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08-24-2014, 09:21 AM   #1
JMC
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Research into MAP as the cause of Crohn's

I know there are a lot of people interested in whether MAP is the cause of Crohn's, so rather than having a separate thread for each new paper, I thought it might be useful to have a single discussion for cataloguing the research. I do not propose listing all of the historical papers as a short list of those is available here, so this is just for papers published after 1st January 2014. The main areas of interest are:
  • MAP in the environment and the mechanism of human infection
  • Testing for MAP infection
  • The effect of MAP on the immune system
  • The effect of current biologic drug treatments on MAP
  • The aetiology Crohn's
  • MAP vaccines

Facts, myths and hypotheses on the zoonotic nature of Mycobacterium avium subspecies paratuberculosis
http://www.ncbi.nlm.nih.gov/pubmed/25128370

From mouth to macrophage: mechanisms of innate immune subversion by Mycobacterium avium subsp. paratuberculosis
http://www.ncbi.nlm.nih.gov/pubmed/24885748


Spread of Mycobacterium avium subsp. paratuberculosis Through Soil and Grass on a Mouflon (Ovis aries) Pasture.

http://www.ncbi.nlm.nih.gov/pubmed/24880776

Disruption of Mycobacterium avium subsp. paratuberculosis-specific genes impairs in vivo fitness.
http://www.ncbi.nlm.nih.gov/pubmed/24885784

Development and evaluation of a novel multicopy-element-targeting triplex PCR for detection of Mycobacterium avium subsp. paratuberculosis in feces.
http://www.ncbi.nlm.nih.gov/pubmed/24727272

Effect of inflammatory bowel disease therapies on immunogenicity of Mycobacterium paratuberculosis proteins.
http://www.ncbi.nlm.nih.gov/pubmed/24256081

Last edited by JMC; 08-24-2014 at 06:57 PM.
08-24-2014, 01:29 PM   #2
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Awesome thread idea
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08-24-2014, 03:54 PM   #3
Mattie
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Thanks for doing this JMC. Very useful.
08-24-2014, 06:14 PM   #4
JMC
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Another interesting looking anti-MAP vaccine, this one coming from the veterinary world.

A single or multistage mycobacterium avium subsp. paratuberculosis subunit vaccine
https://www.google.com/patents/WO201...ed=0CCsQ6AEwAg

Along with some test results published at the recent ICP in Parma.

I dropped Prof Gregers Jungersen an email to see what he planned to do with the vaccine, below is his reply:

"We are in the process of funding the further studies needed to get the vaccine registered as a vaccine in cattle and sheep. Our results are promising so far, but to get a vaccine registered we need to move production into GMP standards and then we need to document a number of production, safety and efficacy parameters. This is very costly, but we are still hopeful we will get a product on the market within some years.

Obviously it would be wonderful if our vaccine also has an effect on Crohn’s disease, but it is quite a different ball game to get a human vaccine registered and I can’t see any human oriented medical company putting any funds in our vaccine before we have shown it works and is safe in livestock."

Last edited by JMC; 08-25-2014 at 08:47 AM.
09-04-2014, 04:44 PM   #5
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A new paper from one of the biggest names in the field, Prof Borody. I am trying to get hold of the PDF.

‘Global warming’ to Mycobacterium avium subspecies paratuberculosis
Gaurav Agrawal, Thomas J Borody, and William Chamberlin
Future Microbiology, July 2014, Vol. 9, No. 7 , Pages 829-832
(doi: 10.2217/fmb.14.52)

Last edited by JMC; 09-06-2014 at 04:35 AM.
09-04-2014, 05:26 PM   #6
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Let us know if you get ahold of it plz!
09-05-2014, 06:48 AM   #7
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I have a PDF of the paper, below are some interesting quotes from it:

Developing therapeutic vaccination
One of the most exciting developments from John Hermon-Taylor’s laboratory is the anti-MAP vaccine capable of driving MAP from infected tissues [20]. It is envisaged that the stimulation of immune responses in the CD host, contrary to current immune-suppression, will be another co-therapy in the eradication of the intracellular pathogen/s driving the chronic inflammation in CD.

