Research into MAP as the cause of Crohn's

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JMC

JMC

Joined
Sep 10, 2011
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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
 
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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/WO20...&sa=X&ei=diX6U4OiEdbtaKKIgqAE&ved=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."
 
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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)
 
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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].
 
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.
 
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.
 
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.
 
JMC said:
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.
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F-e-c-a-l T-r-a-n-s-p-l-a-n-t, restoring colonization resistance!!!
 
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)
 
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/info:doi/10.1371/journal.ppat.1000234
 
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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/content/45/1/112/abstract
 
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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.
 
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.
 
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/crohns_04C_teaser_email.html
 
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.
 
happy poo poo said:
I read this ^^^^ as 'if you are on infliximab and semi ok, dont go off it.'
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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.
 
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
 
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.
 
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.
 
Application of multiple laboratory tests for Mycobacterium avium ssp. paratuberculosis detection in Crohn's disease patient specimens.

http://www.ncbi.nlm.nih.gov/pubmed/26147146

The difficulties involved in detecting and enumerating Mycobacterium avium subsp. paratuberculosis (MAP) as a pathogen potentially involved in Crohn's disease (CD) are well known. This study aimed to improve this situation through the application of multiple laboratory diagnostic tests to detect and isolate this bacterium from different specimens collected from CD-patients and non-CD subjects as controls. A total of 120 samples (terminal ileum and colon biopsies, blood and stool) were obtained from 19 CD-patients and from 11 individuals who did not have a clinicopathological diagnosis of CD (non-CD controls) attending for ileocolonoscopy. All samples were processed by staining techniques, culture on both solid and liquid media, and Insertion Sequence 900/F57 real-time PCR. The MAP frequency in CD-patients was found in a significantly greater proportion than in non-CD subjects; the most positive samples were biopsies from CD-patients tested by real-time PCR. MAP detection in biopsies, and in the other samples, by applying multiple and validated laboratory diagnostic tests, could be a marker of active infection, supporting MAP involvement in CD.
 
It's interesting how MAP was detected at the same levels in the blood and stool of both CD patients and healthy control group, suggesting that the bacteria may be present in the environment and carried in most humans, but that somehow the inability of macrophages in CD patients to kill it may contribute to the disease state.

I also learned that MAP can be present in both a cell-wall defective and cell-wall intact form, to which different staining techniques exhibit different results and perhaps why it is difficult to detect in conventional lab environments. They were able to make the highest correlation in active CD patients (94.7%) only when using real-time PCR of biopsy samples.
 
xeridea said:
I also learned that MAP can be present in both a cell-wall defective and cell-wall intact form, to which different staining techniques exhibit different results and perhaps why it is difficult to detect in conventional lab environments.
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This is something that was noted by Prof Hermon-Taylor a long time ago. It is also why a lot of the earlier MAP studies produced contradictory results.
 
New info from Brazil.
Old Mike
http://www.ncbi.nlm.nih.gov/pubmed/26176833

Presence of Mycobacterium avium subsp. paratuberculosis (MAP) in Brazilian patients with inflammatory bowel diseases and in controls.

Carvalho IA1, Schwarz DG2, Pietralonga PA2, Faria AC2, Braga IF2, Carvalho GD3, Valente FL2, Machado JP1, Guimarães LM4, Ferrari ML4, Silva Júnior A2, Moreira MA2.



Author information






Abstract

CONTEXT AND OBJECTIVE:

Mycobacterium avium subsp. paratuberculosis (MAP) has attracted the interest of researchers because of similarities between paratuberculosis and Crohn's disease (CD). The aim of this study was to evaluate the frequency of MAP through cultures, histology and polymerase chain reaction (PCR) on intestinal biopsies from Brazilian CD patients. Quantitative real time PCR (qRT-PCR) was performed on positive samples.

DESIGN AND SETTING:

Analytical cross-sectional study with control group at two federal universities.

METHODS:

Fresh samples were collected from 25 patients; five with CD, eight with ulcerative colitis (UC) and 12 controls with non-inflammatory bowel disease (nIBD). Formalin-fixed paraffin-embedded (FFPE) samples from 143 patients were also collected: 44 CD, 49 UC and 56 nIBD.

RESULTS:

None of the fresh samples was positive for MAP. Five FFPE samples (one CD, two UC and two nIBD) and three fresh samples (one in each group) were positive through IS900-PCR. qRT-PCR was performed on these eight samples. Among the FFPE samples, there were 192.12 copies/μl in the CD group, 72.28 copies/μl in UC and 81.43 copies/μl in nIBD. Among the fresh samples, there were 432.99 copies/μl, 167.92 copies/μl and 249.73 copies/μl in the CD, UC and nIBD groups, respectively. The highest bacterial load was in the CD group.

CONCLUSION:

This study does not provide evidence for a role of MAP in the etiology of CD, although MAP DNA was detected in all three patient groups. This is the first report of MAP presence in human intestinal biopsies in Brazil
 
Great thread. This isn't really a research article, but a cool beststory.ca article about Dr. Borody and tons of other into on MAP and Crohns. Well worth the 40 cents.

