# Research into MAP as the cause of Crohn's



## JMC

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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## rollinstone

Awesome thread idea


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## Mattie

Thanks for doing this JMC. Very useful.


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## JMC

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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## JMC

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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## rollinstone

Let us know if you get ahold of it plz!


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## JMC

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]._


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## JMC

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.


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## JMC

*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._


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## JMC

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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## ConnectheDots

This is great news. 

So it's either MAP or AIEC


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## rollinstone

ConnectheDots said:


> This is great news.
> 
> So it's either MAP or AIEC


Probably both, just like pneumonia has multiple culprits that can cause it.


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## wildbill_52280

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._


F-e-c-a-l   T-r-a-n-s-p-l-a-n-t, restoring colonization resistance!!!


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## wellen1981

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)


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## mf15

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/article/pii/S1201971214014349


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## sir.clausin

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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## JMC

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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## sir.clausin

Not found, here is the correct link 
http://www.veterinaryresearch.org/content/45/1/112/abstract


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## JMC

I fixed my link too, it was definitely working when I first posted it


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## mf15

Here is an old 1991 paper.
Old Mike
http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC2399081&blobtype=pdf


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## JMC

*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._


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## JMC

*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


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## rollinstone

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.


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## Malgrave

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


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## JMC

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._


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## AJC - Australia

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


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## JMC

happy poo poo said:


> 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.


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## AJC - Australia

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


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## 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._


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## JMC

*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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## JMC

*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.*_


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## xeridea

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.


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## JMC

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.


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.


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## mf15

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


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## irishgal

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.


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## mf15

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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## xeridea

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


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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## irishgal

This is exactly what the docs who have helped me say! They just put up a core research pack on their symposium website which has the best studies illustrating this. It's a great resource to bring to your doc!

http://thecrohnsinfection.org/core-research-pack/


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## JMC

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.


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


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## JMC

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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## xeridea

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.


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.


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## JMC

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._


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## JMC

*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._


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## JMC

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._


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## irishgal

JMC - love the Potential Public Health Impact article. I found the entire thing as linked below and am planning on reading it when I have a few minutes. It clearly shows that most people familiar with MAP think it's a problem and that the govts should contain it.

http://www.researchgate.net/publica...is_Global_Opinion_Survey_of_Topic_Specialists


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## AJC - Australia

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?


----------



## irishgal

happy poo poo - you can get tested now via John Aitken's lab in New Zealand if you'd like. I went this route almost a year ago and was quite pleased. Contact him via his web site:
http://www.otakaropathways.co.nz/contact


----------



## irishgal

Dr. Chamberlin's Immunikas and EpiBro talk is up! Dr. Amy and the MAP vaccine are next.

http://thecrohnsinfection.org/symposium-information/


----------



## Mommabear

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.


----------



## JMC

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.


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.


----------



## Mommabear

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.


----------



## kim006rn

Has anyone heard of hematomas on vocal chords as a part of Crohn's


----------



## JMC

*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._


----------



## JMC

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.

_


----------



## JMC

*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._


----------



## JMC

More on Hruska:

https://books.google.co.uk/books?id...ywC6#v=onepage&q=The Hruska postulate&f=false


----------



## JMC

*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. _


----------



## JMC

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._


----------



## sir.clausin

thanks, this is what I need to show my doctor who wants to put me under the knife.

Thanks


----------



## irishgal

New post by John Aitken: Victory
http://thecrohnsinfection.org/presenter-blog/

Sorry if you're seeing this multiple times. Just wanted to post on a few threads so everyone would have access.


----------



## ganesha

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.


----------



## JMC

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.


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!


----------



## ganesha

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!


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.


----------



## wildbill_52280

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!


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.


----------



## ganesha

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.


Thanks. I know, but I'll stick to my opinion - sharing builds knowledge.


----------



## JMC

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.


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...


----------



## irishgal

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.


----------



## JMC

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.


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


----------



## SauceySciencey

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...


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.


----------



## irishgal

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!


----------



## xeridea

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. ...


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.


----------



## JMC

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.


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.


----------



## JMC

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.


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.


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...


----------



## SauceySciencey

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...



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

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.


----------



## JMC

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.


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.


----------



## JMC

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._


----------



## irishgal

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.


----------



## JMC

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.


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...


----------



## ganesha

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...


----------



## D Bergy

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


----------



## xeridea

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


----------



## AJC - Australia

great video - that bird knows her stuff.


----------



## mf15

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


----------



## xmdmom

Posting the link to the full article for irishgal
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4690169/


----------



## irishgal

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!


----------



## JMC

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!


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.


----------



## mf15

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


----------



## ppk

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.


----------



## JMC

*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_


----------



## JMC

*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._


----------



## mf15

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/


----------



## JMC

mf15 said:


> JMC: Interesting paper,now perhaps raises more questions.
> Only finding 29% MAP in the N=22 CD people.


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.


----------



## irishgal

Also interesting that the one isolate they discuss had an amazing ability to adapt, and was resistant to all but clarithromycin.


----------



## mf15

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


----------



## JMC

mf15 said:


> JMC: Interesting paper,now perhaps raises more questions.
> Only finding 29% MAP in the N=22 CD people.


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%.


----------



## JMC

mf15 said:


> But the real point of interest from the paper is that MAP may be a an after the fact bystander.


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.


----------



## mf15

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


----------



## irishgal

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.


----------



## mf15

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


----------



## Zim

It's rather semi official, but still..

Comment from one of the prof. John Hermon-Taylor's team member on the statement "MAP found in ~95% of Crohn's sufferers":

"_The 95% is old data. Currently we are finding MAP (in varying degrees) in 100% of those tested, but need to complete the research before making that claim._" (Original here)

Everything I can say on this is simply "WOW!". One hundred percent. No more, no less.


----------



## medicaljohndoe

I see that there's a lot of excitement here about the vaccine in progress, but if I'm not mistaken there are other options that are currently available, reportedly effective in some patients, and cheap. I'm on a trial of Dapsone right now, a few days in. I'll let everyone know how it goes.


----------



## Zim

medicaljohndoe, your updates would be appreciated.

About "cheap/expensive" issue - I think in fact it's not an issue for anyone of us, undoubtedly any sum will be sacrificed for the proven cure. This excitement is rather about overall progress with research of causativity of MAP, simply vaccine team with their cheap and simple MAP test came closest to the final solution.


----------



## JMC

Zim said:


> Everything I can say on this is simply "WOW!". One hundred percent. No more, no less.


Yes, but caution is needed.  I have been tested twice by Prof John Hermon-Taylor, both times positive for MAP.  Although the test design is very good and John is very confident of the results, it still needs to be properly validated to confirm that what it is detecting is MAP and not another similar but harmless bacteria.  