Competitively inhibiting MAP
Dietzia subspecies C79793-74, previously known as Mycobacterium gordonae, is a potentially useful and novel step in treating MAP. Acting to displace MAP from the macrophage represents a novel therapeutic method of removing
MAP from its niche so taking away its survival environment. By using an evolutionarily more ‘adept and inert’ member of the same family
to replace its ‘cousin’, we could be utilizing a naturally occurring method in evolutionary competition. Data for this potential therapy are based on its effectiveness as a prophylactic therapy in cattle [15]. Dietzia is a nonpathogenic microorganism used to competitively displace
and inhibit MAP infection. Some 40% of cattle with early Johne’s disease – which is notoriously difficult to treat – were cured with this oral probiotic
and the effect was long lasting compared with the use of antimycobacterial antibiotics. Hence, it could be used in the same manner for
Crohn’s patients [16].
09-23-2014, 04:40 AM   #8
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Although MAP is not mentioned in the abstract, mutations of this gene have been shown to compromise the ability of the immune system to clear mycobacteria

An alteration in ATG16L1 stability in Crohn disease

http://www.ncbi.nlm.nih.gov/pubmed/25136803

Individuals who harbor a common coding polymorphism (Thr300Ala) within a structurally unclassified region of ATG16L1 are at increased risk for the development of Crohn disease. Recently, we reported on the generation and characterization of knockin mice carrying the ATG16L1 T300A variant. We demonstrate that multiple cell types from T300A knock-in mice exhibit reduced selective autophagy, and we mechanistically link this phenotype with an increased susceptibility of ATG16L1 T300A to CASP3- and CASP7-mediated cleavage. These findings demonstrate how a single polymorphism can result in cell type- and pathway-specific disruptions of selective autophagy and alterations in the inflammatory milieu that can contribute to disease.
10-02-2014, 10:50 AM   #9
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The Mycobacterium avium ssp. paratuberculosis specific mptD gene is required for maintenance of the metabolic homeostasis necessary for full virulence in mouse infections

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132290/

Mycobacterium avium subspecies paratuberculosis (MAP) causes Johne's disease, a chronic granulomatous enteritis in ruminants. Furthermore, infections of humans with MAP have been reported and a possible association with Crohn's disease and diabetes type I is currently discussed. MAP owns large sequence polymorphisms (LSPs) that were exclusively found in this mycobacteria species. The relevance of these LSPs in the pathobiology of MAP is still unclear. The mptD gene (MAP3733c) of MAP belongs to a small group of functionally uncharacterized genes, which are not present in any other sequenced mycobacteria species. mptD is part of a predicted operon (mptABCDEF), encoding a putative ATP binding cassette-transporter, located on the MAP-specific LSP14. In the present study, we generated an mptD knockout strain (MAPΔmptD) by specialized transduction.
10-14-2014, 11:15 AM   #10
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Another review paper:
Mycobacterium avium subspecies paratuberculosis in the etiology of Crohn’s disease, cause or epiphenomenon?
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177485/

The controversy regarding MAP and IBD has persisted far too long. Firstly, it is necessary to ratify criteria for sample collection, test performance and interpretation of results. Secondly, in order to establish a causal role of MAP in the etiology of CD, it is necessary to determine if clearance of MAP using drugs that specifically act against this organism, selectively change the natural history of the disease, guarantee a sustained clinical remission and an improvement in histological activity.

The interest in a possible link between MAP and CD would be of clinical relevance (development of diagnostic methods) and for the prevention of the disease (implementation of public health measures, modifications in food processing practices, develop screening MAP infection).

