Another Clue That IBDs May Be Caused By A Mycobacterium

[tex]

Hi All,

I'm sure that many of us recall that in the past, Polly and I, (and probably others), have wondered about, and discussed the possibility that inflammatory bowel diseases might be caused by some yet undiscovered bacteria species. Specifically, a variety related to the Mycobacterium Avium subspecies Paratuberculosis, (or MAP, for short), that is known to cause a similar disease in livestock, called Johne's disease. For a brief refresher course, please see this thread, from almost 4 years ago:

http://www.perskyfarms.com/phpBB2/viewt ... obacterium

Now, (as published in the New England Journal of Medicine), some Chinese researchers have found evidence that people with Crohn's disease, share certain genes with people who have leprosy, specifically, two genes known as NOD2 and TNFSF15. In the researchers' own words, "It is therefore all the more notable that leprosy and Crohn's disease have common immunologic features, including a Th1-cell response with granuloma formation". The reason why I believe that this is very important information, is because leprosy has long been known to be caused by a bacterium known as Mycobacterium leprae, and, of course, the cause of Crohn's, (and the other IBDs), is unknown. Of course, this could just be some sort of coincidence, but the fact that the diseases share these genes, and similar immunological responses, could be very, very significant. Here's an article about the discovery:

http://www.medpagetoday.com/Gastroenter ... ease/17579

The article described in this brief abstract, about the dissemination of Mycobacterium tuberculosis and Mycobacterium leprae, within the body, might hold some interesting information. Unfortunately, the article is not free:

http://www.sciencedirect.com/science?_o ... 5bf00a7c57

Leprosy shows a predilection for peripheral nerves, skin and mucosa of the upper respiratory tract. Consider this quote:

Lepromatous Leprosy (LL) is found in those patients with no or very little immune resistance to the Micobacterium leprae organism. They are not able to mount a response because of a lack of Cell-Mediated Immunity (CMI) . In such cases, the very defence cell - the macrophage - which is meant to destroy the bacillus, through phagocytosis (engulfing/digesting) actually is a good environment for the bacillus and plays the role of host, enabling the bacillus to multiply within the cell. It has been known for up to 300 M.leprae to fit into one macrophage which swells up like a balloon instead of retaining its oemeba-like shape. The macrophage, which is meant to contain the spread of the disease by ingesting and digesting such foreign organisms, becomes a convenient vehicle for the M.leprae to be transported, in the blood stream, to all parts of the body.

Isn't that interesting. The bacterium actually use a part of the human immune system, (macrophages), as hosts, to carry the bacteria all over the body. That quote comes from the article at this link:

http://www.webspawner.com/users/LEPROMAT/

Sooooooooo, this all makes me wonder if perhaps some form of the MAP bacterium may have figured out how to live inside the intraepithelial lymphocytes, that are always found in the epithelia of the intestines of patients with MC. Once situated, these lymphocytes don't circulate in the blood, the way that macrophages do - instead, they stay put. But that would explain why the inflammation remains in the intestines, rather than spreading to the skin, and other epithelia, all over the body. Or, perhaps there is some other type of immune system cells that are used as hosts, by the bacterium, and we simply have overlooked their increased presence, in MC patients. There are a lot of possibilities, but whatever the case, this new discovery adds another "smoking gun" to the collection of clues that researchers have to work with, in trying to track down the origin of MC, and the other IBDs.

Note that the paragraph above, is strictly speculation on my part - just thinking out loud, here.

Tex

[Gloria]

With every discovery, we are getting closer to an explanation. It would be great if your thesis were investigated for MCers, too. Thanks for sharing this information.