POSTED: JUNE 2015
Medical pioneer from Down Under leads world in Crohn’s treatment
Analysis by WARREN PERLEY
Writing from Montreal

Dr. Thomas Borody of Australia enjoys the highest remission rate of any doctor in the world when it comes to treating Crohn’s patients. Now he and U.S.-based Dr. William Chamberlin, who like Dr. Borody treats Crohn’s as an infectious disease, talk about the antibiotic formulas they use, their success rates, and their views on the future direction of Crohn’s treatments. Microbiologist Dr. Saleh Naser of the University of Central Florida explains why the connection between MAP bacterium and Crohn’s continues to confound most microbiologists and gastroenterologists.
 
mf15 said:
Here is a video on crohns autoimmune or infectious
https://www.youtube.com/watch?v=7x3lq8QEg5g&feature=youtu.be

here is the lab site
https://www.mcgill.ca/molepi/

Old Mike
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Here's a recent report where the doctor they interview (at 1:00 mark) says that though it parallels many of the symptoms as autoimmunity, Crohn's is not an autoimmune disease, but rather, a chronic inflammatory disease. It's refreshing to see a shift away from the autoimmune mislabeling of CD.
 
xeridea said:
Here's a recent report where the doctor they interview (at 1:00 mark) says that though it parallels many of the symptoms as autoimmunity, Crohn's is not an autoimmune disease, but rather, a chronic inflammatory disease. It's refreshing to see a shift away from the autoimmune mislabeling of CD.
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Crohn's is not and never has been an autoimmune disease. Any medical practioner who tells you Crohn's is an autoimmune should be avoided immediately. The best explanation is given by Prof Marcel Behr in this youtube video which is worth an hour of anybody's time: https://youtu.be/7x3lq8QEg5g
 
To put it in perspective, even Wikipedia reflects the fact that Crohn's is not an autoimmune disease. That Crohn's is a "multi-factorial" disease with genetic and environmental elements is now mainstream, whereas even 5 years ago, most people would have described it (wrongly) as an autoimmune disease.
 
JMC said:
To put it in perspective, even Wikipedia reflects the fact that Crohn's is not an autoimmune disease. That Crohn's is a "multi-factorial" disease with genetic and environmental elements is now mainstream, whereas even 5 years ago, most people would have described it (wrongly) as an autoimmune disease.
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No disagreement from me that it's not an autoimmune (AI) disease. I'm more of the persuasion that it's something related to the innate immune system activating the adaptive one. I posted the video on other boards too, where some still regard CD as AI, thought maybe some here would appreciate it too.
 
Another interesting piece in the puzzle...

Mechanism of action of the tuberculosis and Crohn disease risk factor IRGM in autophagy.

http://www.ncbi.nlm.nih.gov/pubmed/26313894

Polymorphisms in the IRGM gene, associated with Crohn disease (CD) and tuberculosis, are among the earliest identified examples documenting the role of autophagy in human disease. Functional studies have shown that IRGM protects against these diseases by modulating autophagy, yet the exact molecular mechanism of IRGM's activity has remained unknown. We have recently elucidated IRGM's mechanism of action. IRGM functions as a platform for assembling, stabilizing, and activating the core autophagic machinery, while at the same time physically coupling it to conventional innate immunity receptors. Exposure to microbial products or bacterial invasion increases IRGM expression, which leads to stabilization of AMPK. Specific protein-protein interactions and post-translational modifications such as ubiquitination of IRGM, lead to a co-assembly with IRGM of the key autophagy regulators ULK1 and BECN1 in their activated forms. IRGM physically interacts with two other CD risk factors, ATG16L1 and NOD2, placing these three principal players in CD within the same molecular complex. This explains how polymorphisms altering expression or function of any of the three factors individually can affect the same process - autophagy. Furthermore, IRGM's interaction with NOD2, and additional pattern recognition receptors such as NOD1, RIG-I and select TLRs, transduces microbial signals to the core autophagy apparatus. This work solves the long-standing enigma of how IRGM controls autophagy.
 
The potential Public Health Impact of Mycobacterium avium ssp. paratuberculosis: Global Opinion Survey of Topic Specialists.

http://www.ncbi.nlm.nih.gov/pubmed/26272619

Global research knowledge has accumulated over the past few decades, and there is reasonable evidence for a positive association between Mycobacterium avium spp. paratuberculosis and Crohn's disease in humans, although its role as a human pathogen has not been entirely accepted. For this reason, management of public health risk due to M. paratuberculosis remains an important policy issue in agri-food public health arenas in many countries. Responsible authorities must decide whether existing mitigation strategies are sufficient to prevent or reduce human exposure to M. paratuberculosis. A Web-based questionnaire was administered to topic specialists to elicit empirical knowledge and opinion on the overall public health impact of M. paratuberculosis, the importance of various routes of human exposure to the pathogen, existing mitigation strategies and the need for future strategies. The questionnaire had four sections and consisted of 20 closed and five open questions. Topic specialists believed that M. paratuberculosis is likely a risk to human health (44.8%) and, given the paucity of available evidence, most frequently ranked it as a moderate public health issue (40.1%). A significant correlation was detected between topic specialists' commitment to M. paratuberculosis in terms of the number of years or proportion of work dedicated to this topic, and the likelihood of an extreme answer (high or low) to the above questions. Topic specialists identified contact with ruminants and dairy products as the most likely routes of exposure for humans. There was consensus on exposure routes for ruminants and what commodities to target in mitigation efforts. Described mandatory programmes mainly focused on culling diseased animals and voluntary on-farm prevention programmes. Despite ongoing difficulties in the identification of subclinical infections in animals, the topic specialists largely agreed that further enhancement of on-farm programmes in affected commodities by the agri-food industry (68.4%) and allocation of resources by governments to monitor the issue (92%) are most appropriate given the current state of evidence.
 
Including this paper because I had doubts about whether MAP caused the fistulating form of Crohn's and it appears tuberculosis (rather than paratuberculosis) can cause fistulas which are hard to distinguish from Crohn's. Although not conclusive it suggest to me MAP could also cause fistulas.