Heterogeneous clinical and histological features, disease course and response to therapies make CD a highly polymorphic entity[83] and is better identified as a “syndrome”. In this respect, CD may not have a singular etiology, but rather result from the concomitant action of multiple causal agents and triggering factors, including MAP.
10-15-2014, 10:12 AM   #11
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This is great news.

So it's either MAP or AIEC
10-15-2014, 10:24 AM   #12
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This is great news.

So it's either MAP or AIEC
Probably both, just like pneumonia has multiple culprits that can cause it.
10-16-2014, 09:28 AM   #13
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Another review paper:
Mycobacterium avium subspecies paratuberculosis in the etiology of Crohn’s disease, cause or epiphenomenon?
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177485/

The controversy regarding MAP and IBD has persisted far too long. Firstly, it is necessary to ratify criteria for sample collection, test performance and interpretation of results. Secondly, in order to establish a causal role of MAP in the etiology of CD, it is necessary to determine if clearance of MAP using drugs that specifically act against this organism, selectively change the natural history of the disease, guarantee a sustained clinical remission and an improvement in histological activity.

The interest in a possible link between MAP and CD would be of clinical relevance (development of diagnostic methods) and for the prevention of the disease (implementation of public health measures, modifications in food processing practices, develop screening MAP infection).

Heterogeneous clinical and histological features, disease course and response to therapies make CD a highly polymorphic entity[83] and is better identified as a “syndrome”. In this respect, CD may not have a singular etiology, but rather result from the concomitant action of multiple causal agents and triggering factors, including MAP.
F-e-c-a-l T-r-a-n-s-p-l-a-n-t, restoring colonization resistance!!!
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10-16-2014, 01:34 PM   #14
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bacteriaphage - not like it hasn't been done and known for 100+ years

oh western medicine, you suck in your ignorance.

I normally have more sensible and mature things to post on here but knowing that Soviet Georgia have understood and been treating gut conditions appropriately since a century ago and then finding out once i got my diagnosis that the West just ignores progress made elsewhere in the world - feels like medical neglect to me.

And for anyone wondering, yes today was a bad day for me - went to see my GI specialist only for him to palm off the consultation to some girl who literally had NONE of my history, notes or other things held on the hospital system. She couldnt even hold a sensible conversation with me as she didnt have the facts - it was like a first visit to a GP before diagnosis! 2months i waited for that appointment and they say they are booking me another one...for a months time!

</vent> (sorry op)
10-17-2014, 09:11 AM   #15
mf15
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This was posted on the site in the past.
But it is interesting that they are calling the whole gi medical community since
1942,basically stupid.
Old Mike
http://www.sciencedirect.com/science...01971214014349
10-21-2014, 07:47 AM   #16
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John I´m adding this article here, very very interesting stuff.

Where Are All the Mycobacterium avium Subspecies paratuberculosis in Patients with Crohn's Disease?

Mycobacterium avium subspecies paratuberculosis (MAP) causes a chronic granulomatous inflammation of the intestines, Johne's disease, in dairy cows and every other species of mammal in which it has been identified. MAP has been identified in the mucosal layer and deeper bowel wall in patients with Crohn's disease by methods other than light microscopy, and by direct visualization in small numbers by light microscopy. MAP has not been accepted as the cause of Crohn's disease in part because it has not been seen under the microscope in large numbers in the intestines of patients with Crohn's disease. An analysis of the literature on the pathology of Crohn's disease and on possible MAP infection in Crohn's patients suggests that MAP might directly infect endothelial cells and adipocytes and cause them to proliferate, causing focal obstruction within already existing vessels (including granuloma formation), the development of new vessels (neoangiogenesis and lymphangiogenesis), and the “creeping fat” of the mesentery that is unique in human pathology to Crohn's disease but also occurs in bovine Johne's disease. Large numbers of MAP might therefore be found in the mesentery attached to segments of intestine affected by Crohn's disease rather than in the bowel wall, the blood and lymphatic vessels running through the mesentery, or the mesenteric fat itself. The walls of fistulas might result from the neoangiogenesis or lymphangiogenesis that occurs in the bowel wall in Crohn's disease and therefore are also possible sites of large numbers of MAP. The direct visualization of large numbers of MAP organisms in the tissues of patients with Crohn's disease will help establish that MAP causes Crohn's disease.

