# MAP: A Possible explanation of how Crohn's develop



## Deleted member 431298 (Jun 4, 2017)

I thought I would share a link to this concise explanation of how a bacteria could be the cause of at least some cases of Crohn's. 

http://www.crohnsmapvaccine.com/treatment/map/

If this is true, we have a case of 'history repeating' with reference to peptic ulcers. Its cause was unknown for a long time, and many suffered from symptoms, surgery and ineffective drugs. Once it was discovered that a bacteria caused the ulcers and which antibiotics cured it, the prognosis improved considerably.

Let us hope that some day either the British vaccine gets approved, or we get an effective antibiotics regimen against this nasty bug!

In the meantime, as a precautionary measure I have completely stopped consuming anything where the word 'milk', 'cream' or 'butter' is found on the label. Also processed foods/meat if it is a possibility the protein/fat in it comes from dairy cow meat.


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## Dawn101 (Jun 5, 2017)

Very interesting.  Totally believe our gut bacteria is the key and it is something we can change through diet.  Just recently been taken off all dairy, beef, sugar and wheat.  Has made a huge difference.


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## wildbill_52280 (Jun 5, 2017)

OleJ,

I'm pretty sure there at least a few threads already dedicated to this concept over the years. What will also interest you is that the good bacteria in the intestine, oppose th e growth bad bacteria we come in contact with, so if any of the good become extinct, this may invite pathogens to dominate chronically or permanently.

Studies in IBD show a lack of diversity among a certain good bacteria which regulate inflammation, and chronic inflammation creates molecules that pathogens can live on, this creates a state is dysbiosis where bacteria in the intestine is out of balance, this is another model of how IBD develops, at this point many different types of bad bacteria could easily live in our intestines. Fecal Microbiota transplants restore missing bacteria and seem to improve IBD some studies believed patients may be cured, see link below for more info.


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## Dawn101 (Jun 5, 2017)

Could it maybe explain how young kids develop the disease.
Babies flora would be linked to the mother's. Poor diet, or just eating foods that the body has a hard time digesting due to lack of enzymes or just feeding the bad bacteria.  Sorry just rambling.  I developed crohns in my late 30's (now 50), so I had lots of years of bad diet, stress etc.  Always wondered how kids could develop it so young.  And by no means I'm I blaming mothers.  The western diet to me is a big player in the cause of a lot of woes


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## Deleted member 431298 (Jun 7, 2017)

Wildbill and Dawn_101:
Thank you for your relevant comments. I looked around and did indeed find another highly interesting thread about MAP.
http://www.crohnsforum.com/showthread.php?t=59071

Last year I attended a lecture series by a microbiologist, and he echoed what you are saying. I remember he showed an illustration of the types / numbers of bacteria they found in healthy humans, vs. the types and numbers found in IBD patients. The latter group had reduced diversity, and different kinds. I guess the critic would argue that why can it not be that some autoimmune condition destroys the gut wall, disrupting the microflora.

I would not be able to dismiss such critique in a scientitic maner, but I do know that changes in diet has helped me and others tremendously, and that indicates the disease is not autoimmune, but is influenced, and maybe even triggered, by what we eat.

Wildbill: Thank you for the long thread on FMT expiriences. I will look into that.


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## Tuff (Jun 7, 2017)

From what I have read, Johne's in cattle is contagious. One sick new animal will infect the others. The calves can get it in utero or from the milk. Crohn's on the other hand is not considered contagious. How is that? Non-ruminants such as omnivores or carnivores (birds, raccoons, fox, mice, etc.) may become infected with MAP, but rarely do they become sick because of the infection.


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## Scipio (Jun 7, 2017)

wildbill_52280 said:


> Studies in IBD show a lack of diversity among a certain good bacteria which regulate inflammation, and chronic inflammation creates molecules that pathogens can live on, this creates a state is dysbiosis where bacteria in the intestine is out of balance, this is another model of how IBD develops, at this point many different types of bad bacteria could easily live in our intestines. Fecal Microbiota transplants restore missing bacteria and seem to improve IBD some studies believed patients may be cured, see link below for more info.


The altered state of the gut bacteria in TBD is pretty well established.  What is less will established is whether that altered state is a cause or an effect of the IBD.