Clinical features of tuberculous versus Crohn's anal fistulas in Korea.


http://www.ncbi.nlm.nih.gov/pubmed/26374663


TB anal fistula is clinically very similar to CD anal fistula. In Korea, the incidence of CD anal fistula has recently increased in prevalence, while the prevalence of TB anal fistula is decreasing but is still persistent. We recommend that clinicians should prepare for a possibility of TB as well as CD anal fistula in TB-endemic countries including Korea.
 
thanks JMC - very informative. I wonder how long it will be until there is a MAP diagnostic test available to us??? To tell if we have MAP in our bodies…or not. Any news from london?
 
JMC, anecdotally, when I consulted with Dr. Chamberlin and mentioned fistulas, he said having them was another indication that it is MAP, and initially suggested AMAT, saying that it would also help to heal them. He convinced me, but upon learning that antibiotics were poorly tolerated and dangerously so, he suggested Remicade. In the end, it was surgery, Humira and luck that seems to have worked ... at least for now.
 
Mommabear said:
JMC, anecdotally, when I consulted with Dr. Chamberlin and mentioned fistulas, he said having them was another indication that it is MAP, and initially suggested AMAT, saying that it would also help to heal them.
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The reason why I questions whether MAP caused fistulas is that it is not a feature of Johnes disease which is closer in nature, as I understand it, to the stricturing form of Crohn's. I know diseases do not present with identical symptoms in all species, but you do have to wonder why there appears to be distinct variants of Crohn's. I have not read any papers which can directly explain why that should be the case, if anyone else has, I would be interested to know.
 
In retrospect I should have asked that he point me to a paper to support his opinion. I did come across a study that I am sure you have already read about mouth ulcers which were infected with MAP: http://www.biomedcentral.com/content/pdf/1757-4749-5-18.pdf

I agree, it is curious that Crohn's has such varied manifestations. Perhaps genetics plays a role? MAP being the underlying cause, but depending on genetic mutations, it manifests differently? In time hopefully, we will have most of the answers, if not all.
 
Mycobacterium paratuberculosis as a cause of Crohn's disease.

http://www.ncbi.nlm.nih.gov/pubmed/26474349

Crohn's disease is a chronic inflammatory bowel disease of unknown cause, affecting approximately 1.4 million North American people. Due to the similarities between Crohn's disease and Johne's disease, a chronic enteritis in ruminant animals caused by Mycobacterium avium paratuberculosis (MAP) infection, MAP has long been considered to be a potential cause of Crohn's disease. MAP is an obligate intracellular pathogen that cannot replicate outside of animal hosts. MAP is widespread in dairy cattle and because of environmental contamination and resistance to pasteurization and chlorination, humans are frequently exposed through contamination of food and water. MAP can be cultured from the peripheral mononuclear cells from 50-100% of patients with Crohn's disease, and less frequently from healthy individuals. Association does not prove causation. We discuss the current data regarding MAP as a potential cause of Crohn's disease and outline what data will be required to firmly prove or disprove the hypothesis.
 
My understanding of this article is that previous exposure to MAP changes the response of the immune system to subsequent exposure. I would be interested in other views who have greater expertise than I do.

Macrophage polarization in cattle experimentally exposed to Mycobacterium avium subsp. paratuberculosis

http://www.ncbi.nlm.nih.gov/pubmed/26454271

Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of Johne's disease (JD) in cattle, has significant impacts on the livestock industry and has been implicated in the etiology of Crohn's disease. Macrophages play a key role in JD pathogenesis, which is driven by the manipulation of host immune mechanisms by MAP. A change in the macrophage microenvironment due to pathogenic or host-derived stimuli can lead to classical (M1) or alternative (M2) polarization of macrophages. In addition, prior exposure to antigenic stimuli has been reported to alter the response of macrophages to subsequent stimuli. However macrophage polarization in response to MAP exposure and its possible implications have not previously been addressed. In this study, we have comprehensively examined monocyte/macrophage polarization and responsiveness to antigens from MAP-exposed and unexposed animals. At three years post-exposure, there was a heterogeneous macrophage activation pattern characterized by both classical and alternate phenotypes. Moreover, subsequent exposure of macrophages from MAP-exposed cattle to antigens from MAP and other mycobacterial species led to significant variation in the production of nitric oxide, interleukin-10 and tumour necrosis factor α. These results indicate the previously unreported possibility of changes in the activation state and responsiveness of circulating monocytes/macrophages from MAP-exposed cattle.

 
The Hruska postulate of Crohn's disease.


http://www.ncbi.nlm.nih.gov/pubmed/26432629

Crohn's disease is due to the loss of immunological tolerance within the gastrointestinal tract to the antigenic array of Mycobacterium avium subspecies paratuberculosis (MAP) and closely related polymorphic variants. The loss of immune tolerance results in an effector cytokine responsive upon re-exposure to MAP. For immune tolerance to MAP to be induced, infection must occur when acquired immunity is markedly underdeveloped.
 
Crohn’s disease and related inflammatory diseases: frommany single hypotheses to one “superhypothesis”