This is why fund raising for the MAP Test is still on-going as is the research work.  So, I would advise people to wait for the patent to be granted and the paper to be published in a refereed journal before cracking open the champagne, which hopefully should be some time this year.


----------



## my little penguin

Agree with JMC 
95-100% of what sample size and what exclusion criteria etc
Any data needs validation especially new testing .
Good luck


----------



## irishgal

Oxidative stress due to Mycobacterium avium subspecies paratuberculosis (MAP) infection upregulates selenium-dependent GPx activity

http://gutpathogens.biomedcentral.com/articles/10.1186/s13099-016-0090-8

Conclusion
This study demonstrated a strong correlation between MAP and the elevation of GPx activity. This was especially evident in Crohn’s patients, which further supports the association of MAP and Crohn’s disease. GPx activity may also be used to predict MAP infection status and to show that Crohn’s disease patients who are infected with MAP have higher tendency to develop oxidative stress than Crohn’s disease patients who are negative for the bacteria.


----------



## medicaljohndoe

I've been on Dapsone now for three weeks. I started at 100mg/day but had to stop after a week due to side effects, namely clear signs of hemolytic anemia. After a few days to let my bone marrow regenerate red blood cells, I started again at 50mg/day. At the lower dose, I've had almost no notable side effects. (I weigh about 150lbs for reference--I know I'm going to have GI problems when my weight goes above 152lbs.) When I started at the lower dose, I also added a multivitamin supplement (Centrum), a 400mcg folic acid supplement, and 4000IU Vitamin D-3.

My GI symptoms have not been perfect--there have been two or three days when I have felt bloated, and I had one episode that reminded me of what things were like before my diagnosis. However, on average I'd say that I generally feel far better. On most of the days I've felt completely normal, with no GI symptoms at all. The one episode that took place also seemed less severe than previous ones. I have also noticed that I have gotten more work done in the past few days than I probably got done in the past three months, simply because I have more energy and can focus more.

My skin symptoms are not gone, but they have also improved. The most important point is that the constant itching that used to plague me is basically gone (a known effect of Dapsone), and the flaking is not nearly as bad as before. The inflammation has largely, but not completely, subsided in the few psoriatic lesions that I have. My skin is still pink, but not angry red like it was before.

In the last few months many of my facial hairs and hair along my temples have turned gray--not totally impossible since I'm 32--and most have remained that way, but one has started growing back in black. I saw this in a few other hairs previously after starting to take the multivitamin more regularly. I suspect it's related to the folic acid supplement, though I now also wonder if perhaps I should be taking additional amounts of B-12.

Overall I would suggest inquiring about Dapsone (and folic acid or other Vitamin B supplementation) as possible treatment options, especially for those with skin manifestations of IBD.


----------



## my little penguin

Medicaljohndoe what skin manifestations do you have ???


----------



## medicaljohndoe

Psoriasis, and various minor non-flaking non-itching rashes which have thankfully disappeared.


----------



## my little penguin

Thanks
Ds is currently being checked for sweets syndrome and one of the drugs is dapsone 
Still waiting on biopsy results


----------



## kickingcrohns

JMC said:


> Yes, but caution is needed.  I have been tested twice by Prof John Hermon-Taylor, both times positive for MAP.  Although the test design is very good and John is very confident of the results, it still needs to be properly validated to confirm that what it is detecting is MAP and not another similar but harmless bacteria.
> 
> This is why fund raising for the MAP Test is still on-going as is the research work.  So, I would advise people to wait for the patent to be granted and the paper to be published in a refereed journal before cracking open the champagne, which hopefully should be some time this year.


I really hope you are right about it being this year. Thank you for the updates


----------



## Malgrave

Not directly CD related and 14 years old paper, but still extremely interesting:

"This report suggests a pathogenic role of MAP for immunocompromised patients, raising the question of whether this strain so far has not been detected because of its limited growth, whether it has been misidentified as M. avium, or whether its occurrence in infections is low. However, herd prevalence of bovine paratuberculosis has been reported to range from 7% to 55% in Europe and to reach approximately 40% in stocks of >300 animals in the United States (4). Thus, consumption of inadequately pasteurized dairy products may be a possible risk for infection, especially for immunocompromised patients."

http://wwwnc.cdc.gov/eid/article/8/7/01-0388_article


----------



## eleanor_rigby

Does anyone know what the time frame is for drugs to be approved for prescription following phase 3 clinical trials? I am interested to know for the ongoing MAP antibiotic trial going on around the world. If the results are good when can we get prescribed this drug?


----------



## xeridea

eleanor_rigby said:


> Does anyone know what the time frame is for drugs to be approved for prescription following phase 3 clinical trials? I am interested to know for the ongoing MAP antibiotic trial going on around the world. If the results are good when can we get prescribed this drug?


My guess, 2018/2019.

Here I'm speaking about the FDA process, and not the European. 

Typically the Phase III stage takes 3 years to complete, and if the drug is safe and effective, then another 2 years for it to go through new drug application stage for final approval. This process may be sped up if the company had received fast-track designation at the time of their application.

As far as I can tell, the RedHill RHB-104 trials still have a ways to go. They recently finished enrolling half of the patients and once those complete 26 weeks of therapy, the company will release preliminary results, expected in second half of this year. They're probably continuing to recruit the second half of their patients and then those will need to complete their 26 week course. At the current rate that'll probably wrap up mid-2017. Then the NDA and hopefully approval. 

RedHill is probably pretty motivated to get the drug to market; by all indications, they'll only have patent cover until 2029.


----------



## JMC

xeridea said:


> and if the drug is safe and effective, then another 2 years for it to go through new drug application stage for final approval.


Stop and think for one minute, what are they actually _doing _for _2 whole years_ to get final approval?  The sluggishness of these processes drives me crazy!  I bet you could do it in a couple of days with proper focus!


----------



## xeridea

JMC said:


> Stop and think for one minute, what are they actually _doing _for _2 whole years_ to get final approval?  The sluggishness of these processes drives me crazy!  I bet you could do it in a couple of days with proper focus!


This FDA article gives a pretty good run-down. In the application, they're looking at pre-clinical (animal studies), phase I-III data, safety and effectiveness results, inspecting manufacturing facilities, etc. I have read other places they may be reviewing as much as 100,000 pages of supporting documents. It's a laborious process. 

I'm not rationalizing the long approval times, but can understand why, as they are generally responsible for public health, including veterinary medicine, our food supply, tobacco, cosmetics, etc. Out of their $4.7B budget, about $1.3B is allocated toward human drugs, with another $300M to biologics. 

And, it's a bureaucracy.


----------



## Mattie

So, Xeridea, Prof JHT's vaccine which is due to start phase 1 trials this year, and phase 2 next year, will probably not be available, if all goes well, until 2020 at the earliest by this reckoning?