Personally, I suspect that the gut bacteria play a big role in the pathogenesis of many cases of IBD, but I'm not a MAP True Believer.  That particular species of bacteria may indeed play a role in some cases, but it seems to me there are far too many instances of IBD where no sign of MAP infection can be found for it to be the one big answer to the IBD question.

Some of these cases still respond to the anti-MAP antibiotic therapy, but that could easily be due to either the anti-inflammatory properties of the antibiotics themselves, or the drug killing off other non-MAP bacteria species that were helping to drive the IBD, or a combination of both.

In any case I think the MAP thing is intriguing enough for the research to continue, but I'm not holding my breath with anticipation that MAP vaccines or anti-MAP drugs are going to magically wipe out IBD.   I think it will prove to be one more piece of a very complex and heterogeneous puzzle.


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## Crohn2357 (Jun 8, 2017)

Scipio said:


> or anti-MAP drugs


If only we had some inside information on the results so far in the rhb-104 trials.

I am living with a colostomy, and surgeons will resect my rectum in six months due to the increased cancer risk associated with the unused section of the large bowel. So, that'd mean a permanent stoma for me.


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## wildbill_52280 (Jun 10, 2017)

OleJ said:


> Wildbill and Dawn_101:
> . I guess the critic would argue that why can it not be that some autoimmune condition destroys the gut wall, disrupting the microflora.


That is definitely an important question to address. I will show you some studies soon that explored this possibility such as antibiotics exposure showing higher rates of IBD, 5 studies in fact showed a link. I also just recently found a study that specifically tested amoxicillin on the suspected class of bacteria which are commonly found less diverse in IBD and the bacteria are very sensitive to amoxicillin among other antibiotics.

But either way, as this theory is being tested some people have had dramatic turnarounds in IBD from FMT, and in other diseases like autism. The cases of possible cure have maintained no signs of disease ranging from 13 to 25 years post FMT. If you cant call that a cure, well its close enough in my book some scientists say its likely. Main issue now is performing a successful FMT more frequently as they identify and control the variables that affect FMT success or failure, such as pill form of FMT which is already available to researcher by openbiome. 

Some other issues are other microorganisms that also be involved like viruses, fungi or even bacteriophages although i think there is a wide agreement the bacteria play the largest role, there is a possible scenario where bacterial communities become disrupted say through antibiotics or something, certain other organism disappear too. If we only restore the bacteria in an FMT, it may not be a complete fix. I'm not sure how important that is though. Also when you replace a certain core species, it actually can allow you to acquire other species more easily by chance in your environment, but that is a bad way to ensure things are restored so if we only have a bacterial fecal transplant, that could still be very good.



> I would not be able to dismiss such critique in a scientitic maner, but I do know that changes in diet has helped me and others tremendously, and that indicates the disease is not autoimmune, but is influenced, and maybe even triggered, by what we eat.


The good bacteria eat fiber from plant foods to grow and function. So a low fiber diet is always a variable in the development of IBD and you are correct to believe so.


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## Deleted member 431298 (Jun 13, 2017)

_but it seems to me there are far too many instances of IBD where no sign of MAP infection can be found for it to be the one big answer to the IBD question._

It has been reported, though, that Crohn's patients have an odds ratio of 7-1 in favor of testing positive for MAP:

_Compared with individuals free of IBD, the pooled odds ratio (OR) from studies using PCR in tissue samples was 7.01 - Feller, M et.al, Lancet, 2007_

I know other studies have found lesser odds ratios, but in every study I have read on the topic the researchers have found MAP more frequently in IBD patients. Yet again association does not equal causation - so it would indeed be very intersting to know about the Redhill study (interim) findings.

I would also very much like a read through your references wildbill, do post if possible!


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## wildbill_52280 (Jun 13, 2017)

OleJ said:


> _but it seems to me there are far too many instances of IBD where no sign of MAP infection can be found for it to be the one big answer to the IBD question._
> 
> It has been reported, though, that Crohn's patients have an odds ratio of 7-1 in favor of testing positive for MAP:
> 
> ...


Nice to see you are being real methodical about your research, good job!