http://vri.cz/docs/vetmed/59-12-583.pdf

The aetiology of Crohn’s disease and paratuberculosis are the subjects of intensive study and also frequently, of dispute. However, a number of other nosological entities have a similar history, namely type 1 diabetes, multiple sclerosis, sarcoidosis, asthma, psoriasis, spondylarthritis, Blau syndrom etc. The zoonotic risk of Mycobacterium avium subsp. paratuberculosis (MAP) has been discussed for more than one hundred years. „The problem remains open, further research is needed“, is the sentence which seems to be obligatory in the conclusions of many scientific articles. A number of hypotheses have been suggested, all with a grain of truth in them.
The infection hypothesis has many supporters and opponents, but it does not fit to all Crohn’s disease cases. The contribution of the genetic factor has been admitted a long time ago and has been experimentally confirmed by recent excellent studies. An environmental factor is expected and has been often mentioned, but has yet to be
discovered. Muramyl dipeptide, derived from peptidoglycans of the bacterial cell wall is one of the triggers, mentioned in connection with chronic inflammatory diseases. The immunomodulatory ability of this compound has been recognised for decades and is exploited in Freund’s adjuvant. A critical amount of muramyl dipeptide can affect immunity during some bacterial infections but the long latent period between infection and onset of the clinical form of the disease could explain why a causative relationship between the primary infection and chronic inflammation is not considered. Different species of mycobacteria can be found in the environment, in water, dust,
soil and aerosol. Although severe infections with mycobacteria have been described, these species are not thought to be typical zoonotic pathogens. Muramyl dipeptide derived from mycobacteria obviously plays a starring role as a bacterial trigger in the aetiology of many autoimmune and autoinflammatory diseases. Paratuberculosis in
cattle and other ruminants is a source of enormous contamination of the environment but also of milk and meat by MAP. Muramyl dipeptide from mycobacteria, namely MAP, and Crohn’s disease as a representative of diseases often called civilization threats, are important pieces of the gigantic puzzle. Mycobacteria in the environment and foodstuffs have to be acknowledged as a public health risk, which can never be completely eliminated. There is no reason to push the panic button, but we must learn how to live together with this microorganism, how the pool of immunomodulator sources can be diminished, and how the pathogenic relationship between triggers and target tissues can be disrupted. The dissemination of knowledge, the availability of rapid and inexpensive tools for identification of mycobacteria in different matrices, and the establishment of a maximal allowed limit for mycobacteria in milk and meat should contribute to food safety and consumer protection.
 
New paper from Thomas Borody demonstrating remarkable success with curing fistulas by combining anti-Map therapy with Infliximab and a new hyperbaric oxygen therapy.

http://www.future-science.com/doi/full/10.4155/fso.15.77

Combining infliximab, anti-MAP and hyperbaric oxygen therapy for resistant fistulizing Crohn's disease

Background: Fistulizing Crohn's disease (CD) presents a therapeutic challenge as fistulae are notoriously difficult to heal. Mycobacterium avium ss paratuberculosis (MAP) treatment in CD is gaining attention. Aim: We evaluated healing of CD fistula(e) using a novel combination therapy. Study: Nine consecutive patients who failed to heal fistulae on conventional treatment including anti-TNF, were treated with at least three doses of infliximab, 18–30 courses of hyperbaric oxygen therapy and anti-MAP antibiotics comprising rifabutin, clarithromycin and clofazimine. Results: All patients achieved complete healing of fistulae by 6–28 weeks and follow-up for mean 18 months. Conclusion: Combining infliximab, hyperbaric oxygen therapy and anti-MAP, seems to enable healing of recalcitrant fistulae and although a small case series, all nine patients achieved complete healing.
 
ganesha said:
I've seen the articles on crohnsforum but I've searched and did not find this compilation:

http://crohnsmapvaccine.com/pdfs/literature-supporting-hypothesis-that-map-causes-crohns.pdf
Quite an interesting summary.
Click to expand...

That is the brief summary, there is a much bigger list of about 500 papers compiled by Prof John Hermon-Taylor which will be put on the CMV website at some point. Unfortunately, the vast majority of research is still published in journals which require a paid subscription to read the papers, so it is not possible to legally share the full articles. I find this situation in the internet age, frankly, rather ridiculous and I believe is a factor holding back scientific progress. The sooner everyone has access to all scientific knowledge ever published the better!
 
JMC said:
That is the brief summary, there is a much bigger list of about 500 papers compiled by Prof John Hermon-Taylor which will be put on the CMV website at some point. Unfortunately, the vast majority of research is still published in journals which require a paid subscription to read the papers, so it is not possible to legally share the full articles. I find this situation in the internet age, frankly, rather ridiculous and I believe is a factor holding back scientific progress. The sooner everyone has access to all scientific knowledge ever published the better!
Click to expand...

Indeed, this is just a brief summary. I've read much more and downloaded lots of interesting articles (thanks to access granted by a university subscription). I cannot agree more on scientific information sharing. Paying $30-50 for every single article (or subscribing to tens of journals) in the internet era is definitely ridiculous.
 
JMC said:
That is the brief summary, there is a much bigger list of about 500 papers compiled by Prof John Hermon-Taylor which will be put on the CMV website at some point. Unfortunately, the vast majority of research is still published in journals which require a paid subscription to read the papers, so it is not possible to legally share the full articles. I find this situation in the internet age, frankly, rather ridiculous and I believe is a factor holding back scientific progress. The sooner everyone has access to all scientific knowledge ever published the better!
Click to expand...

you can rent limited access to papers cheaply on sites like readcube and deepdyve, its like 4-5 bucks for 48 hours access with no printing abilities, that's good enough for someone who doesn't do it for a living.
 
wildbill_52280 said:
you can rent limited access to papers cheaply on sites like readcube and deepdyve, its like 4-5 bucks for 48 hours access with no printing abilities, that's good enough for someone who doesn't do it for a living.
Click to expand...

Thanks. I know, but I'll stick to my opinion - sharing builds knowledge.
 
wildbill_52280 said:
you can rent limited access to papers cheaply on sites like readcube and deepdyve, its like 4-5 bucks for 48 hours access with no printing abilities, that's good enough for someone who doesn't do it for a living.
Click to expand...

Given a lot of University research is funded by tax payers money, does it not seem a little strange that the knowledge it generates is then sold back to us by multi-billion dollar publishing companies? In the era of journals printed on paper, you might have been able to justify some of the cost, but now? It just feels like robbery...
 