http://www.plospathogens.org/article...l.ppat.1000234

Last edited by sir.clausin; 10-24-2014 at 04:28 AM.
11-05-2014, 05:13 PM   #17
JMC
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The paper with the test results of Prof Hermon-Taylor's vaccine trial in cattle conducted by Tim Bull

Immunity, safety and protection of an Adenovirus 5 prime - modified Vaccinia virus Ankara boost subunit vaccine against Mycobacterium avium subspecies paratuberculosis infection in calves

http://www.veterinaryresearch.org/co...1/112/abstract

Last edited by JMC; 11-07-2014 at 04:42 PM.
11-07-2014, 03:56 PM   #18
sir.clausin
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Not found, here is the correct link
http://www.veterinaryresearch.org/co...1/112/abstract
11-07-2014, 04:43 PM   #19
JMC
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I fixed my link too, it was definitely working when I first posted it :-)
11-30-2014, 07:39 AM   #20
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Here is an old 1991 paper.
Old Mike
http://europepmc.org/backend/ptpmcre...1&blobtype=pdf
02-06-2015, 02:26 PM   #21
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The vesicle-associated function of NOD2 as a link between Crohn’s disease and mycobacterial infection

http://www.gutpathogens.com/content/7/1/1


The polymorphism of the NOD2 gene, coding for an intracellular pattern recognition receptor, is a factor of predisposition to mycobacterial infections and CD. Recent findings on NOD2 interactions and functions provide the missing pieces in the puzzle of a NOD2-mediated mechanism common for mycobacterial infections and CD. Implications of these new findings for the development of a better understanding and treatments of CD and mycobacterial infections are discussed.
02-19-2015, 05:19 PM   #22
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Crohn's disease therapy with Dietzia: the end of anti-inflammatory drugs.

http://www.ncbi.nlm.nih.gov/pubmed/25689526

Although I cannot access the article, I believe Dietzia is a probiotic which has proven to be effective for treating MAP infection in cattle
02-19-2015, 11:29 PM   #23
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As far as I had heard dietza was showing little benefit in humans but I know Borody was using it for a while (I think they were struggling to get ahold of it) if anyone has a future med subscription please do us a favour and share/repost the article for us here on CF.
02-20-2015, 01:26 AM   #24
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New article (costs 40 cents (USD)) on on www.BestStory.ca connecting the MAP bacterium which causes Johne's disease in animals to the same MAP bacterium found in many Crohn's and colitis patients. The 8,500-word analysis was written by Dr. Michael T. Collins of the University of Wisconsin, who is one of the top MAP experts in the world.

It is a very important story because it lays out the science, step by step, which opens the door to Crohn's being treated was an infectious disease; rather than strictly as an autoimmune condition, as is currently the case by most gastroenterologists. That means Crohn's could be treated, and possibly cured, by a mix of antibiotics (anti-MAP Protocol), whereas it is now usually treated with expensive immunosuppressant drugs and biologic medicines, and has no cure.

Based in Montreal, BestStory.ca is Canada's only ad-free, long-form journalism site. Below is a link to Dr. Collins' analysis:

https://www.beststory.ca/teasers/cro...ser_email.html
02-25-2015, 03:41 PM   #25
JMC
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One of the authors of this paper is Tim Bull, who has worked on the Crohn's MAP Vaccine.