Here is my first piece of evidence for the case that certain antibiotics have the ability to suppress the growth and survival of the Commensal Clostridia bacteria which is frequently found to be less diverse in IBD. These bacteria have been shown to influence regulatory t cells, which regulate the inflammatory process. This is likely why Fecal transplant helps IBD and could be the cure but of course you'll need more evidence then just this, I'll post more soon. I took Amoxicillin Clavulanic acid for bronchitis before my health took a major dive, soon I developed IBD.

https://www.ncbi.nlm.nih.gov/core/l...e to zoom&p=PMC3&id=4153770_gmic-5-333-g1.jpg
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153770/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC356823/

more
https://www.ncbi.nlm.nih.gov/pubmed/11208510
http://www.practicalgastro.com/pdf/January09/PG_Jan09_DharmarajanArticle.pdf




 Here is a study that examined the Microbiome in IBD patients and found the disruptions existed despite being in remission, which would provide evidence that its not the inflammatory process itself that has disrupted the microbiome, and the missing bacteria could be the reason why the inflammation exists in the first place. 



> We do not have an explanation for this observation. It was also noted in our study that the changes were noted in both active and quiescent IBD, suggesting that the changes were not secondary to gut inflammation and ulceration and presence of pus and blood in the lumen.


https://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-13-20


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## Scipio (Jun 13, 2017)

OleJ said:


> It has been reported, though, that Crohn's patients have an odds ratio of 7-1 in favor of testing positive for MAP:
> 
> _Compared with individuals free of IBD, the pooled odds ratio (OR) from studies using PCR in tissue samples was 7.01 - Feller, M et.al, Lancet, 2007_
> 
> I know other studies have found lesser odds ratios, but in every study I have read on the topic the researchers have found MAP more frequently in IBD patients.


That's great.  A 7.01 OR is impressive, but even that elevated prevalence still represents only a minority of Crohn's patients.  In the papers I've seen, between ~67 to 75% of Crohn's patients show no signs of MAP infection at all, even when using the most sensitive DNA PCR techniques.

This is why I'm willing to believe MAP might be part of the story.  Maybe MAP is the Crohn's trigger in a subset of patients who have some particular susceptibility.  But it's very unlikely to be The One Big Answer to all the Crohn's causation questions.  

I think people just get too smitten with the Johne's disease animal model and pin all their hopes for human Crohn's on anti-MAP therapy or vaccines.  I think they are in for a big disappointment in the majority of Crohn's patients.  IMO MAP is more likely to be simply one more piece of a very complex puzzle.


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## irishgal (Jun 15, 2017)

Hi All - Lots of great discussion and information here! I'm involved with the Human Para Foundation as mentioned above, so will try to address some of the questions from my point of view. Full disclosure - I have a Bio degree and am not a doctor. I'm also a decades long Crohn's patient who was fully healed by AMAT, and I now also take LDN. I consider my case nothing short of a miracle, and I'm hesitant to apply it to all patients since I know antibiotics don't work for everyone.

That said, the question of MAP is that there are more questions than answers. Why aren't there higher rates of MAP found in CD patients if that is the trigger or cause? It could possibly be that the detection techniques are poor and there are a lot of false negatives. It has also been suggested that for some patients MAP acts solely as a trigger, where it kicks off a cascade of immune destruction, then goes away or goes dormant. A critical piece of the puzzle that some Penn State researchers are looking at is where MAP fits into the microbiome dysbiosis seen in CD patients. Does it appear before or after? Does it cause the dysbiotic imbalance, or does the dybsbiotic imbalance come first, allowing MAP to gain a foothold?

And then there's AMAT (atypical mycobacteria antibiotic therapy). For some CD patients like me it affords us a functional cure for a period of time, sometimes stretching years or decades with a few Dr. Borody patients. Other patients improve slower, and some doesn't improve at all or react terribly to the meds. I know that there are a lot of emerging strains of human MAP as tested by John Aitken and Dr. Tim Bull (I think they mentioned 34 now at the Philly conference.) The DNA runs that John Aitken presented on his cultures from CD patients showed a pretty decent variety. Some had the IS900 DNA sequence, some had F57, and oddly - some had NEITHER. 

