Is Crohn’s disease caused by Mycobacterium avium pseudotuberculosis (MAP)?

In an article out yesterday, Australian Dr. Thomas Borody claims yes, and that the medical community is simply too “stuck in their ways” to admit it. I explain below why I think this is incorrect–or at least, premature.

I mentioned several times in the various AIDS threads and in the prostate cancer/virus thread that it’s often difficult to determine an infectious cause of a so-called “chronic” disease. Not only is there generally a time lag between infection and disease development, but it may be that only certain strains of the microbe cause the disease, or that they only cause the disease in those with certain genetic susceptibilities, or perhaps only in combination with other microbial agents. Chronic disease epidemiology itself is difficult, but tracking infectious causes of these diseases is even more difficult because you’re dealing with a moving target; a virus or bacterium may have evolved so much in the 10 or 20 years (or even 5) from infection to chronic disease development that it’s difficult to do retrospective studies on serology, for example.

New technology is helping. As I mentioned in the prostate cancer post, there are now chips that can contain pieces of up to 20,000 viruses–so we can screen folks for the presence of a host of pathogens, which previously would have taken years and a ton of money. However, this will be most helpful for diseases where the agent is still present. In some diseases, as I mentioned, the agent may no longer be present–the damage is done by the immune system itself, as a reaction to the pathogen.

Additionally, what if similar diseases are caused by more than one agent, either singly or in combination? I used pneumonia as an example in the AIDS post. Imagine pneumonia was a chronic disease–something that developed months or years after exposure to the infectious agent. Since we know pneumonia is caused by 20+ main organisms (plus dozens other minor ones), we’d never see a 1:1 correlation between disease and pathogen if we were doing retrospective studies.

So, keeping that in mind, let’s get to Crohn’s disease. This is an intestinal disease of unknown etiology that affects 380-480,000 people in the U.S. Onset is generally between the ages of 15 and 40, and it often persists for life. It’s more common in women and those of Jewish descent. Though rare in Africa, incidence in the U.S. is similar in Caucasians and African Americans, suggesting an environmental cause (possibly coupled with genetic susceptibility).

There are a number of lines of evidence that do, indeed, point to an infectious cause, which was first hypothesized almost 100 years ago. MAP–a species of mycobacterium that’s kind of a cousin to those which cause tuberculosis and leprosy–causes a similar disease similar to Crohn’s disease in cattle, called Johne’s disease. MAP has been isolated from some patients with Crohn’s (for example, as reported in this 2004 Lancet paper), and some patients have improved after antibiotic treatment. However, antibiotic treatment can also kill a host of other intestinal bacteria which may also contribute to disease, and some (such as ciprofloxacin) also have anti-inflammatory effects: so their action in alleviating Crohn’s disease may be distinct from bacterial killing. Others, however, have been unable to find MAP in Crohn’s patients, either by culture or DNA techniques. Finally, even if MAP is present, it remains to be confirmed that it is necessary for the development of Crohn’s, or if it is simply a secondary colonizer of damaged intestinal tissue. Animal studies have been done, but again are inconclusive: when fed to young goats, they developed colitis in about 6 months’ time, and a Crohn’s-like disease developed in infected mice, but not other laboratory animals.

Therefore, despite what Borody claims, it’s simply not a straightforward, established cause-effect issue, and it’s not because the medical establishment is simply closed-minded that MAP causation of Crohn’s hasn’t been accepted. Additionally, the acceptance of Helicobacter causation of ulcers, contrary to frequent claims, actually was relatively quick, when one considers the additional experimentation and replication of results that had to be performed by laboratories other than Marshall’s.

However, it’s understandable that some researchers get frustrated when they feel their ideas aren’t being taken seriously by “the establishment.” I, personally, hope Crohn’s is caused by MAP, or another bacterial agent–that points to an easier treatment, and perhaps even a vaccine. But the evidence simply isn’t clear-cut, making it much more difficult to accept such causation, even for those of us who’d welcome it. Just something to consider the next time you see the scientists or doctors being accused of being “closed-minded” by not accepting a claim–perhaps there’s simply more to it than outlined in the story.