----------



## Clash

Maybe longer depending on a number of factors on both sides of the coin.


----------



## xeridea

Mattie said:


> So, Xeridea, Prof JHT's vaccine which is due to start phase 1 trials this year, and phase 2 next year, will probably not be available, if all goes well, until 2020 at the earliest by this reckoning?


I don't know Mattie, and will defer to someone more closely tied to the CMV effort to respond.


----------



## Zim

xeridea said:


> I don't know Mattie, and will defer to someone more closely tied to the CMV effort to respond.


According to the *"crohn's MAP vaccine" website* access to the vaccine should be granted to the most severely ill patients in the *end of 2017*:

"_As soon as there is evidence of safety and efficacy, we can apply for use of the vaccine on compassionate grounds; this will enable people who wish to have the vaccine but are unable to be part of the trial to access it on a named-patient basis outside of the trial. 

Indeed, under the newly proposed ‘Early Access to Medicines’ scheme in the UK, severely ill patients who have failed existing treatments may be granted access to new medicines that are proven to be safe, even before efficacy has been fully established. 

This means that the earliest the vaccine could be made available to patients on a named-patient basis would be *late 2017*._"​
So, in advance: happy new year 2018! =)


----------



## Mattie

Thanks. From what I understand about 'named patient basis' programmes, the patient has to be seriously ill and have exhausted all other available forms of treatment. An application to be considered under the named patient programme will most probably have to be made by the doctor and not the patient? Am I correct here? If so, can anyone hazard a guess as to the earliest date 
the vaccine, provided it proves to be the answer we are all looking for, could be made available to those who don't fall into the above category?


----------



## Zim

Mattie said:


> can anyone hazard a guess as to the earliest date
> the vaccine, provided it proves to be the answer we are all looking for, could be made available to those who don't fall into the above category?


From the *same source*:

_In addition, following the demonstration of safety and efficacy, it is anticipated that the Vaccine technology would be licenced to a pharmaceutical company to make it available to all who need it through health services worldwide -as part of this, larger Phase 3 trials inviting wider participation would be expected._​
I understand it as such: vaccine (or placebo of course, 50/50..) will be available to anyone who is willing to participate and is eligible for phase 3 trial. If phase 2 finishes by the end of 2017, we could be optimistic enough to expect phase 3 to start in the beginning of 2018.

That's why i said "happy new year 2018!" =)

Not sure, but common sense says that for ethical reasons those who got in placebo group still should be vaccinated, but later, after demonstration of the  undoubtful fail of placebo for this certain patient.


----------



## Mattie

Thanks a lot Zim. Very useful.


----------



## irishgal

New post at The Crohn's Infection by Dr. Robert Click, of Dietzia fame. Dietzia seems to be a probiotic combating the effects of MAP in cattle, and may have human applicability. An intro summarizing the published research and giving some background can be found here:

http://thecrohnsinfection.org/whats-new/

Would be so amazing if this worked! Very excited to see if there will be trials starting in the future.


----------



## Scared1

irishgal said:


> New post at The Crohn's Infection by Dr. Robert Click, of Dietzia fame. Dietzia seems to be a probiotic combating the effects of MAP in cattle, and may have human applicability. An intro summarizing the published research and giving some background can be found here:
> 
> http://thecrohnsinfection.org/whats-new/
> 
> Would be so amazing if this worked! Very excited to see if there will be trials starting in the future.


Thanks Irishgal!


----------



## Scared1

http://www.healio.com/gastroenterol...-rather-than-ulcerative-colitis-crohns-binary

Thought this was interesting - one statement said that ileal and colonic crohns are as distinct as crohns is from uc based on these three genes...so do all crohn's sufferers have at least one of these genes?


----------



## Scared1

https://m.youtube.com/watch?v=7x3lq8QEg5g

This is perfect


----------



## JMC

It's interesting that this approach is effective against "16 MAP clinical strains and 19 other mycobacteria"

*RHB-104 triple antibiotics combination in culture is bactericidal and should be effective for treatment of Crohn’s disease associated with Mycobacterium paratuberculosis
*

_http://gutpathogens.biomedcentral.com/articles/10.1186/s13099-016-0115-3

Mycobacterium avium subspecies paratuberculosis (MAP) has been implicated as an etiological agent of Crohn’s disease (CD), a debilitating chronic inflammatory bowel disease. Clarithromycin (CLA), clofazimine (CLO), rifabutin (RIF) and other antibiotics have been used individually or in combinations with other drugs to treat mycobacterial diseases including CD. The treatment has varied by regimen, dosage, and duration, resulting in conflicting outcomes and additional suffering to the patients. RHB-104, a drug formula with active ingredients composed of (63.3 %) CLA, (6.7 %) CLO, and (30 %) RIF, has been recently subjected to investigation in an FDA approved Phase III clinical trial to treat patients with moderate to severe CD. In this study, we determined the efficacy of RHB-104 active ingredients against MAP strains isolated from the blood, tissue, and milk of CD patients. Based on fluorescence quenching technology using the Bactec MGIT Para-TB medium, we determined the minimum inhibitory concentration (MIC) of CLA, CLO, RIF individually and in dual and triple combinations against 16 MAP clinical strains and 19 other mycobacteria._


----------



## Scared1

JMC said:


> It's interesting that this approach is effective against "16 MAP clinical strains and 19 other mycobacteria"
> 
> *RHB-104 triple antibiotics combination in culture is bactericidal and should be effective for treatment of Crohn’s disease associated with Mycobacterium paratuberculosis
> *
> 
> _http://gutpathogens.biomedcentral.com/articles/10.1186/s13099-016-0115-3
> 
> Mycobacterium avium subspecies paratuberculosis (MAP) has been implicated as an etiological agent of Crohn’s disease (CD), a debilitating chronic inflammatory bowel disease. Clarithromycin (CLA), clofazimine (CLO), rifabutin (RIF) and other antibiotics have been used individually or in combinations with other drugs to treat mycobacterial diseases including CD. The treatment has varied by regimen, dosage, and duration, resulting in conflicting outcomes and additional suffering to the patients. RHB-104, a drug formula with active ingredients composed of (63.3 %) CLA, (6.7 %) CLO, and (30 %) RIF, has been recently subjected to investigation in an FDA approved Phase III clinical trial to treat patients with moderate to severe CD. In this study, we determined the efficacy of RHB-104 active ingredients against MAP strains isolated from the blood, tissue, and milk of CD patients. Based on fluorescence quenching technology using the Bactec MGIT Para-TB medium, we determined the minimum inhibitory concentration (MIC) of CLA, CLO, RIF individually and in dual and triple combinations against 16 MAP clinical strains and 19 other mycobacteria._


Hi JMC - that is very interesting. The link won't work for me though, I think it may be my computer....any update on the vaccine status timeline? I keep checking and it is not updated. I am so anxious to know that at least some of the trials have begun!