Not sure if this one is on the thread, and I can only see the abstract. Very frustrating. Looks interesting.

http://www.ncbi.nlm.nih.gov/pubmed/25994082

Prevalence of Mycobacterium avium subsp. paratuberculosis and Escherichia coli in blood samples from patients with inflammatory bowel disease.

Abstract
Mycobacterium avium subsp. paratuberculosis (MAP) and adherent-invasive Escherichia coli (AIEC) have been implicated as primary triggers in Crohn's disease (CD). In this study, we evaluated the prevalence of MAP and E. coli (EC) DNA in peripheral blood from 202 inflammatory bowel disease (IBD) patients at various disease periods and compared against 24 cirrhotic patients with ascites (CIR) (non-IBD controls) and 29 healthy controls (HC). MAP DNA was detected by IS900-specific nested PCR, EC DNA by malB-specific nested PCR and AIEC identity, in selected samples, by sequencing of fimH gene. CD patients with active disease showed the highest MAP DNA prevalence among IBD patients (68 %). Infliximab treatment resulted in decreased MAP detection. CIR patients had high individual and coinfection rates (75 % MAP, 88 % EC and 67 % MAP and EC), whilst HC controls had lower MAP prevalence (38 %) and EC was undetectable in this control group. EC DNA prevalence in IBD patients was highly associated with CD, and 80 % of EC from the selected samples of CD patients analyzed carried the fimH30 allele, with a mutation strongly associated with AIEC. Our results show that coinfection with MAP and AIEC is common and persistent in CD, although the high MAP and EC detection in CIR patients suggested that colonization is, at least, partially dependent on increased gut permeability. Nevertheless, facilitative mechanisms between a susceptible host and these two potential human pathogens may allow their implication in CD pathogenesis.
 
irishgal said:
http://www.ncbi.nlm.nih.gov/pubmed/25994082

Prevalence of Mycobacterium avium subsp. paratuberculosis and Escherichia coli in blood samples from patients with inflammatory bowel disease.
Click to expand...

Great paper with some very interesting results. Looking back through my email I read a pre-print of this back in May 2015. One of the authors is Tim Bull who has done a lot of work with Prof John Hermon-Taylor on MAP.

A few other papers from JHT on EColi you might find interesting:
http://www.ncbi.nlm.nih.gov/pubmed/25809337

http://www.ncbi.nlm.nih.gov/pubmed/26137941
 
JMC said:
Given a lot of University research is funded by tax payers money, does it not seem a little strange that the knowledge it generates is then sold back to us by multi-billion dollar publishing companies? In the era of journals printed on paper, you might have been able to justify some of the cost, but now? It just feels like robbery...
Click to expand...

We have to pay to publish our research, too, in most journals. There are some free ones for scientists to publish in that are top quality, not many though. That can be something of a problem, sometimes. I remember two particular papers that were an absolute joke - but because they were published and in my field, dufus here had to spend 3 months trying to replicate their work (which I couldn't).

It's a careful balance...the editors and workers for these places need the cash, most already have full time jobs in research...it's either increase the fees that scientists have to pay to publish their work so they can hire someone full time to take some of the load, versus charging a prescription fee for the same purpose. Most journals strike a balance, but some are blatantly unfair, usually the "higher end" journals, like nature medicine or some such, though I've read the odd piece of woo woo in there too.

A way around this for access though, and it may not work these days as you usually have to log on to a computer at universities, is to simply walk into one and access them via the computer. Any university with a standard science/medical faculty will have access to pubmed central etc. Alternatively, be very nice to anyone in research. Most would be on your side and download 'em for you to a usb.
 
Thanks SauceyScience for the additional info. There are always two (or more!) sides to every story. The researchers I know sometimes send me these, and would if I ask, but I hate bugging them since they're so busy researching! I figure if it's something they need me to know, it will appear in my inbox. Plus, the abstracts are usually an excellent summary and good enough for my purposes. I didn't know that journals charged the scientists. Seems that charging the scientists would lead to bias, as you describe. I figured they'd get their income from subscriptions or ads.

Appreciate the info and wish you the best!
 
irishgal said:
Not sure if this one is on the thread, and I can only see the abstract. Very frustrating. Looks interesting.

...whilst HC controls had lower MAP prevalence (38 %) and EC was undetectable in this control group. EC DNA prevalence in IBD patients was highly associated with CD, and 80 % of EC from the selected samples of CD patients analyzed carried the fimH30 allele, with a mutation strongly associated with AIEC. ...
Click to expand...

Quite interesting that the AIEC was undetectable in the healthy control group while MAP was present in 38% of that same control group. Like MAP on its own is not the culprit, and suggests AIEC may play a much more important role in CD than MAP.

I'm so glad the Qu trials are happening right now too and that they'll be releasing some data in the next three months or so. It may help shed some needed light on this disease and raise hope that we can one day soon be able to control this disease much more effectively.
 
xeridea said:
Quite interesting that the AIEC was undetectable in the healthy control group while MAP was present in 38% of that same control group. Like MAP on its own is not the culprit, and suggests AIEC may play a much more important role in CD than MAP.
Click to expand...

MAP causes dysregulation of the immune system which then leads to nasty infections such as AIEC - see this infographic for a simple explanation:

http://crohnsmapvaccine.com/map/

If it can be proven that Crohn's patients have AIEC infection without MAP, then that would be significant.
 
SauceySciencey said:
It's a careful balance...the editors and workers for these places need the cash, most already have full time jobs in research...it's either increase the fees that scientists have to pay to publish their work so they can hire someone full time to take some of the load, versus charging a prescription fee for the same purpose.
Click to expand...

The internet has changed fundamentally, how information is distributed, why is that not happening with scientific? Web based publishing allows you scale massively without needing to employ large numbers of paid staff or incur proportionate costs. I would seriously question why there continues to be a need to employee many of these people and would be interested to know exactly what they are doing!?