Image from http://www.microscopyconsulting.com/Gallery/images/Mycobacterium%20avium.jpg

Comments

  1. #1 Hank Barnes
    March 17, 2006

    How about Koch’s Postulates? Do they apply or not?

    Some people discard them, when they are not met, which seems unscientific to me.

    If MAP fulfills Koch’s Posulates, then I will agree that MAP causes Crohn’s disease. Very simple.

    Hank

  2. #2 Ewen M Callaway
    March 17, 2006

    This is one of my favorite topics, too, Tara!

    It’s difficult and in many cases impossible to fulfill Koch’s postulates in diseases for which there is no relevant animal model. Just because a microbe infects mice doesn’t mean the disease is the same. A while back I wrote about how mouse infection with Salmonella does not model human infection. It involves different cells, and the bacteria behave differently. I think for Koch’s postulates to hold up, the animal disease must recapitulate the human disease.

    Chronic diseases pose an additional problem. In many cases a genetic susceptibility may be necessary and it may take years to develop symptoms, both are the case in leprosy or Hansen’s disease. There was a highly unethical attempt to prove Koch’s postulate in leprosy on a condemned inmate in Hawaii, but the tests proved inconclusive, as he develeped the disease several years after being exposed to the causative agent, and he had been exposed to other patients.

    Additionally, a lot of diseases, especially immune diseases, can create an environment more prone to certain microbes. Look at cystic fibrosis, which is caused by a single mutation in the CFTR gene. Most people die from CF due to infection with Pseudomonas aeurugonasa (PA), and one could erroneously infer that PA causes cystic fiborsis.

    I’m not sure I buy the link between Crohn’s and MAP–yet. People with Crohn’s also are much more likely to have antibodies to S. cerevisiae (baker’s yeast) than the general population.

  3. #3 Dave S.
    March 17, 2006

    Hank –

    Didn’t Koch himself find exceptions to his own postulates? When he discovered that it was possible to be an asymptomatic carrier (e.g. Typhoid Mary), and when he discovered that TB did not always cause disease when introduced into a healthy host.

    Look at polio. Not everyone infected with the polio virus ended up in a wheelchair, but the success of the vaccine showed that the virus was indeed causing the crippling effects in those people.

    Also, viruses (which Koch knew nothing about) do not grow in pure culture.

    As for infecting healthy animals with the agent to prove it causes disease, kinda unethical when the agent is a potentially lethal human pathenogen like HIV.

    Koch (and Henle) gave some good rules, but IMO their postulates are not applicable directly in many instances.

    Finally, we have modern molecular tools at out disposal which allows us to focus better on virulence.

  4. #4 Tara C. Smith
    March 17, 2006

    Didn’t Koch himself find exceptions to his own postulates? When he discovered that it was possible to be an asymptomatic carrier (e.g. Typhoid Mary), and when he discovered that TB did not always cause disease when introduced into a healthy host.

    Yep. In later writings he mentioned that, while they’re good guidelines, we shouldn’t be legalistic about employing them (I’m paraphrasing, obviously). Rather than making it strictly necessary to fulfill the postulates, we should take into account all the evidence and make the determination from the collective–which just makes good scientific sense. I’m not aware of any microbe that could strictly fulfill Koch’s original postulates.

  5. #5 Hank Barnes
    March 17, 2006

    More wishy-washiness from the usual suspects.

    Look, if someone has Crohn’s Disease, and after extensive searching (blood test, culture, antibodies, PCR, electron microscope, whatever), and you find no MAP, what does that tell you about the causal connection?

    Of course, the converse is true, as well. If you continually find MAP, you may have something. But, of course, you’d have to rule out other potential causes (like S. cerevisiae, as noted by Ewan above)

    Are you bozos now arguing that big ‘ole bacteria can cause damage without being detected?!!?

    Hank

  6. #6 Tara C. Smith
    March 17, 2006

    Hank, have you read anything I’ve written on this?

    Are you bozos now arguing that big ‘ole bacteria can cause damage without being detected?!!?

    Does Strep pyogenes cause rheumatic heart disease? Yes, I and other “bozos” argue that many bacteria can indeed cause damage without being detected. That’s, as I mentioned, one thing that makes determining these infectious causes so difficult–much more difficult than with an acute disease, where the agent is likely still present at relatively high levels in the body.