I am also following the Qu SSI - I think the combination of the two can be a powerful way to clear out this infection in the body....


----------



## irishgal

I also found this article very interesting in that they tried each antibiotic alone and each of the combinations of just two together, and found that the Mean Inhibitory Concentration was the lowest when the three were used together. They have a synergistic effect together. I guess the refrain of "we're all stronger together" applies not only to us, but to our antibiotics as well!


----------



## Scared1

Finally got it to open! This is very interesting - the Redhill trial is still going on until November, correct? Based on the info I see at ClinicalTrials.gov. But if this is any indication - this would be great. The only thing I am concerned about is that the results of the Redhill can be skewed - I mean, I am hoping they enroll those that are positive for MAP, kinda of like SSI Qu biologics - they have to have positive AIEC cultures to be enrolled based on the website criteria (or maybe I am mistaken)? Whatever the case, I am so anxious to see the results of this!


----------



## JMC

Scared1 said:


> I keep checking and it is not updated. I am so anxious to know that at least some of the trials have begun!


I don't know when this will be completed, I have asked, but not received a reply.  Please contact Amy or John Hermon-Taylor directly so they know you are interested.


----------



## Kaevata

Thanks for all this information.

It has made me cast my mind back to Ireland 1976 living on my father-in-laws farm for a year and drinking unpasteurized milk.

The old man got TB from the cattle and I suffered the worst bout of food poisoning ever while I was living there and I was never quite right after that.
We returned to the UK and in 1984 I was diagnosed with IBS then finally Crohn's.

Have to wonder if that milk had MAP in it but I did have three maternal aunts with Crohn's, all who drank unpasteurized farm milk in the 1930s onward.

:shifty-t:


----------



## irishgal

Yikes Kaevata! Sorry you have CD. Sounds like your family has history of Crohn's so there may be some genetic susceptibility there. My entire family is littered with autoimmune diseases as well, so I think I probably have the mutations they look for in CD. Plus to compound things in your case, unpasteurized milk was probably doing you no favors. From what you say, sound like something in that milk triggered your disease. I was triggered by a bad stomach flu, and I've heard of others who can pinpoint the time when their disease began to a solid event. It would make sense with the MAP theory of CD at least.

I've also heard speculation that IBS may really just be pre-Crohn's, so it's interesting that you had IBS which escalated into CD. Hope your disease is under control now!


----------



## Scared1

http://crohnsmapvaccine.com/vaccine/#

Looks like they updated the MAP vaccine timeline with more detail than before - this is great!


----------



## Scared1

Scared1 said:


> http://crohnsmapvaccine.com/vaccine/#
> 
> Looks like they updated the MAP vaccine timeline with more detail than before - this is great!


But I just noticed that the human trial piece got pushed out until 2018!:-(


----------



## JMC

Scared1 said:


> But I just noticed that the human trial piece got pushed out until 2018!:-(


I think the more interesting date(s) are when the trial(s) will actually start.  I would be very happy to see the phase I trial start this year.  Once it begins, the end date will become clearer.  Phase IIa is also currently _*unfunded*_, but I would not say that is a big concern right now.


----------



## Scared1

JMC said:


> I think the more interesting date(s) are when the trial(s) will actually start.  I would be very happy to see the phase I trial start this year.  Once it begins, the end date will become clearer.  Phase IIa is also currently _*unfunded*_, but I would not say that is a big concern right now.


Yes, I agree. I just want at least some data presented -maybe then everyone will get on the bandwagon funding wise. For Qu Biologics, it took them a while to get the word out but one you have some data to show that it works, I think that will be a huge step forward!


----------



## eleanor_rigby

delete


----------



## Scared1

Redhill update! http://www.reuters.com/article/idUSFWN19E01X

And a new interesting article about Johne's and Crohn's:
http://www.independent.ie/business/...ntial-timebomb-for-dairy-sector-34817140.html


----------



## Scared1

http://www.bionapcfa.com/2016/07/redhills-phase-3-crohns-drug-is.html

Very nice article - but it seems the redhill antibiotic would be around $1500 a month if it does work (and fingers crossed it will


----------



## irishgal

This isn't from RedHill, though it's interesting. I think this is a guy who evaluates pharma companies, so he's just speculating on the cost and what the market could bear.


----------



## Scared1

irishgal said:


> This isn't from RedHill, though it's interesting. I think this is a guy who evaluates pharma companies, so he's just speculating on the cost and what the market could bear.


Yes, I saw that it is from an analyst discussing the valuation of Redhill.  But made me wonder - cost-wise what it would be, and if it turns out well - which I really am certain it will - if insurance will cover it. Same with the MAP vaccine...either way, I am soo looking forward to the results!


----------



## irishgal

Scared - guessing it will be priced based on other non-generic Crohn's meds, but it will be interesting to see if the price may be lower since the active ingredients in this pill are available in generics. Certainly, this pill has big advantages in combining them (from a previous study about how they're synergistic) and clofaz isn't really available in the US, but people are basically using these three drugs now, just seperately. I wonder if that will lower the cost some? The RedHill pill may also have some secret non-active ingredient that does something critical, either for absoprtion, buffering, etc which is why it may work better than the generics. Plus, the dosage is highly adaptable in the RedHill pill (since the daily dose is 10 pills) so it could be tapered to the individual based on body weight. A huge advantage if it gets approved for pediatric cases.Much harder to do that with the generics since some only come in standard dosages.

Also, if the FDA approves it for CD, I'm guessing that most likely insurance will cover it. I think it's the off label stuff that's harder to get covered, but once it's approved, the insurance usually covers all of the other standard CD treatments. Why not this one too?

Not sure about the Vaccine. If it goes through the US FDA application process as an approved CD treatment, then probably that would be covered too. I think the government approval is key for insurance coverage.


----------



## Scared1

http://www.enterome.fr/site/eb8018-ibd210/

I think this is so interesting- not regarding MAP but AEIC and the drug they are doing almost mirrors the logic behind the MAP vaccine initiative I think...very exciting though


----------



## Scared1

Here is their pipeline summary:

http://www.enterome.fr/site/#pipeline


----------



## irishgal

Very interesting Scared. Plus, it's another venture that Nestle is involved in. Takeda and Johnson & Johnson are partners as well. The microbiome research is drawing some big names. It will be interesting to see how this AIEC theory works in CD.


----------



## eleanor_rigby

Scared1 said:


> http://www.enterome.fr/site/eb8018-ibd210/
> 
> I think this is so interesting- not regarding MAP but AEIC and the drug they are doing almost mirrors the logic behind the MAP vaccine initiative I think...very exciting though


When does this hit trials?


----------



## Scared1

Just saw this publication but can't seem to find the actual paper! 