Increased viability but decreased culturability of Mycobacterium avium subsp. paratuberculosis in macrophages from inflammatory bowel disease patients under Infliximab treatment.

http://www.ncbi.nlm.nih.gov/pubmed/25702170

Mycobacterium avium subsp. paratuberculosis (MAP) has long been implicated as a triggering agent in Crohn's disease (CD). In this study, we investigated the growth/persistence of both M. avium subsp. hominissuis (MAH) and MAP, in macrophages from healthy controls (HC), CD and ulcerative colitis patients. For viability assessment, both CFU counts and a pre16SrRNA RNA/DNA ratio assay (for MAP) were used. Phagolysosome fusion was evaluated by immunofluorescence, through analysis of LAMP-1 colocalization with MAP. IBD macrophages were more permissive to MAP survival than HC macrophages (a finding not evident with MAH), but did not support MAP active growth. The lower MAP CFU counts in macrophage cultures associated with Infliximab treatment were not due to increased killing, but possibly to elevation in the proportion of intracellular dormant non-culturable MAP forms, as MAP showed higher viability in those macrophages. Increased MAP viability was not related to lack of phagolysosome maturation. The predominant induction of MAP dormant forms by Infliximab treatment may explain the lack of MAP reactivation during anti-TNF therapy of CD but does not exclude the possibility of MAP recrudescence after termination of therapy.
03-04-2015, 04:54 AM   #26
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I read this ^^^^ as 'if you are on infliximab and semi ok, dont go off it.'

thoughts?

I wonder how the MAP progress is going --->

g'day from OZ
03-04-2015, 03:13 PM   #27
JMC
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I read this ^^^^ as 'if you are on infliximab and semi ok, dont go off it.'
Yes, that is a pretty accurate summary. Infliximab will put MAP into a dormant state, but whilst in a dormant state, they will not be killed off. Once you stop treatment there is a risk that those dormant MAP bacteria become active again and your disease will come back strongly.
03-04-2015, 07:40 PM   #28
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for someone like me, who has been on inflix for 8 years, you stuggle with should you keep taking it or not….i think the MAP thing keeps me thinking i should stay on it.

thanks JMC
04-10-2015, 02:38 PM   #29
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Resolution of Crohn's disease and complex regional pain syndrome following treatment of paratuberculosis


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385555/


A cohort of family members with various chronic diseases including Crohn’s disease, asthma, complex regional pain syndrome, hypothyroidism, type 1 diabetes mellitus, and lymphangiomatosis and/or evidence of infection by Mycobacterium avium subsp. paratuberculosis (MAP) are described in this series of case reports. MAP was cultured from the blood of three members affected by the first five diseases and there was accompanying elevated anti-MAP IgG in two members. The patient affected by the sixth disease has a markedly elevated anti-MAP titer. The two patients affected by the first four diseases have been treated with a combination of anti-MAP antibiotics and ultraviolet blood irradiation therapy with resolution of the disease symptomatology and inability to culture MAP in post treatment blood samples. These case reports of patients with MAP infections provide supportive evidence of a pathogenic role of MAP in humans.
04-14-2015, 01:06 PM   #30
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Mycobacterium avium ss. paratuberculosis Zoonosis – The Hundred Year War – Beyond Crohn’s Disease

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349160/

The factitive role of Mycobacterium avium ss. paratuberculosis (MAP) in Crohn’s disease has been debated for more than a century. The controversy is due to the fact that Crohn’s disease is so similar to a disease of MAP-infected ruminant animals, Johne’s disease; and, though MAP can be readily detected in the infected ruminants, it is much more difficult to detect in humans. Molecular techniques that can detect MAP in pathologic Crohn’s specimens as well as dedicated specialty labs successful in culturing MAP from Crohn’s patients have provided strong argument for MAP’s role in Crohn’s disease. Perhaps more incriminating for MAP as a zoonotic agent is the increasing number of diseases with which MAP has been related: Blau syndrome, type 1 diabetes, Hashimoto thyroiditis, and multiple sclerosis. In this article, we debate about genetic susceptibility to mycobacterial infection and human exposure to MAP; moreover, it suggests that molecular mimicry between protein epitopes of MAP and human proteins is a likely bridge between infection and these autoimmune disorders.
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