  7. #7 Dave S.
    March 17, 2006

    Hank –

    It’s not wish-washy to recognize that the real world is more complex and subtle than you once thought, and that new facts may render obsolete your old ideas. It’s part of doing science as Koch recognized full well, and requires one to not have a rigid mind-set…like yourself.

  8. #8 Hank Barnes
    March 17, 2006

    Yes, I and other “bozos” argue that many bacteria can indeed cause damage without being detected

    Well Dr. Borody disagrees with you.

    Over the past 20 years he has conducted a series of studies showing not only the presence of bacteria in Crohn’s patients ..

    Are you sure you’re not a lawyer, Tara? You argue even the most basic, simple, points imaginable.

    Hank Barnes

  9. #9 Tara C. Smith
    March 17, 2006

    Hank–again, I ask if you read anything I write. Yes, Borody has found MAP in Crohn’s patients. Some others have as well–and some haven’t, as I noted. That wasn’t your question. Your question was, “Are you bozos now arguing that big ‘ole bacteria can cause damage without being detected?!!?” And indeed, they can. Is MAP one of these? I don’t know, as I don’t feel we can conclusively say yet that MAP causes Crohn’s disease–the subject of my post. Is that clearer yet?

  10. #10 Dave S.
    March 17, 2006

    Hank says:

    Well Dr. Borody disagrees with you.

    Well call the duhh police because I think we have a felony.

    Since Tara said in the opening post that she doesn’t agree with Dr. Borody (“I explain below why I think this is incorrect–or at least, premature.”) then obviously Dr. Barody doesn’t agree with her!

    This doesn’t mean Dr. Borody must be wrong, only that his conclusion is not justified by the evidence. As I understand Tara’s opinion.

  11. #11 Spotted Quoll
    March 17, 2006

    Nice post. Don’t have time for details but I deal with this general problem of trying to retrospectively determine primary but not necessarily ongoing infectious causality in chronic disease frequently in my field and it is very tricky indeed, one of the most difficult technical issues in medical science. Particularly difficult are so-called ‘hit-and-run’ infectious agents that do the underlying damage and then depart before it becomes clinically significant, which can often be years or even decades later. And the problem of interacting infectious agents is also very difficult. But very interesting!

    Science has only begun to understand infectious disease and there are a lot more suprises to come yet. Which is good news for those wanting a career in infectious disease. :-)

  12. #12 Tara C. Smith
    March 17, 2006

    Indeed! I (obviously) think it’s a fascinating–if difficult–area of study.

  13. #13 Scott Kirwin
    March 17, 2006

    I’ll let you all tussle with Hank over the larger issues.
    I found this quote infuriating:

    Dr. Ramona Rajapakse, an assistant professor at Stony Brook University Hospital and a specialist in inflammatory bowel disorders, said there were tests in the past involving antibiotics, which proved negative. She added that ciprofloxacin, the antibiotic used to treat anthrax, is often prescribed for Crohn’s because it is a powerful anti-inflammatory agent.

    “Patients have actually brought information to me about [Borody],” Rajapakse said, “especially patients in the Jewish community. I explain to them that it’s a theory, it’s not proven and it’s a theory that has been in existence for a long time.” emph. add.

    I have spent much time trying to educate people on the “if you don’t think theories aren’t worth much stand next to an atomic blast” theory vs fact argument.

    Then this doctor goes on and confuses the two.

    Now go back to your intellectual slap-fest…

  14. #14 Hank Barnes
    March 17, 2006

    Hank–again, I ask if you read anything I write.

    Yeah, I try to slog thru it:)

    Yes, Borody has found MAP in Crohn’s patients.

    Right. Which is the first step in satisfying Koch’s postulates – finding pathogen X in patients with disease Y.

    Some others have as well–and some haven’t, as I noted.

    Right.

    That wasn’t your question. Your question was, “Are you bozos now arguing that big ‘ole bacteria can cause damage without being detected?!!?”

    A fine question, too, I might add.

    And indeed, they can.

    Dubious at best.

    Is MAP one of these? I don’t know, as I don’t feel we can conclusively say yet that MAP causes Crohn’s disease–the subject of my post.