In humans, MAP sheds it's cell wall and hudes inside the macrophages. We know that much from John Aitken's work. It's hard to get antibiotics there, since MAP is not replicating. So I'm not sure the current antibiotics available could even kill all of the human strains of MAP, which could explain why some people do very well, and some don't. We know that CD treatments have MAP effectiveness (thank to Dr. Bach, Dr. Greenstein and a few others) and we also know that these standard CD treatments cause resistance in MAP (John Aitken and other's work.) There was one intriguing study that I read where they isolated MAP from a UC patient and it was resistant to most of the antibiotics that are commonly used in AMAT. So if that patient would have tried AMAT, they likely would have failed to recover - not because they didn't have MAP, but because they had resistant MAP.

The RedHill study should release interim results this summer sometime, and that will tell us a lot. The trick with RedHill is that they MUST link MAP levels to improvement, otherwise the MAP question will remain open.

And then you have many other diseases like T1D and MS where it's clear that those patients have a significant increase in MAP antibodies over controls (thanks Dr. Sechi and Dr. Cossu!) and those patients also have defects in the MHC gene which predisposes them to autoimmunity - so the hypothesis is that MAP is acting as a trigger through a mimicry mechanism. But who knows? We need more research.

So if this has been around for 100 years or more, why aren't these questions put to rest? One huge factor is the terribly run Selby study, which was poorly designed, showed AMAT was effective, but the author messed with the data to find the opposite. So now every GI thinks the MAP issue is closed, despite a ton of peer reviews refuting that study. Also, until now, there hasn't been a reliable test or culture method for MAP. Once John Aitken publishes, we're good on that front and can begin working on more research with a superior test. Lastly, there's no incentive for the big pharma companies to fund MAP research. It's not as much a conspiracy, as it is a question of their bottom line. Why would they fund a study to show that antibiotics (or another immune modulator like SSI) is more effective than Remi or Humira? There's no money in it for them. RedHill was able to get a patent on their delivery system, so there is a potential source of revenue. Plus, I've met their team a bunch of times and they seem like great guys who have a heart for the patients, in addition to having a business motive. And then there's the issue of this bacteria being transmitted to humans by dairy. Good luck fighting the dairy and beef lobbies in the US.

That bring up another point - someone asked why isn't this transmitted human to human like in cattle. In cattle, the primary transmission is feces. Since we don't go wallowing around in each others feces like cows, and don't nurse our children with contaminated nipples, that wouldn't be the mode of transmission in humans (though it does pass through breast milk, which is a HUGE unresolved question.) Additionally, how MAP acts in humans is different in cows. It doesn't want to be in humans. It wants to be in cows which have a higher body temp. So it's doing everything it can to survive, which means dormancy and shedding the cell wall. There's one 2016 reported case in India of a man shedding bison strain, cell-wall INTACT MAP from his stool. That is incredibly rare. He was given antibiotics and was healed. Now - India is a hotbed of bacterial resistance. And MAP is trying desperately to form a cell wall in humans, and has amazing mutation capacity. What do you think will happen when MAP figures out how to thrive in humans in a country with as many people as India?

So Human Para is in a race to fund as much research and provide as much education before this potentially reaches crisis level. We need to fill those knowledge gaps. We need to know which antibiotics are the most effective against which strains, and we need a quick, solid test. We need to know how humans are contracting MAP, and which genetic defects predispose people to MAP infection. And why is MAP showing up in a host of different diseases? I firmly believe that the term "Crohn's disease" may be overbroad, and treatment may someday be targeted to the cause rather than the symptoms. Maybe MAP is at play in a subset of cases? In the end, we'll get there, and there's a lot of great researchers working away quietly in their labs to help all of the patients. 

Sorry this is so long! Feel free to comment or question things I didn't explain well. Most of the material on this can be found at HumanPara.org.


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## Deleted member 431298 (Jun 15, 2017)

Scipio - I agree we should be careful not to believe in the MAP hypothesis just because it sounds plausible. All too often we see flawed reasoning behind a hypothesis, yet that hypothesis gets elevated to a bad theory, and maybe even a wrong paradigm. All because of either a "miracle thinking" or maybe the opposite - fear of a conspiracy. 
The difficult part is differentiating the theories arising from "miracle thinking" from the ones which actually arise from sound, critical science. The research that currently happens regarding MAP and the microbiome seems to be much to serious to be hopeful. Namely, the researchers often reiterate that CD is indeed very complex and that MAP can not be the whole puzzle, which is also what Irishgal is saying.

