This study does not address the possible implications of the M. paratuberculosis signal noted in the specimens from individuals with ulcerative colitis". Also, it must be noted that the study numbers were small, and it is possible that these results could be a statistical anomaly.

In the paper "Mycobacteria in Crohn's disease: DNA probes identify the wood pigeon strain of Mycobacterium avium and Mycobacterium paratuberculosis from human tissue.", researchers describe finding DNA from Mycobacterium avium, a species closely related to Mycobacterium paratuberculosis, in a patient with ulcerative colitis, but conclude that "There are too few isolates to speculate about the etiological significance of mycobacteria and inflammatory bowel disease, but it is reasonable to conjecture that M. paratuberculosis may be responsible for some cases of Crohn's disease and that the wood pigeon strain of M. avium may also be an inflammatory bowel disease pathogen in humans."

Contradictory evidence

Many biopsy studies, when searching for Mycobacterium paratuberculosis in Crohn's disease patients, include Ulcerative Colitis patients as control patients, and often find that a few Ulcerative Colitis patients do indeed have Mycobacterium paratuberculosis DNA in their tissues, but at a prevalence that is no higher thatn the population at large. To see these studies, see the page "Biopsy studies of Crohn's Disease Patients".

In the paper "Mycobacteria and the aetiology of Crohn's disease", researchers describe finding Mycobacterium avium DNA in a similar percentage of Crohn's disease, Ulcerative Colitis and non-IBD patients. However, they describe finding Mycobacterium paratuberculosis DNA in a higher percentage of Crohn's disease patients than Ulcerative Colitis patients and other control patients. Since Mycobacterium avium is found equally in all three groups, but Mycobacterium paratuberculosis is present in a much higher percentage of Crohn's patients, they conclude that this is solid evidence that Mycobacterium paratuberculosis is involved in the pathogenesis of Crohn's disease, and, by implication, that it is not involved in the pathogenesis of Ulcerative Colitis.

Ulcerative Colitis and antibiotic treatment.

To date, no research has been published that has described the treatment of Ulcerative Colitis patients with antibiotics, although anecdotal reports of improvement of Ulcerative Colitis on treatment with antibiotics have appeared.

Crohn's colitis

It is not uncommon for patients with Ulcerative Colitis to be rediagnosed as having Crohn's disease. There are two possible reasons for this.

1. The patient was misdiagnosed in the first place. Ulcerative Colitis and Crohn's disease are similar diseases by nature, and can be hard for a clinician to tell apart. Particularly, Crohn's disease of the colon is frequently misdiagnosed as Ulcerative Colitis. The diagnosis only becomes Crohn's disease when the Crohn's begins to manifest itself in other areas of the GI tract besides the colon. Also, the treatments for Ulcerative Colitis and Crohn's disease have much in common, and are identical in many cases, e.g. steroids, immunsuppressives, etc.
2. The patient developed Crohn's disease as a complication of their Ulcerative Colitis. If it is true that Crohn's disease is a bacterial infection, then the damage caused to the GI tract by Ulcerative Colitis would provide the ideal "opportunity" for pathogenic bacteria to colonize the GI tract, thus causing Crohn's disease on top of Ulcerative Colitis. This condition is known as "Crohn's-colitis". So, if Crohn's disease is caused by Mycobacterium paratuberculosis, it is important that sufferers of Ulcerative Colitis avoid exposure to this pathogenic bacterium, since they are far more likely to develop clinical symptoms from a paratuberculosis infection than the public at large.

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