    Right. But a step in the right direction would be to find MAP in patients with Crohn’s disease, which Borody claims he has done. Ok, by me.

    All you’re doing is trying to make excuses for not finding pathogen X, yet still trying to establish medical cause in some hypothetical disease Y — which, frankly, is silly.

    Is that clearer yet?

    Getting better:)

    Hank

  15. #15 Tara C. Smith
    March 17, 2006

    Right. But a step in the right direction would be to find MAP in patients with Crohn’s disease, which Borody claims he has done. Ok, by me.

    Correct. But when others have tried to replicate his findings, they’ve been unable to do so–which is a big reason “the establishment” hasn’t accepted his claim: not because we’re all closed-minded.

    All you’re doing is trying to make excuses for not finding pathogen X, yet still trying to establish medical cause in some hypothetical disease Y — which, frankly, is silly.

    You’re conflating the two issues.

    Issue 1: Crohn’s disease. Right now, some association with MAP, but not reproducible in all settings. Animal models have had some usefulness, but also suffer due to lack of reproducibility and some conflicts with human pathology of Crohn’s.

    Issue 2: general infectious cause of chronic disease difficulty: “hit and run” infection as mentioned above, or post-infectious sequelae that occurs after organism has been cleared (such as rheumatic heart disease, which is due to streptococcal infection but generally occurs after the bacterium has been cleared).

  16. #16 Guitar Eddie
    March 17, 2006

    Hank,

    Are you sure you understand the Scientific Method?

    GE

  17. #17 Hank Barnes
    March 17, 2006

    Ahh, a late hit from the sidelines by Tara’s flunkie!

    Why, Yes, Eddie, the scientific method is fairly easy to understand, but often hard to implement:

    1. Make a hypothesis
    2. Think about what evidence would support it
    3. Think about what evidence would falsify it.
    4. Test the hypothesis
    5. Faithfully gather and interpret the results
    6. Faithfully conclude whether said results support or falsify the stated hypothesis.

    Of course, it’s much easier to avoid the rigors of the above, and simply declare, “I had asthma, drugs work, therefore drugs good,” but that ain’t real scientific.

    Hank

  18. #18 Joseph O'Donnell
    March 17, 2006

    There is also the problem surrounding proving MAP causes Cronh’s because mycobacteria have very long generation times and cause infection slowly. Sometimes years or months, which poses a considerable problem in figuring out what they are doing in a host. Additionally, many people can be infected by mycobacteria, such as Mycobacterium tuberculosis or MAP and never develop disease at all.

    As only a minority of people infected go on to get disease, proving that MAP is the cause of Crohn’s or just an exacerbating factor is very difficult. It’s thought that certain genetic mutations are important in the causation of certain disease, such as tuberculosis or Crohn’s, which is a fairly convincing explanation as numerous polymorphisms are associated with increases susceptibility to mycobacterial infections.

    The other point is that some studies that “look” for MAP and don’t find it, often do not consider the unique physiology of the mycobacterial cell wall. As it’s difficult to culture and somewhat difficult to just cut someones bowels open while they are alive, the detection of the potential pathogens is often done via sequencing of 16S RNA sequences or looking for specific mycobacterial insertion sequences.

    Mycobacteria are highly resistant to the solvents and chemicals used to destroy a normal bacterial cell wall. If you don’t use a methodology that can destroy the mycobacterial cell wall, you naturally will not be able to detect any mycobacteria giving an incomplete impression that MAP may not cause Crohn’s.

    By no means however is it certain that MAP causes Crohn’s and nobody has definitively demonstrated this association. My area of interest is tuberculosis in cattle and deer, although I’ve also taken an interest in Johne’s disease, which is a considerable problem in sheep. Johne’s has been demonstrated to be caused by MAP and is very similar to the disease pathology of crohn’s. The situation is different from the human one, because experimental infection models in sheep have clearly demonstrated the link between Johne’s and MAP.

    While I agree the jury is still out on linking MAP to Crohn’s disease, I would still conclude that the evidence (in light of a better explanation) still points to MAP (or another related mycobacterium) causing Crohn’s in humans.