And - Irishgal - thank you so much for the elaborate thread reply. It is just fantastic that you are making an effort to communicate the current research.  I have watched all of the references and videos, and find it a great resource in getting an idea about where MAP research is now. 

I hope you will stay in remission on the AMAT regimen. 
Out of curiosity: You list the "no gluten/dairy/sugar/coffee or processed food" diet as a failed treatment. Are you now eating a normal western diet? Have you tried a semi-vegetarian diet?


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## irishgal (Jun 15, 2017)

OleJ said:


> Out of curiosity: You list the "no gluten/dairy/sugar/coffee or processed food" diet as a failed treatment. Are you now eating a normal western diet? Have you tried a semi-vegetarian diet?


In my case, altering my diet actually did help with symptom relief - for a while, but then the CD always found a work around. I had a pretty severe, persistent case though, and ended up with a skin version too. Basically at that point, I think my immune system was just crashing and couldn't handle anything (I had weird scent issues too) and probably nothing short of wiping out the MAP with meds would do. I eat a pretty normal diet now, though probably not "Western." I figure why bother to stress my system and cause a relapse! I eat some gluten, no milk, very little dairy, very little processed foods and focus on fruits and veggies first. I used to be incredibly strict with my diet, since it was keeping me barely alive, but now I notice I can "cheat" and I don't feel sick. Soft dairy (ice cream, sour cream, cream cheese, etc) still gives me loose stools, and processed food like pizza and fast food make me feel horrible for days. I don't eat any of that. Generally, I considered the diet "failed" as to healing. It certainly didn't fail as a good diet, and I still maintain a lot of it now that I'm better. I eat mostly a semi-vegetarian diet now, having small portions of meat 3-4 times a week only at dinner. The SCD research is interesting to me too.

A little more info about my case and MAP: I had Otakara do a MAP test on me 2 weeks before starting AMAT and then another at 12 months in when I was healed (per blood work and colonoscopy markers.) My MAP levels went from "too numerous to count" to just a few dormant forms left sporadically. My doc didn't have anything left for me when I tried AMAT, so it was worth the gamble. I felt pretty good in 6 weeks, and had full mucosal healing by 12 months. I've gained 25 needed pounds, all my vitamin and mineral levels came back to normal, and I feel amazing. I never thought I would feel like this, so I do what I do because if there are others out there who have nothing left, it may be worth it for them too. To say this has been life changing is an understatement. Even if the MAP theory is only valid for a portion of patients like me, those are people who are transformed and everyone around them benefits. It certainly doesn't work for everyone, but for a portion it's miraculous. We need better diagnostics to find out who those "miracle responders" will be.

Such a complex disease, and we need SO much more research! But I've been very encouraged with what I've been seeing in the last few years. Even if MAP plays some role (which I believe it does) there are still a LOT of factors contributing to CD.


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## Scipio (Jun 15, 2017)

irishgal said:


> Lastly, there's no incentive for the big pharma companies to fund MAP research. It's not as much a conspiracy, as it is a question of their bottom line. Why would they fund a study to show that antibiotics (or another immune modulator like SSI) is more effective than Remi or Humira? There's no money in it for them.


If this were the way pharma companies actually behaved then then they never would have developed the drugs and protocols and paid for the clinical trials for curing peptic ulcers by treating _H. pylori_ infection.  They would have ignored or suppressed the _H. pylori_ story and stuck with the elaborate and less-effective, older therapies for ulcers rather than go for the cheap and easy antibiotic approach.  

In reality, if big pharma actually believed that MAP is the compelling answer to Crohn's, at least one and probably several of the big houses would be all over it - perfecting the combinations and doses of antibiotics to go wipe out the MAP and win fame and fortune for themselves.  Janssen, Takeda, AbbVie, and the other big IBD biologics firms are not the only game in town.  There are plenty of other big and mid-sized pharma companies who would love to disrupt their competitors by wiping out and replacing their IBD/biologics business with a cheap and effective antibiotic regimen - companies such as Eli Lilly, for example, that are late to the anti-TNF game and do not currently have a lot of IBD biologic revenue that would be put at risk by an anti-MAP breakthrough.