SauceySciencey said:
A way around this for access though, and it may not work these days as you usually have to log on to a computer at universities, is to simply walk into one and access them via the computer. Any university with a standard science/medical faculty will have access to pubmed central etc. Alternatively, be very nice to anyone in research. Most would be on your side and download 'em for you to a usb.
Click to expand...

This must surely be illegal, otherwise all papers would be downloaded and redistributed. Was this not exactly what Aaron Swatz may have been intending to do? He certainly felt the full force of the US authorities when this hugely lucrative business was threatened...
 
JMC said:
The internet has changed fundamentally, how information is distributed, why is that not happening with scientific? Web based publishing allows you scale massively without needing to employ large numbers of paid staff or incur proportionate costs. I would seriously question why there continues to be a need to employee many of these people and would be interested to know exactly what they are doing!?



This must surely be illegal, otherwise all papers would be downloaded and redistributed. Was this not exactly what Aaron Swatz may have been intending to do? He certainly felt the full force of the US authorities when this hugely lucrative business was threatened...
Click to expand...


https://www.plos.org/publications/publication-fees/

That's what they're doing.

Also, plos is a good example. 100,000 articles, almost. And growing. That's pdfs. Plus other formats. I believe the last paper my group submitted was almost 18 Mb. And that was a small paper with few images. Maintaining, backing up, keeping access open on the internet. Costs pile up.

Whose going to format and put these papers in publishable format? The editor? The editors of most journals are not paid. Maybe expenses if they have to fly somewhere for a meeting, etc, otherwise zilch. They spend most days, including weekends reading papers, assessing their worth for further review, coordinating with peer reviewers, authors. And that's on top of a job that anyone who knows anything about research knows it is not a 9-5 job, and one that's usually on the line every 3-5 years dependent upon funding. So they hire desktop publishers, graphic designers. Peer reviewers are rarely, if ever, paid either. Although I have heard of some reimbursement, such as with the Lancet, overall it's rare.
 
LeafCrAzY said:
Hey JMC,

I've seen you mention that MAP is in milk and such, but have you looked into other things its in.

http://www.telegraph.co.uk/news/sci...-bathroom-showers-trigger-Crohns-disease.html

In this article it suggests MAP is in our water supply.
Click to expand...

That article refers to a paper published in 2014, Prof John Hermon-Taylor was one of the authors (see here and here). One of the significant open questions is how people are getting infected with MAP and whether it is through consuming dairy produce or another route.
 
I think the significance of this paper will become clear in the coming months, as the results from the MAP Test are published.

On deaf ears, Mycobacterium avium paratuberculosis in pathogenesis Crohn's and other diseases.

http://www.ncbi.nlm.nih.gov/pubmed/26730151

The historic suggestion that Mycobacterium avium subsp. paratuberculosis (Map) might be a zoonotic pathogen was based on the apparent similarity of lesions in the intestine of patients with Crohn's disease (CD) with those present in cattle infected with Map, the etiological agent of Johne's disease. Reluctance to fully explore this possibility has been attributed to the difficulty in demonstrating the presence of Map in tissues from patients with CD. Advances in technology have resolved this problem and revealed the presence of Map in a significant proportion of patients with CD and other diseases. The seminal finding from recent investigations, however, is the detection of Map in healthy individuals with no clinical signs of disease. The latter observation indicates all humans are susceptible to infection with Map and lends support to the thesis that Map is zoonotic, with a latent stage of infection similar to tuberculosis, where infection leads to the development of an immune response that controls but does not eliminate the pathogen. This clarifies one of the reasons why it has been so difficult to document that Map is zoonotic and associated with the pathogenesis of CD and other diseases. As discussed in the present review, a better understanding of the immune response to Map is needed to determine how infection is usually kept under immune control during the latent stage of infection and elucidate the triggering events that lead to disease progression in the natural host and pathogenesis of CD and immune related diseases in humans.
 
JMC - Fully agree. I saw this a couple days ago and was incredibly frustrated that I couldn't read the full article! The naysayers seem to think that the presence of MAP in controls works against it being classified as zoonotic/pathogenic, but I think it's just the opposite - that the human MAP variant is finding a way to live in the majority of the population which corresponds to the rise in CD and other immune mediated conditions. MAP in controls is a very scary prospect to me. Because of the latent nature of onset of these conditions post initial infection, it will probably be too late to prevent the spread of MAP by the time long term studies are completed. It may be too late now.
 
irishgal said:
JMC - Fully agree. I saw this a couple days ago and was incredibly frustrated that I couldn't read the full article! The naysayers seem to think that the presence of MAP in controls works against it being classified as zoonotic/pathogenic, but I think it's just the opposite - that the human MAP variant is finding a way to live in the majority of the population which corresponds to the rise in CD and other immune mediated conditions. MAP in controls is a very scary prospect to me. Because of the latent nature of onset of these conditions post initial infection, it will probably be too late to prevent the spread of MAP by the time long term studies are completed. It may be too late now.
Click to expand...

When I first started looking at MAP test results, and everyone was testing positive, I was initially alarmed, but it makes sense.

Ask yourself this, though, If MAP is the cause of many immune mediated diseases, what are the other factors that determine whether you get Crohn's, psoriasis, diabetes, RA, etc? Why don't we get all of them at once?

Is it another bacteria, a virus, a specific genetic defect in your immune system? I don't think anyone can answer that question at the moment (and I have asked the right people).

If I was a betting man, there certainly seems to be some evidence that MAP + AIEC = Crohn's...
 