  19. #19 Chris Noble
    March 17, 2006

    Hank writes:

    If MAP fulfills Koch’s Posulates, then I will agree that MAP causes Crohn’s disease. Very simple.

    Do you believe that Mycobacterium tuberculosis causes TB?

    90% of carriers are asymptomatic. Of those only about 10% will progress to TB disease.

    Koch himself clearly recognised that M. tuberculosis did not fulfil his postulates. Despite this he still argued that M. tuberculosis indeed causes TB disease.

    Duesberg apparently believes that M. tuberculosis causes disease yet he argues that because a proportion of people infected with HIV do not progress to AIDS therefore HIV cannot cause AIDS.

    Cognitive dissonance?

    I also find it ironic that people that accuse the “orthodoxy” of dogmatism resort to dogmatic laws.

  20. #20 Hank Barnes
    March 17, 2006

    Umm Tara, could you post a “clueless” alert for some of your flunkies/groupies?

    First of all, Noble, not every thread here is about HIV or Duesberg.

    Second of all, Yes, I’m familiar with asymptomatic carriers of pathogens. Who isn’t?

    The import of Koch’s Postulates is that if you find a disease without pathogen, then “cause” is dubious; the converse (finding pathogen, without disease), however, does not necessarily negate cause. This it totally basic, and that you can’t understand it is mind-boggling.

    So, I accept that that Mycobacterium tuberculosis causes TB, because I haven’t seen TB cases without said bacterium.

    Now, if you show me a cohort of people who have been diagnosed with clinical, traditional TB — in all its phlegmlike glory –but for some reason cannot culture Mycobacteria tuberculosis or view it by electronmicroscope, then you have something of interest, and I would have to rethink the standard view.

    Really, Chris, this is pathetic.

    Hank Barnes

  21. #21 Chris Noble
    March 17, 2006

    Hank writes:

    The import of Koch’s Postulates is that if you find a disease without pathogen, then “cause” is dubious; the converse (finding pathogen, without disease), however, does not necessarily negate cause. This it totally basic, and that you can’t understand it is mind-boggling.

    Tell Duesberg and the other Denialists that go on about Koch’s 3rd postulate.

    So, I accept that that Mycobacterium tuberculosis causes TB, because I haven’t seen TB cases without said bacterium.

    The diagnostic criteria for TB includes detetction of M. tuberculosis so of course M. tuberculosis is seen in all cases of TB. Can’t you see the circular logic here?

    All of the symptoms of TB – cough, hemoptysis, weight loss, fever, anorexia, night sweats, chest pain, dyspnea are all seen in people not infected with M. tuberculosis. If they occur with the presence of M. tuberculosis then you have TB.

    Regarding Koch’s first postulate:

    Does the hepatitis B virus cause hepatitis? It is not present in all cases of hepatitis?

    Do rhinoviruses cause the common cold? They are not present in all cases.

    It would be nice if we could just follow a simple set of rules to establish the causation of disease. Unfortunately things are not this simple.

  22. #22 Chris Noble
    March 18, 2006

    Hank writes:

    Now, if you show me a cohort of people who have been diagnosed with clinical, traditional TB — in all its phlegmlike glory –but for some reason cannot culture Mycobacteria tuberculosis or view it by electronmicroscope, then you have something of interest, and I would have to rethink the standard view.

    Can you culture Mycobacterium leprae from people with leprosy? Mycobacterium leprae does not fulfil Koch’s second postulate. Does M. leprae cause leprosy?

    Duesberg cites this paper in his attempt to win the Continuum Challenge.

    For some strange reason Duesberg forgets to mention the data in Table 1 where HIV was cultured from 100% of people with AIDS, 99% of people with ARC and 98% of people with aymptomatic HIV infection.

    The paper by Jackson et al has been cited 100 times in the scientific literature but not once by HIV Denialists (Continuum was not a scientific journal). Anybody find that strange?

  23. #23 haliaeetus
    March 18, 2006

    I’m just wondering what color the sky is in Hank’s black and white world? Black? Too bad for him biology is full of shades of gray.

  24. #24 pough
    March 18, 2006

    In some diseases, as I mentioned, the agent may no longer be present–the damage is done by the immune system itself, as a reaction to the pathogen.