Gloria

[Rosie]

Tex, I found your comments very interesting and did a bit of looking around in PubMed about MAP and colitis. I found a very interesting recent article in PLoS Pathology, titled "Where are all the Mycobacterium avium subspecies paratuberculosis in patients with Crohn's Disease?" Since it's in PLoS, it's free access, and here is the url
http://www.ncbi.nlm.nih.gov/pmc/article ... ool=pubmed

It's not your usual scientific article, but a well thought out plea for researchers to take a closer look at MAP in Crohn's and othe IBD's. The article provides a very nice review of what's been found, and why she thinks that MAP is most likely the cause of Crohn's. Here is what the author says:

The author is severely disabled by irreversible complications of Crohn's disease and is unable to test the ideas presented in this article. She reminds microbiologists, pathologists, surgeons, and other scientists and physicians in training that Barry Marshall was an internal medicine fellow when he and pathologist Robin Warren published observations of the direct visualization of H. pylori organisms in gastric biopsies [106]. The first step in establishing that a bacterium causes a disease is the consistent direct visualization of the organism by light microscopy “in such numbers, and … in such a manner as to explain the lesions of the disease” [108]. Let's take that first step.

Rosie

[tex]

Rosie,

That's a great article. It's a bit verbose, and full of redundancy, but I can't legitimately fault the author for that, since I tend to present information in a similar fashion.

I still have a long way to go, before I finish reading and absorbing it, but what I've read so far, appears to be logical, and well thought-out.

Many thanks for the link - that article is a keeper.

Tex

P. S. As a side issue, I find it interesting that the author laments the fact that, "consistent direct visualization of the organism by light microscopy", is accepted as the "gold standard" for defining the presence, (or absence), of an organism in tissues. I'd like to make the observation that whoever proclaimed "direct visualization", (by any means), to be the criterion de rigueur, for determining the presence of anything, (let alone a tiny pathogen), naively flattered himself, (or herself), with the misconception that human vision is capable of detecting all forms of matter, within the field of view, (subject to appropriate magnification by external means, of course). Whoever said that human vision is capable of seeing all? How do we know that we see everything within the field of view? The human eye is a complex organ, but it can only detect a limited range of light wavelengths. Why should we think that this allows us to "see" everything within the field of view, when our vision capabilities are actually so limited? Perhaps we are overlooking objects, because of our limited perception of certain wavelengths of light. In fact, we know this to be the case, because it is a common practice to use stains, in order to make pathogens, and other histologic components, visible to the human eye. Perhaps the discovery of MAP, in tissue from the intestines of patients with Crohn's disease, is contingent upon the development, (or the discovery), of something so simple as the correct stain, (which may not even exist, at this point in time).

[Rosie]

Tex said

Whoever said that human vision is capable of seeing all?

That's so true. As scientists look at insect/animal/plant sensory abilities, you realize how little our senses actually detect. Birds and insects use a lot more of the spectrum than we do. For example, some birds that appear drab in color are actually quite colorful in areas of the spectrum our eyes can't detect. And elephants primarily vocalize in lower frequencies than we can detect.

A good analogy is the role of viruses in diseases. A hundred years ago, the best microscopes couldn't visualize them, and in many cases bacteria that took advantage of the viral damage to set up their own infection were thought to be the causitive agent. Now we can visualize viruses in the electron microscope, but who knows what else might be hiding out unrecognized for now.

Also, you have to look for infectious agents at the right time. It could be that the infectious agent, such as MAP, is only directly visible in large numbers at a certain early time period in the course of the disease, and sets up the conditions for the subsequent inflamation. And since a person isn't symtomatic early on, no biopsies are ever taken, and no bacteria ever seen.....a classic "Catch 22".

It's never simple, but evidence is accumulating that infectious agents might be involved in many autoimmune diseases, and at some point the "smoking gun" will be found.

Rosie

[tex]

Also, you have to look for infectious agents at the right time. It could be that the infectious agent, such as MAP, is only directly visible in large numbers at a certain early time period in the course of the disease, and sets up the conditions for the subsequent inflamation. And since a person isn't symtomatic early on, no biopsies are ever taken, and no bacteria ever seen.....a classic "Catch 22".