Increased Milk Consumption but Decreased Risk of Crohn's Disease (CD): Critical Evidence Negated Causative Role of Mycobacterium avium Subspecies paratuberculosis (MAP) in CD


----------



## Scared1

eleanor_rigby said:


> When does this hit trials?


Hi Eleanor, I am not sure - but I do think based on the video's I have watched - 3-4 yearish...


----------



## Zim

Scared1 said:


> Just saw this publication but can't seem to find the actual paper!
> 
> Increased Milk Consumption but Decreased Risk of Crohn's Disease (CD):  Critical Evidence Negated Causative Role of Mycobacterium avium  Subspecies paratuberculosis (MAP) in CD


Does "Critical Evidence Negated Causative Role" sound like scientifically neutral humble statement? I wouldn't say so. 

Why wouldn't Qin Xiaofa (the only author of this unpublished paper without abstract) add something like "magnificent, brilliant, glorious, stunning critical evidence completely, totally, entirely, wholly negated causative role" to the title?..


----------



## Scared1

Zim said:


> Does "Critical Evidence Negated Causative Role" sound like scientifically neutral humble statement? I wouldn't say so.
> 
> Why wouldn't Qin Xiaofa (the only author of the publication) add something like "magnificent, brilliant, glorious, stunning critical evidence completely, totally, entirely, totally, wholly negated causative role" to the title?..


Sounded really weird to me to be honest...that is why I was curious and wanted to read it since it just came out like a few days ago and I haven't read anything recent on MAP. Yet, it is no where to be found...except if you pay which I wont do.

And you are right, the certainty in the title based on correlation between Milk consumption (only) is odd.


----------



## JMC

Zim said:


> Does "Critical Evidence Negated Causative Role" sound like scientifically neutral humble statement? I wouldn't say so.
> 
> Why wouldn't Qin Xiaofa (the only author of this unpublished paper without abstract) add something like "magnificent, brilliant, glorious, stunning critical evidence completely, totally, entirely, wholly negated causative role" to the title?..


Maybe Qin Xiaofa would like to explain this paper in more detail


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## Scipio

Zim said:


> Does "Critical Evidence Negated Causative Role" sound like scientifically neutral humble statement? I wouldn't say so.
> 
> Why wouldn't Qin Xiaofa (the only author of this unpublished paper without abstract) add something like "magnificent, brilliant, glorious, stunning critical evidence completely, totally, entirely, wholly negated causative role" to the title?..


I presume he wouldn't say that because he's trying to sound scientific.  Scientific findings are usually reported in understated, cautious language.  Use of over-the-top superlatives and exaggerations is the language of quacks and charlatans.


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## Scipio

The fact that the Qin piece has only one author and no abstract makes me wonder whether it is an opinion piece or editorial, or maybe a review, rather than report of new data.


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## Scared1

Scipio said:


> The fact that the Qin piece has only one author and no abstract makes me wonder whether it is an opinion piece or editorial, or maybe a review, rather than report of new data.


That's what I was wondering, but there is no way to know. And if it is an opinion piece, it would still be a strange way to state the title almost with certainty without data to validate. I would be interested in reading it though.


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## irishgal

I've heard this basic argument before, which is "If MAP is in milk, why do those who drink more milk have less CD?" I think there's an old study about that, but the basic answer is that MAP won't do a thing to you unless you have the genetic predisposition to not allow your immune system to recognize intracellular infections and also a triggering event, like stress, a loss of someone close, Vit D deficiency, the flu, antibiotic use, some other environmental exposure that no one knows about yet. So a great study would be to only look at patients with IBS or those with the genetic predisposition for CD, randomize a huge group of them, then make half consume dairy and the other half stay away from it completly - for like 10 years. And then see which group develops higher incidence of CD. So you can see it's completely impractical. Milk isn't the only issue going on with CD. There are a whole chain of issues, and the increased MAP in milk due to more herds being infected (and especially infant formula) may result in a higher level of MAP exposure at a younger age, therefore precipitating higher CD rates in those genetically susceptible. Dr. Collins talked about this at the symposium. And it's just a theory right now.

I was trying to get this paper any way possible, but it's published in e-print ahead of the Sept. 22nd journal publication. Also, it looks like this journal is the publication of the CCFA, so it may be a bit biased, since they seem to dislike the MAP theory of CD. If I can get it, I'll let you know! Reserving judgment until I read it.


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## Scipio

The quote below is taken from Dr. Qin's LinkedIn page and spells out his theory of the cause of IBD.  Presumably he views MAP as a competing theory.


_" Engaged in medical research in the academic for more than twenty years. More than a decade ago, a series of accidental findings made him suspect that impaired inactivation of digestive proteases due to the reduction in gut bacteria along with improved hygiene and inhibition by some dietary chemicals may have played important causative role in inflammatory bowel disease (IBD, including ulcerative colitis and Crohn's disease), which emerged and dramatically increased in last century. During the last decade he published a series of papers and proposed that damage of gut by the poorly inactivated digestive proteases may be the root cause of IBD. Not only IBD, more and more studies revealed many other diseases that are dramatically increasing in modern society, such as irritable bowel syndrome (IBS), multiple sclerosis, type I and type II diabetes, asthma, atopic eczema/ dermatitis, obesity, autism, etc, all accompanied by increased gut permeability, suggesting damage of gut barrier would have also contributed to the development of these diseases. He recently started a company, GI Biopharma Inc, with the goal to develop new treatments for these diseases."_


----------



## Clash

The author you guys are discussing often posts here. He posts most often in this thread

http://www.crohnsforum.com/showthread.php
?t=36726

At least I think it's the same guy. He's posted some interesting theories and discusses them with other member quite often!


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## Scipio

Dr. Qin himself has provided a link to a review paper of his theories over on the other thread.


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## Scared1

New article:

J Crohns Colitis. 2016 Aug 23. pii: jjw148. [Epub ahead of print]
Inflammatory bowel disease incidence is on the continuous rise among all pediatric patients except for the very young - a nationwide registry-based study on 28-year follow-up.
Virta LJ1, Saarinen MM2, Kolho KL3.
Author information
Abstract
BACKGROUND AND AIMS:
The burden of inflammatory bowel disease (IBD) in health care is high. We conducted research on the temporal changes in the incidence of pediatric IBD (PIBD) using nationwide registry-based data in Finland.
METHODS:
All PIBD cases diagnosed at less than 20 years of age during 1987-2014 (in total, 5,415 patients) were retrieved from a database documenting reimbursements for drug costs. Incidence rates were calculated by dividing the number of annual new PIBD cases by the size of the pediatric population at risk during each calendar year. Temporal trends in the incidences of PIBD and its subtypes, ulcerative colitis (UC) and Crohn's disease (CD), were estimated using Poisson regression analyses.
RESULTS:
The mean annual incidence of PIBD increased from 7/100,000 for the years 1987-1990 to 23/100,000 for the years 2011-2014. The average rate of increase was 4.1% (95% CI: 3.6-4.5) per annum. In the period 2000-2014, the increase rate in the annual incidence of UC (3.8%; 95% CI: 2.7-5.0), was steeper than for CD (2.5%; 95% CI: 1.0-3.8). The most pronounced increase occurred in UC among adolescents aged 16-19 years: 4.8% (95% CI: 2.9-6.7). For children less than 10 years of age, the rate of change remained low. Approximately 0.17% of the birth cohort for the years 1999-2000 was diagnosed with PIBD by the age of 14 years.
CONCLUSION:
The incidence of PIBD is primarily increasing among adolescents, challenging the identification of the possible environmental triggers for the disease.