    That seems simple and obvious enough to me, but since someone is calling you a bozo for believing something so silly, I just want to make sure I’m getting it.

    So if, for example, bacteria “A” enters a host, it triggers the immune system to create A-killer “Ak”, which not only kills A, it also destroys parts of the host, which results in a disease seemingly caused by the host’s own immune system but in reality was caused by the no-longer-present bacteria A?

    I’m far from being a biologist of any kind, so perhaps I’m way off on some details, but that doesn’t seem terribly silly to me. It does sound like a total pain in the ass for doctors, though…

  25. #25 Joseph O'Donnell
    March 18, 2006

    Pough, that is exactly the sort of explanation that has been proposed for why some researches don’t find an association between MAP and Crohn’s. It’s interesting to note that a similar model of pathology can be seen with tuberculosis. The immune system just gets it wrong every so often.

  26. #26 Chris Noble
    March 19, 2006

    The analogy I would uses is:
    1) a fire starts in a library
    2) smoke detectors trigger the sprinkler system
    3) by the time anyone gets there the fire is out but the books are destroyed by water damage

  27. #27 Adam
    March 24, 2006

    Dr. Herman Taylor of Britain has developed a vaccine to immunize people against MAP. It is currently undergoing final safety approval and should be released near the end of the year.

    You can read the article here: http://www.crohnscanada.org/english/researchsites/vaccine%20clip.jpg

    As far as whether or not the bacterium causes the disease?
    Obviously time will tell now.

    After studying with a leading researcher in Montreal about the bacteria I can tell you the following.
    The MAP bacteria is extremely slow dividing, therefore antibiotics have to be taken for prolonged periods of time, and even then, there are no specifically developed antibiotics to kill the bacteria.

    It is extremely common for patients to develop pernial fissures, which are openings in the skin where infection drains, puss to be exact.

    If you view the scaring lesions of Johne’s disease and compare it to Crohn’s disease, they are remarkably similar.

    M.Laprae is known to cause leprosy, however to this day it cannot be accurately identified or grown in culture.

    We are all aware of the Mad Cow scare, that if you eat the meat of a diseased animal, you can contract the disease.

    We have similar bacteria, of the tuberculosis family, which has been found in milk and drinking water, and is known to cause disease in animals.

    On top of this, the CDC has issued a warning to AIDS patients to avoid drinking milk because several patients developed Crohn’s from consuming milk.

    There is more than likely is a secondary infection process, however the possible root cause is probably the MAP.

  28. #28 Andrea
    July 6, 2006

    Hmmm seems the jury is not out on this one.
    Thomas Borody is not just anyone.. he has a long history with bowel Disease. He worked with Barry Marshall on a cure for H.Pylori (before Barry swallowed the nasty stuff). Marshall is a doctor caught between two worlds, the world of science and the world of medicine. He is trying to change the Immune disease myth that has so long persisted that it has caused the medical community to stop seeking a CURE. Merely controlling the symptoms is not enough. People are dying or worse yet being cut into pieces over this disease.
    Crohn’s patients can not have their blood tested for MAP in nor can they get the triple antibiotic treatment in this country . Medical doctors in this country laugh at patients who approach them with this information. I know I approached my GI MD with this and he wouldn’t even make a call to talk to Wm Chamberlain (md working with Borody in El Paso). He did call the drug rep for Ramicade.. actually he knew the number by heart.
    I then took my Dear Hubby to El Paso where the only doctor in the country will test and treat for the MAP bacterium.

    As for Dr. Ramona Rajapakse, an assistant professor at Stony Brook University if she was truly interested in helping her patients she would at least test for the bacterium. Or better yet talk to Borody.

    Sadly medicine in this country is controlled by the Drug companies. Borody is on of the bravest men to go against medical thought.. I thank God for him.
    Now search Thomas Borody MAP see how many hits you get.

  29. #29 Tara C. Smith
    July 6, 2006

    Sadly medicine in this country is controlled by the Drug companies. Borody is on of the bravest men to go against medical thought.. I thank God for him.

    But antibiotics are also made by the drug companies, and they were accepted for treatment for H. pylori. The problem, as I noted in the post, is that studies linking MAP to Crohn’s have been inconsistent–including trials using antibiotics to treat it.