And, to add to the difficulty in capturing a glimpse of them, am I not correct that all mycobacteria are fungi? That means that they play by a totally different set of rules than the bacteria that doctors and researchers are accustomed to dealing with. Also, in reference to your observation that MAP might be visible in significant numbers only at certain times - if I recall correctly, fungi do indeed go through stages in their development, during which they might be undetectable by ordinary means. Or am I thinking of something else? Spores, for example, can lie dormant for many years, if necessary, waiting for the right conditions to become active. Of course, spores are produced by many organisms, not just fungi.

The fact that most doctors don't seem to have a clue about Candida overgrowth, for example, suggests to me that a general lack of a working knowledge about fungi, and how they affect the human digestive system, may be the primary obstacle, preventing their "discovery" of the role that MAP plays in the development of IBDs.

Tex

[harvest_table]

This is interesting, and complicated as noted.

What do you think might be the "Vector" for this transference?

Happy New Year from Fergus Falls.

Love,
Joanna

[tex]

Hi Joanna,

I think it's milk. Pasteurization does not kill MAP.

Happy New Year to you, too.

Love,
Tex

[tex]

From the article that Rosie cited above:

As mentioned above, “creeping fat” is the phenomenon whereby the mesenteric fat attached to segments of intestine affected by Crohn's disease thickens, stiffens, and wraps around the bowel wall [83]. Creeping fat is absolutely unique in human pathology to Crohn's disease [84]. There is no other disease in humans where the mesenteric fat wraps around the bowel wall. Creeping fat is, however, present in dairy cows with Johne's disease [85].

The red emphasis is mine, of course. IMO, for such a unique phenomenon to occur in both Crohn's disease, and Johne's disease, (in cattle), is about as close to a "smoking gun" as one can get, without actual proof. So why aren't researchers pursuing this?

Below is a quote from an abstract of an interesting article that suggests that treatment by antibiotics in the macrolide class seem to be effective against MAP. This class of antibiotics includes Azithromycin, (Zithromax, Zitromax, Sumamed, etc.), Clarithromycin, (Biaxin, Fromilid, Klacid, Klabax, etc.), Dirithromycin, (Dynabac), Erythromycin, Roxithromycin, (Rulid, Surlid, Roxid), Telithromycin, and others.

Antibiotic macrolides are typically used to treat respiratory tract, and soft tissue, infections. The macrolides have a wider antimicrobial spectrum than penicillin, and therefore they're commonly substituted for patients with a penicillin allergy. They're effective against pneumococci, staphylococci, enterococci, and certain strains of streptococci. And, unlike penicillin, they have been shown to be effective against chlamydia, some rickettsia, mycoplasma, and mycobacteria.

Although Crohn's disease is considered to be autoimmune in origin, there is increasing evidence that it may have an infectious cause. The most plausible candidate is Mycobacterium avium subspecies paratuberculosis (MAP). Intriguingly, Koch's postulates may have been fulfilled for MAP and Crohn's disease, even though they still have not been met for Mycobacterium leprae and leprosy. In animals MAP causes Johne's disease, a chronic wasting intestinal diarrhoeal disease evocative of Crohn's disease. Johne's disease occurs in wild and domesticated animals, including dairy herds. Viable MAP is found in human and cow milk, and is not reliably killed by standard pasteurisation. MAP is ubiquitous in the environment including in potable water. Since cell-wall-deficient MAP usually cannot be identified by Ziehl-Neelsen staining, identification of MAP in human beings requires culture or detection of MAP DNA or RNA. If infectious in origin, Crohn's disease should be curable with appropriate antibiotics. Many studies that argue against a causative role for MAP in Crohn's disease have used antibiotics that are inactive against MAP. However, trials that include macrolide antibiotics indicate that a cure for Crohn's disease is possible.

The red emphasis is mine, of course.

http://www.ncbi.nlm.nih.gov/pubmed/12901893

Tex

[Gabes-Apg]

Tex
your review and summary of these articles is very much appreciated.

my mother had crohns (15 years) and when i was having tests and procedures was preparing myself for that diagnosis.
when i first got this diagnosis i didnt know what was the better or worse diagnosis. Given my current status, strict diet and medications I am symptom free, i think i got the better deal

talking about my diagnosis with friends, we discussed why is there an increase in these conditions occurring, and also occurring in younger people. the findings of that study give some clues to that.

it has been a long time coming but slowly but surely money and time is being spent to investigate basis for IBD's. now that the chinese have published this study i am sure someone in America / UK / Australia will do a similar study.