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## Scared1

Very interesting article:
Dig Liver Dis. 2016 Aug 5. pii: S1590-8658(16)30546-1. doi: 10.1016/j.dld.2016.07.036. [Epub ahead of print]
Occupational risk for Crohn's disease: A two-center study.
Liu S1, Ding J1, Wang M1, Wang G2, Wu X2, Feng M1, Song P1, Ren J3, Guan W4.
Author information
Abstract
BACKGROUND:
Occupational factors have been suggested as possible elements in the etiology of Crohn's disease, although evidences have not been fully obtained.
AIMS:
This study is to investigate possible associations between occupation and development of Crohn's disease.
METHODS:
This prospective study was carried out in two major hospitals during January 2010 and December 2014. Demographic and clinical data were collected for the calculation of standard incidence ratios and 95% confidence intervals by occupation.
RESULTS:
A total of 401 patients with Crohn's disease were recruited into this study. Participants were distributed into 8 major occupational groups, among which "professionists" (17.7%), "service and sales" (18.7%) and "unclassified individuals" (mainly students) (20.2%) took up the most proportions. Increased standard incidence ratios were found in "service and sales" (2.526±0.135, 95% CI: 1.939-3.290), "professionists" (4.216±0.142, 95% CI: 3.194-5.565), and most significantly, in "administrative staffs" (5.476±0.170, 95% CI: 3.926-7.639). In contrast, decreased standard incidence ratios for Crohn's disease were observed in the category of "workers in agriculture, forestry, animal husbandry, fishery and water conservancy" (0.088±0.146, 95% CIs: 0.066-0.117).
CONCLUSION:
Occupational elements are implicated in the likelihood of development of Crohn's disease.


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## irishgal

Scared - I wonder if more active professions have less incidence than more sedentary desk jobs because exercise has been shown to help CD? Also thinking that the stress factor of office life may play a role too. The poor admins! Will have to read the whole thing.


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## Scared1

irishgal said:


> Scared - I wonder if more active professions have less incidence than more sedentary desk jobs because exercise has been shown to help CD? Also thinking that the stress factor of office life may play a role too. The poor admins! Will have to read the whole thing.


That could be a contributing factor - who knows, maybe these active professions may have the incidence but it is under control and they are not diagnosed? but its interesting they all have to do with exposure of some kind to "nature" and consequently, could be related to healthier microbiome? I am not sure...it is really interesting all this research though, but I have yet to see one that talks about how there are different types of crohn's in the sense - MAP associated, AEIC associated...etc...


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## Zim

Something noticeably wrong just happened to US portion of Red Hill's RHB-104 study.. 

You can track progress of the study (as well as history of changes) here: 
https://clinicaltrials.gov/ct2/show/NCT01951326 

And on July 17th main parameters of the study were silently updated. Wikipedia-style history of changes for that day: 
https://clinicaltrials.gov/archive/NCT01951326/2016_07_17/changes

So, two things changed:

1. Estimated Primary Completion Date was changed from 2016-07 to *2017-09*
2. Estimated Study Completion Date was changed from 2016-11 to *2018-09*

Also, as you can see, if earlier they were good with just 4 months between primary and final study completion dates, now they need whole year.

Honestly, I just don't know what to say..

*P.S.:*
On July 25th "2018-09" for Study Completion Date was changed to "2018-04" (https://clinicaltrials.gov/archive/NCT01951326/2016_07_25/changes), so current situation is:

Estimated Study Completion Date: 	April 2018
Estimated Primary Completion Date: 	September 2017


----------



## Scared1

Zim said:


> Something noticeably wrong just happened to US portion of Red Hill's RHB-104 study..
> 
> You can track progress of the study (as well as history of changes) here:
> https://clinicaltrials.gov/ct2/show/NCT01951326
> 
> And on July 17th main parameters of the study were silently updated. Wikipedia-style history of changes for that day:
> https://clinicaltrials.gov/archive/NCT01951326/2016_07_17/changes
> 
> So, two things changed:
> 
> 1. Estimated Primary Completion Date was changed from 2016-07 to *2017-09*
> 2. Estimated Study Completion Date was changed from 2016-11 to *2018-09*
> 
> Also, as you can see, if earlier they were good with just 4 months between primary and final study completion dates, now they need whole year.
> 
> Honestly, I just don't know what to say..
> 
> *P.S.:*
> On July 25th "2018-09" for Study Completion Date was changed to "2018-04" (https://clinicaltrials.gov/archive/NCT01951326/2016_07_25/changes), so current situation is:
> 
> Estimated Study Completion Date: 	April 2018
> Estimated Primary Completion Date: 	September 2017


I remember seeing that too...just like the map vaccine delay...but its either they saw negative results and want to dig in more to see why it didnt have the effect (they said they wanted to learn more about the patient population), or they had great results (but why would they not want to publish as soon as possible), so I am worried that this might be not a pro map sotuation I don't think that would really hurt the map crohns link. But, if there wasn't a link, how could they discount the obvious benefit it gave come people? I mean, its not a massive placebo that has worked on so many...I just wish some validation would come about already. I really believe that if it were the cauae (and I do believe it is for many), that a study like this could get more buy in and more people involved in finding a permanent solution to this mystery.


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## xeridea

It may be they aren't able to recruit enough patients. I think in June they had met only 75% of their recruitment goal for this study (200 out of 270). The study has 26 weeks of treatment, plus evaluation of duration/maintenance of remission at 52 weeks. I don't know how all this plays into the delays, but it's one explanation.


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## irishgal

Here's from their Aug. 11th Semi annual research report. Looks like they want to get full enrollment, and they are considering some type of US protocol change. But the key thing is that RedHill apparently still remains blinded, so they can't be increasing the timelines because it either works/doesn't work, which I see as good news. I'd rather them take their time and get it right than rush and have another unreliable study, but yes, it's SOOO hard to wait! Especially when GIs will be more likely to prescribe AMAT once results are released. I was hoping for that in Nov. 2016, but I guess it will be Sept. 2017. 