Actually it is the same with any disease. Not everyone exposed to TB, Influenza, yellow fever.... develop the disease. An old term in medicine, although some might consider it obsolete, is idiosyncrasy and is still in use. There are various theories regarding the abnormal susceptibility of developing a disease (NOD2/CARD15 for example). What leads to the polymorphisms is the actual debate.

JMC said:
...

Ask yourself this, though, If MAP is the cause of many immune mediated diseases, what are the other factors that determine whether you get Crohn's, psoriasis, diabetes, RA, etc? Why don't we get all of them at once?

Is it another bacteria, a virus, a specific genetic defect in your immune system? I don't think anyone can answer that question at the moment (and I have asked the right people).

If I was a betting man, there certainly seems to be some evidence that MAP + AIEC = Crohn's...
Click to expand...
 
I think the formula might look something like this:

MAP+AIEC may=Crohns.

MAP+AIEC+H-Pylori may=Crohns.

MAP+AIEC+H-Pyori+Mycoplasma may=Crohns

Mycoplasma may=Crohns.

H-Pylori may=Crohns.

Possibly other variations unknown.

It depends on if, where, and how much of each is present to get to the stage where it is diagnosed.

I think it is likely that MAP & AIEC is present in most cases of Crohns, but it can be further aggregated by the others.

Just my take on it.

Dan
 
This week's announcement by Enterome that it's entered into agreements with two major players in the CD treatment space (J&J and Takeda for Remidcade and Entivyo, respectively) suggests there's some rising interest in AIEC.

Enterome is developing both diagnostic and treatments for AIEC.

Here's a a video on their hypothesis on how AIEC may contribute to CD. It really starts getting into it at around the 1 minute mark.

https://www.youtube.com/watch?v=aTeZZ7ydmfM
 
Colicins, but finding the right probiotic seems somewhat difficult.
Nissle 1917 might have been one, but that is taken off the market by the FDA.
Old Mike
http://www.ncbi.nlm.nih.gov/pubmed/26177305

here is something a little off the wall ecoli is rescued from colicin by B12,
the receptor sites are the same.
http://www.sciencedirect.com/science/article/pii/037810979490104X

http://www.ncbi.nlm.nih.gov/pubmed/4579869

anyone get worse on B12 taken orally

western diet, GPR43 agonists are short chain fatty acids
http://www.ncbi.nlm.nih.gov/pubmed/26742586
 
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Thanks xmdmom!! You're awesome!! Looking forward to reading this tonight. I want to see their proof and theories on healthy controls to see if it's what I expect or if there's something more. Really appreciate this!
 
irishgal said:
Thanks xmdmom!! You're awesome!! Looking forward to reading this tonight. I want to see their proof and theories on healthy controls to see if it's what I expect or if there's something more. Really appreciate this!
Click to expand...

Sorry, I thought I had posted the direct link to the full paper already as it is a Free PMC paper. I also exchanged a few emails with William Davis and he emailed me a few more papers, just pm me if you want to read them and I will forward to you.
 
Let me run this by everyone.

One reason MAP and AIEC can survive inside macrophages is that
either by immune subversion or some genetic defect, the phagasomes are not acidified enough. and low NO production possibly nos2 (macrophage inducible NO) and possibly arginine transport,or some form of alternate activation
which lowers NO.



https://books.google.com/books?id=6...page&q=phasome acidification arginine&f=false

http://www.jleukbio.org/content/49/4/380.short

NO resistant strains
http://iai.asm.org/content/61/5/1980.short

extra NO might make things worse as usual conflicting info
http://www.jimmunol.org/content/162/11/6734.short

NO and human TB
http://immunenetwork.org/DOIx.php?id=10.4110/in.2009.9.2.46

I have UC and when I take arginine I get worse, too much iNOS, a way to
lower inos in the colon is lots of dietary nitrate,which goes into the entero salivary nitrite NO pathway, and curcumin.

Now a question might be would arginine supplementation help with crohns by increasing intracellular macrophage killing of AIEC and MAP.

Start researching phagasome acidification, nos2,intracellular killing.

Has anyone tried arginine for crohn's,.

So in a nutshell high nos2 activity for crohns, low inos activity for UC.
High dietary arginine for crohns, high dietary nitrate for UC.

Old Mike
 
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Not sure, mf15. I know that arginine consumption can bring HSV-1 out of latency, so for anyone that has HSV-1 it might be best to avoid it.

That said, arginine can be purchased in bulk cheaply, so if you don't have HSV-1, or are willing to risk an outbreak, it's probably worth a shot.
 
Crohn’s Disease: A Case for MAP Targeted Therapy

https://www.ecronicon.com/ecmi/pdf/ECMI-01-000S1.pdf

Crohn’s disease (CD) is a severe intestinal inflammatory disease, for which currently no full cure is possible, and of which the pathogenesis is still not fully elucidated. Intestinal bacteria are thought to play a role in the onset, combined with environmental factors, immune factors, and genetic susceptibility of the host. However, we do not fully understand the nature of the disease yet, and as a consequence, this lack in our knowledge may prevent us from developing effective and curative therapies. If we are able to revisit our views on involvement of Mycobacterium avium ssp. paratuberculosis (MAP) a as an important player in this disease, this might open up new options for therapeutic targets
 
The Association of Mycobacterium avium subsp. paratuberculosis with Inflammatory Bowel Disease

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148731

The association of Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) with Crohn’s disease is a controversial issue. M. paratuberculosis is detected by amplifying the IS900 gene, as microbial culture is unreliable from humans. We determined the presence of M. paratuberculosis in patients with Crohn’s disease (CD) (n = 22), ulcerative colitis (UC) (n = 20), aphthous ulcers (n = 21) and controls (n = 42) using PCR assays validated on bovine tissue. Culture from human tissue was also performed. M. paratuberculosis prevalence in the CD and UC groups was compared to the prevalence in age and sex matched non-inflammatory bowel disease controls. Patients and controls were determined to be M. paratuberculosis positive if all three PCR assays were positive. A significant association was found between M. paratuberculosis and Crohn’s disease (p = 0.02) that was not related to age, gender, place of birth, smoking or alcohol intake. No significant association was detected between M. paratuberculosis and UC or aphthous ulcers; however, one M. paratuberculosis isolate was successfully cultured from a patient with UC. We report the resistance of this isolate to ethambutol, rifampin, clofazamine and streptomycin. Interestingly this isolate could not only survive but could grow slowly at 5°C. We demonstrate a significant association between M. paratuberculosis and CD using multiple pre-validated PCR assays and that M. paratuberculosis can be isolated from patients with UC.
 