Interestingly i have taken macrolide antibiotics my whole life. I am allergic to penicillian and was a very sickly child, spent majority of winters with respiratory infections, and had whooping cough for 12 months
I wonder if that has protected me against Chrohns? (mother was not allergic to penicillian)

[tex]

Interestingly i have taken macrolide antibiotics my whole life. I am allergic to penicillian and was a very sickly child, spent majority of winters with respiratory infections, and had whooping cough for 12 months
I wonder if that has protected me against Chrohns? (mother was not allergic to penicillian)

It's certainly possible that might be the case, if you have been taking them somewhat regularly, for many years. Though macrolides are one of the safer types of antibiotics, for people with MC, it's not impossible that prolonged use of them may have triggered your MC, since antibiotics in general, are a common trigger for the disease, (due to their disruption of the "good" bacteria populations in the intestines).

Tex

[tex]

Here's one more observation that I'd like to make, that links leprosy, known to be caused by a mycobacterium), with dermatitis herpetiformis:

Dapsone is an old but very effective drug, that has been used to treat leprosy since the 1940s. In the 1950s it was discovered that Dapsone is very effective for treating dermatitis herpetiformis.

Leprosy and DH are the only diseases that are treated by Dapsone. Am I the only one to view that as quite a coincidence, or what?

Tex

[Rosie]

Tex, interestingly, there is another skin disease that has been treated by Dapsone. It is lichen planus, thought to be an autoimmune in origin, just like DH. My Dad suffered with this disease off and on for much of his life. He also had lots of food allergies. I don't know if had any digestive issues as he was from the old school of never divulging health problems to others. The only way I found out about it is because when I was in college, my mom wanted to find out more about the disease and approached me because I was a biology major. I'm assuming he had some sort of severe flare up that made her concerned.

I actually got to thinking about lichen planus when I was reading the posts about dermatitis herpetiformis, and was struck by some of the similarities. I have had a few "itchy bumps", especially on my shin, and had wondered if it were related. I have noticed that it seems to be getting better now that I'm gluten free. At any rate, this led me to do some research on lichen planus and that's where I saw that Dapsone has been successfully used as a treatment.

http://www.ijdvl.com/article.asp?issn=0 ... ast=Chopra

Our study showed that dapsone is definitely superior to local corticosteroids alone in treating LP cases.

Rosie

[tex]

Hmmmmm. Another mucosal disease of unknown aetiology. (I missed that one, all right, because I only checked on the drugs.com page for indications for Dapsone, and lichen planus wasn't listed there. I don't believe I've ever had that issue, except that the bumps look exactly like the pustules left by the sting of the imported fire ant, (which I've had plenty of, before the fire ants fell on hard times, and began to fade away from the landscape, around here. ).

I can't help but wonder if lichen planus might be an alternative, (unrecognized), form of DE, if the diet helps to suppress it, and dapsone also controls it. If it quacks like a duck, etc.

Thanks for the info.

Tex

[harvest_table]

This is a rather unsettling "MAP Doomsday Scenario" article.

Recognition and acceptance of the true nature of the expanding long term threat to human health posed by widespread exposure to MAP, based upon a perceptive understanding of the problem and the overwhelming balance of reliable scientific evidence, is a matter of urgency. The solutions lie in the identification and incremental introduction of a range of remedial measures which are both scientific and regulatory whose effective application on a global scale requires close international cooperation.

Article here: Not sure what to make of it yet...
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718892/

Regarding dermatitis, I've had an "undiagnosed" rash on my elbows that has come and gone for the last 5 years. Doesn't itch and not all that noticeable- at bay for the time being.

Love, from Fergus.

Joanna