RHB-104 - Crohn’s disease (Phase III) and multiple sclerosis (Phase IIa) 

Crohn’s disease - first Phase III study ongoing

Approximately 200 subjects out of the planned total of 270 have been enrolled to date in the randomized, double-blind, placebo-controlled first Phase III study with RHB-104 for Crohn’s disease (the MAP US study).


Interim data and safety monitoring board (DSMB) analysis is on track to take place in the fourth quarter of 2016 and RedHill remains blinded to the interim and ongoing results.


RedHill is currently reviewing a possible amendment to the Phase III MAP US study protocol intended to further enhance the overall robustness of the study, provide a more precise assessment of RHB-104’s treatment effect, collect additional endoscopic mucosal healing data, further evaluate the Crohn’s disease population enrolled and address retention and early terminations. No changes are planned to the primary endpoint of remission at week 26 or the study’s 90% power. Taking into account a potential protocol amendment, completion of recruitment is expected in 2017 with no anticipated material impact on the Company’s overall cash burn rate through the end of 2017. The Company expects to provide further details in the coming weeks, once plans are finalized.


----------



## Mommabear

Does anyone here know if doctors in the US risk having their license revoked by treating Crohn's with AMAT? After watching Under Our Skin, about Lyme disease and what happened to some doctors who went against protocol, I was wondering if there is the same risk.

Thank you.


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## irishgal

So far I haven't heard of any, though I imagine it's a concern to many. I haven't watched the piece on Lyme's, but there's some really decent research and small study data which could justify treatment of CD with AMAT, so that would be in their favor. Also, patients who don't have traditional treatment options left may be more able to get AMAT due to that. I volunteered to my doc that I'd be happy to sign an informed consent and liability waiver, since it would protect her a slight bit more. She only saw it as a formality, since she thiught the research was valid and due to that wasn't worried about the liability. I think the argument could be made that the RedHill trial (being in stage 3 with promising previous stage data) would insulate docs who decide to follow that protocol. At the end of the day though, it's not an approved treatment pathway, and without the large double blinded study, I think docs are more worried about success and risk to the patient vs. the liability issue to themselves. At this point, they just aren't convinced it works.

(Of course, if RedHill turns out successful, starting a tidal wave of funding on research into this theory which eventually conclusivelyproves CD to be zoonotic, there's going to be liability assessed then too. Who knew what, when did they know, why wasn't research funded, etc. But that's a whole different issue!)


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## xeridea

In this retrospective study, the researchers are theorizing that TB induces an auto-immune reaction to trick the immune system into attacking the lungs which in turn helps its transmission: "...autoimmunity is a critical process exacerbating pathology in TB, leading to cavitation and transmission." 

They support their theory by listing diverse autoimmune phenomena that occur in a portion of TB cases. For example, autoantibodies associated
with diseases such as Wegener's granulomatosis and systemic lupus erythematosus is detected in 40% of TB patients. They also point to cases of uveitis and erythema nodosum, which also occurs in some TB cases. Their strongest argument is that TB and Sarcoidosis, an autoimmune disease with no proof of an infectious etiology,  are virtually indistinguishable.

Even though this is a theory they've got, given TB and MAP are cousins, this may have some interesting implications for MAP research, at least from a layperson's perspective.


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## Ihatefistulas

Hi,

I was looking at the trial "Efficacy and Safety of Anti-MAP Therapy in Adult Crohn's Disease (MAPUS)" for RHB-104 and noted one of the exclusions was 

Presence of active fistulizing Crohn's Disease or healed fistula within 2 months prior to screening.

As someone who is aware of the theory of MAP being associated with causing Crohn's, but not well read, and someone with fistulas, I was wondering if anyone knew why they would exclude these patients from the trial? Mainly I am thinking for the future (if this treatment was proved effective is there something about having a fistula that prevents anti-MAP therapy as an option)?

Not sure if it's something that anyone is going to have an answer for, but I figured it's probably not something I am going to find in a frequently asked questions somewhere regarding the trial.

Cheers,

Cameron


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## Mommabear

Cameron,

My son could not participate for the same reason, and I inquired as to why because AMAT is effective for healing fistulas. The only reason why they exclude fistulas is that having them is considered a separate disease, called Fistulizing Crohn's! Trials are very strict with their criteria and researchers cannot deviate at all from them otherwise they will not get approval. It is very frustrating but unfortunately it is how the process works. 

I have faith that it will win approval though...at least I hope so, and at that time you should be able to get on the treatment.


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## Ihatefistulas

Mommabear said:


> Cameron,
> 
> My son could not participate for the same reason, and I inquired as to why because AMAT is effective for healing fistulas. The only reason why they exclude fistulas is that having them is considered a separate disease, called Fistulizing Crohn's! Trials are very strict with their criteria and researchers cannot deviate at all from them otherwise they will not get approval. It is very frustrating but unfortunately it is how the process works.
> 
> I have faith that it will win approval though...at least I hope so, and at that time you should be able to get on the treatment.


Exactly the information I was looking for, thank you.  :thumright:


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## eleanor_rigby

https://news.wsu.edu/2016/11/04/wsu-researcher-finds-possible-link-cattle-human-diseases/

These have made a MAP vaccine in cattle


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## Crohn2357

Thanks, it's interesting, but it doesn't say they've made a vaccine, it says:


> Davis’ theory linking Crohn’s disease to MAP infections in humans, has driven him to devote a significant part of his career to the development of a vaccine to remove MAP from cattle, and thus from the food supply and the environment.
> Regardless of whether or not MAP is causative, “We’re making significant progress on a vaccine,” explained Davis.  A cattle vaccine provides the greatest promise for controlling Johne’s disease and benefitting cattle, regardless of the uncertainty surrounding the associations to human Crohn’s disease.


Edit: On second thought, semantically, it's not wrong to infer that they have made a vaccine. My bad. I can't delete this post so I'm editing it instead.


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## JMC

eleanor_rigby said:


> https://news.wsu.edu/2016/11/04/wsu-researcher-finds-possible-link-cattle-human-diseases/
> 
> These have made a MAP vaccine in cattle


There are a number of research teams working on vaccines in cattle.  For example this one, which I have mentioned in the past.


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## Crohn2357

eleanor_rigby said:


> https://news.wsu.edu/2016/11/04/wsu-researcher-finds-possible-link-cattle-human-diseases/
> 
> These have made a MAP vaccine in cattle


From the case report article:



> Dr. Prabhat Agarwal took interest in the case and was willing to consider the patient’s illness could be associated with an extensive infection with MAP. Dr. T. J. Borody, who had reported success in treating patients with CD with antibiotics was contacted for advice and recommendation on how to treat the patient (7). Dr. Borody provided copies of recent publications and suggested what antibiotics should be considered for treatment. Based on his suggestions, a regimen of therapy was designed and implemented. The patient was informed that his clinical symptoms were most likely caused by a MAP infection and that a regimen of antibiotic therapy might provide a cure. After obtaining his written consent, he was placed on anti-MAP therapy under the supervision of Dr. Prabhat Agarwal. The antibiotic therapy included clarithromycin, rifampin, ethambutol, levofloxacin, isoniazid, and rifaximin along with mesalazine according to the schedule in Table 1.