JMC: Interesting paper,now perhaps raises more questions.
Only finding 29% MAP in the N=22 CD people.
What worse they raise the question of when is the MAP acquired, since they found
no MAP in the intestinal aphthous ulcer people.
They also found MAP in a few UC people.
I guess the GI community have looked at AIEC and intestinal aphthous ulcers.
We also know that crohn's people are dysbiotic from the start,dysbiosis can
be from inflammation, due to increased ROS/oxygen tension selecting more
facultative anaerobes,diet might also cause some dysbiosis.
If AIEC become virulent due say to a dietary component, will they
cause a general dysbiosis.
Also makes me wonder when do AIEC acquire virulence, and are they
causing the ulcers to form.
Old Mike

If I am reading this right it looks like AIEC and a few others might be there.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112894/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325296/
 
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mf15 said:
JMC: Interesting paper,now perhaps raises more questions.
Only finding 29% MAP in the N=22 CD people.
Click to expand...

Yes, it is interesting that they found a high correlation between CD and MAP and yet the actual incidence was very low in this case, certainly much lower than other studies.
 
Also interesting that the one isolate they discuss had an amazing ability to adapt, and was resistant to all but clarithromycin.
 
Also of interest is the strain that likes to grow at 5 degrees C, that might
suggest a strain that has adapted to refrigeration.

But the real point of interest from the paper is that MAP may be a an after the fact bystander. I wonder if the MAP positive people had worse symptoms, or they were difficult to control with meds.

Old Mike
 
mf15 said:
JMC: Interesting paper,now perhaps raises more questions.
Only finding 29% MAP in the N=22 CD people.
Click to expand...

One of the reasons for this is the stringent criteria they used demanding that all 3 PCR assays were positive. If on the other hand, your measure is that any of the tests were positive, then the result is 13/22 or about 59%.
 
mf15 said:
But the real point of interest from the paper is that MAP may be a an after the fact bystander.
Click to expand...

Having read the paper very carefully, I don't think that is the point they are making.

I think you are referring to this statement:
Although it has been suggested that aphthous ulcers of the GI tract are precursors of CD, we found no evidence of M. paratuberculosis infection in any of our patients with aphthous ulcers. If aphthous ulcers are indeed a precursor of CD our results raise the question as to when M. paratuberculosis infection may occur. One possible scenario is that M. paratuberculosis may colonise only once inflammation has been initiated.

If aphthous ulcers have no relevance to the onset of Crohn's then there is no evidence that MAP infection comes before or after inflammation.

If aphthous ulcers are a precursor to Crohn's disease, the lack of MAP infection at this stage shows that it must come later, maybe absorbed through ulcers in the mouth from drinking milk. What is absent, is someone with aphthous ulcers who then develops Crohn's but is negative for MAP infection. Given the lack of firm evidence either way, I don't think you can draw any conclusions.
 
All good points JMC, I will just leave it there until myself or someone else, comes up with more info on these pre crohn's ulcers.
Read the links I posted on these ulcers above may provide more insight.
I also suspect that this might be somewhat difficult to determine, since you don't know your sick until after the fact, but they do know about the ulcers prior to onset, so some info is out there.
Never the less this study might raise a lot of questions, in many doc's minds
as to whether MAP is causal.
Something more on AIEC
http://www.medscape.com/viewarticle/549397_4

one point from this paper
Moreover, we observed that in any given patient, healthy and ulcerated mucosa were colonized by E. coli strains having the same ribotype profile, which indicates that colonization is independent of the inflammatory state of the mucosa.

here is one more,perhaps they are righ,t or perhaps not concerning iron,
perhaps it is dietary iron that sets off the virulence, prior to inflammation, then the iron from the inflammation makes things much worse.

https://lifesciencesweek.missouri.edu/?post_type=abstract&p=389

Old Mike
 
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Another consideration - maybe their MAP detection techniques are faulty. Or possibly they're looking for MAP when it's really some other mycobacteria that's the culprit. Seems like the rate of positive samples in CDmpatients is quite low compared to other studies, as JMC noted. I'd be interested to see what the detection rates were if the samples were given to John Aitken. He seems to be able to grow these things quicker and more accurately than others.
 
Irish:
Sure anything is possible with this type of work.
I have been a big believer the MAP connection, for years.
For me this study, invokes a somewhat different research path,
as to what is going on with crohn's and the pre crohn's ulcers.

this might be a clue
http://jn.nutrition.org/content/131/5/1452.full

One problem is the doc's don't even know for sure what causes mouth ulcers.

The last time I tried to quit smoking about 2 years ago, was basically cold turkey. Well I got about 10 mouth ulcers that were so deep and painful, I had to carry around a bottle of benzocaine so I could eat or talk. After a month, could not stand it any longer, started smoking again, ulcers gone in about 2 days. Anyhow the next time I try to quit, will be with a long taper, and load up with Zinc. I had found a study,which indicates this procedure to prevent mouth ulcers when quitting smoking.

Old Mike
 
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