> Results
> After 4 months of treatment, the patient exhibited improvement in his physical condition, reduction in stool frequency (two to three times a day from every half hour), and improvement in appetite. During the last months of treatment, the patient experienced continued improvement, with an increase in weight and further reduction in stool frequency (one to two times a day). Recovery from infection was complete following a year of treatment with no signs or symptoms of disease. The follow-up stool microscopy was negative for MAP (Figure 2B) and the follow-up post-treatment stool culture was negative for MAP. As mentioned, biotyping of colonies from cultures of stool showed the bacilli were the “Indian Bison type” of MAP (Figure 3). The ELISA was positive for MAP also, further confirmation that the patient had been infected with MAP (Table 2). The patient is now being monitored every 6 months for recurrence of infection and general health.





> This case provides additional evidence, supporting studies showing MAP is the causative agent in, at least, a subset of patients with CD (26) and that antibiotic therapy may lead to a cure of CD and clearance of infection with MAP. The results are consistent with findings from a group of MAP infected patients treated successfully by one of the coauthors, Dr. J. Todd Kuenstner, in the United States using a regimen of multi-antibiotic therapy combined with ultraviolet blood irradiation (UVBI) (27, 28). Of major importance, the results obtained in this report and the mass survey in India emphasize the need for recognition, at the international level, that MAP is a zoonotic pathogen and that it is a health risk for humans and livestock (29).


Concurrent Resolution of Chronic Diarrhea Likely Due to Crohn’s Disease and Infection with Mycobacterium avium paratuberculosis
http://journal.frontiersin.org/article/10.3389/fmed.2016.00049/full#B25


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## JMC

http://onlinelibrary.wiley.com/doi/10.1111/apt.13840/full

*Endoscopic and clinical responses to anti-tubercular therapy can differentiate intestinal tuberculosis from Crohn's disease*

In layman's terms, take a group of patients with identical symptoms who live in an area of the world where Tuberculosis is prevalent, but Crohn's is also present.  Treat them with anti-Tuberculosis antibiotics and observe their symptoms at regular intervals up to 12 months.  The outcome?  They roughly divide into three groups:
1) The group with Mycobacterium Tuberculosis infection who recover completely -> ITB
2) The group where their general symptoms improve but they are not cured and they do not achieve mucosal healing -> Crohn's probably caused by MAP 
3) The group who show no improvement or their symptoms get worse -> Crohn's caused by ?

The important point though is this, what we call Crohn's has identical symptoms to another mycobacterial infection intestinal Tuberculosis, the only difference is the antibiotics used to treat TB do not kill it off.  Further, the group we label as Crohn's has two clear sub-groups based on how they respond to antibiotics, one of which I believe is a MAP infection.

http://onlinelibrary.wiley.com/enha...111/apt.13840#figure-viewer-apt13840-fig-0004


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## rollinstone

AIEC is probably the other culprit imo, lots of literature stacking up suggesting so, also seems to be a few therapies targeting AIEC in the works... hopefully between the map vaccine and qu biologic's ssi vaccine we can say goodbye to this horrible condition.


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## Scared1

New article: Concurrent Resolution of Chronic Diarrhea Likely Due to Crohn's Disease and Infection with Mycobacterium avium paratuberculosis.

https://www.ncbi.nlm.nih.gov/pubmed/27833911

Abstract
Examination of samples of stool from a 61-year-old male patient, presenting with the clinical symptoms of Crohn's disease (CD), revealed massive shedding of acid fast bacilli with the morphology of Mycobacterium avium paratuberculosis (MAP), the causative agent of Johne's disease in cattle. MAP was cultured from the stool. Biotyping of the bacterium isolated from cultures of stool demonstrated, it was the Indian Bison biotype of MAP, the dominant biotype infecting livestock and humans in India. Based on this finding and because the patient was unresponsive to standard therapy used in India to treat patients with gastrointestinal inflammatory disorders, the patient was placed on a regimen of multi-antibiotic therapy, currently used to treat tuberculosis and CD. After 1 year of treatment, the patient's health was restored, concurrent with cessation of shedding of MAP in his stool. This patient is the first case shown to shed MAP from the stool who was cured of infection with antibiotics and who was concurrently cured of clinical signs of CD.
KEYWORDS:
Crohn’s disease; ELISA; IS900 PCR and IS1311 PCR_RE; Mycobacterium avium paratuberculosis; antibiotic therapy; stool culture and microscopy for MAP


----------



## Scared1

rollinstone said:


> AIEC is probably the other culprit imo, lots of literature stacking up suggesting so, also seems to be a few therapies targeting AIEC in the works... hopefully between the map vaccine and qu biologic's ssi vaccine we can say goodbye to this horrible condition.


Amen to that.


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## irishgal

Prof. Thomas Borody's latest research from October 2016. He did a small study of AMAT in 8 treatment naive patients. All went into remission between 4-21 weeks. Also, the patients experienced deep mucosal healing. Full ACG poster link and his intro below:

http://thecrohnsinfection.org/prof-thomas-borody-amat-success-in-treatment-naive-patients/


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## eleanor_rigby

This is interesting regarding bacteria: http://www.cbc.ca/beta/news/canada/ottawa/cheo-crohns-gut-bacteria-study-1.3864650


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## Scared1

Fingers crossed!

"RedHill's late-stage study of RHB-104 in Crohn's to continue as planned
Dec. 13, 2016 9:21 AM ET|By: Douglas W. House, SA News Editor 
Following a pre-planned review, the independent Data and Safety Monitoring Board (DSMB) unanimously recommends that RedHill Biopharma's (NASDAQ:RDHL) Phase 3 clinical trial, MAP US, assessing combination antibiotic RHB-104 for the treatment of Crohn's disease continue as planned without modification. Two additional independent DSMB reviews will take place after 50% and 75% of subjects have completed 26 weeks in the study. The next review should happen in Q2 2017.
According to ClinicalTrials.gov, the estimated final data collection date for the primary endpoint, remission at week 26, is September 2017. The estimated study completion date is April 2018."


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## eleanor_rigby

Redhill results expected early:

https://www.healio.com/gastroenterology/inflammatory-bowel-disease/news/online/%7B6a9df261-0e7c-41b3-ab92-6983200e1adc%7D/crohns-map-antibiotic-trial-results-expected-early


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## Crohn2357

MAP and RA - Study


----------