_"Big Phama (and/or the FDA) is suppressing my miracle cure"_ has long been the plaintive cry of the little guy - the True Believer who has a Big Idea but has small data and less money.  But in my experience the pharma business (and the FDA) doesn't work that way.  Not that I think big pharma companies are angels by any means.  But they are not in the business of ignoring cures that actually work.  

If big Pharma believes that the little guy's miracle cure actually works, they won't try to suppress it.  Instead they'll try to take it over make it their own.  They'll buy out the little guy.  Or alternatively, they'll out-compete him by inventing around his products and patents and come out with a slightly different version of the same product and sell it as "improved."


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## Deleted member 431298 (Jun 16, 2017)

Wildbill - the articles you refer to are very interesting to read. One of your links leads to a "forbidden"  article (PG_Jan09_DharmarajanArticle.pdf).
Do you have an alternate source for that?

Scipio - I don't think it is totally wrong what Irishgal says: the knowledge that H. Pylori caused peptic ulcers, and the antibiotics to treat it, was not the work of the big pharmacutical companies, but of different researchers, culminating with Berry Marshall infecting himself and thus proving that the bug gave him gastritis, and Thomas Borody formulating the antibiotics-regimen.
Only after these events was it widely accepted that peptic ulcers come from infection. 
I am not saying the current MAP research is a positively a repetition of that story, but I think the reported effects of the AMAP therapy so far (both anecdotal and from studies, especially the reanalysis of the Selby study) are significant enough to keep a close watch on what is going on. 

Irishgal: thank you for elaborating on your diet, MAP diagnostics and treatment. I should have my test results back from Otakara in about a week. 
I am currently reading through an article about the possible side effects of anti-TNFa therapeutics and their role in mycobacterial infection in CD (Naser et.al 2017). I have a special interest in that topic because from 2011-2015, while on first Humira, then Remicade, I suffered kidney infection(s) that has left me with reduced kidney function. Crohn's and the drugs administered today is not all fun and games... 

Figure 1 in that article is a pretty precise graphics, I think, of the factors playing a role in the disease as established by sound research. Here is a replica of it:


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## Scipio (Jun 16, 2017)

OleJ said:


> Scipio - I don't think it is totally wrong what Irishgal says: the knowledge that H. Pylori caused peptic ulcers, and the antibiotics to treat it, was not the work of the big pharmacutical companies, but of different researchers, culminating with Berry Marshall infecting himself and thus proving that the bug gave him gastritis, and Thomas Borody formulating the antibiotics-regimen.
> Only after these events was it widely accepted that peptic ulcers come from infection.
> I am not saying the current MAP research is a positively a repetition of that story, but I think the reported effects of the AMAP therapy so far (both anecdotal and from studies, especially the reanalysis of the Selby study) are significant enough to keep a close watch on what is going on.


Yes, I know the _H. pylori_ story.  And it is true that in a majority of new wonder drugs or therapeutic paradigm shifts that it is the lone researcher or small academic team that makes the initial observation.  But it is also true that it is the pharma companies that transforms the stuff from a test tube in an academic lab into a readily-available proven drug that doctors can prescribe.

What I'm disagreeing with irishgal on is the notion that the reason why big pharma hasn't pounced on MAP and made it a big success is because they don't want to undercut their biologics business.  This implies that companies believe that anti-MAP might actually work but they are suppressing, or at least failing to act on, that belief. 

I'm saying that as soon as the pharma companies get convinced that anti-MAP therapy is the key to solving Crohn's they will jump all over it.  And the _H. pylori_ history is a good example of exactly that.   So a far more likely reason why big pharma hasn't invested in anti-MAP therapies is that they aren't convinced it works.  

MAP has a plausible theory, a nice animal model, and some encouraging anecdotal and small study data behind it.  That's great.  But it's also got enough gaps in the story and failed studies that both the pharma companies and all the prominent IBD experts are not convinced.  The current official Crohn's treatment guidelines published by the American College of Gastroenterology specifically calls out anti-MAP as an ineffective therapy, and they assign a Grade A rating (meaning highest scientific quality) to the evidence against it.

Personally, I'd be thrilled if MAP therapy turned out to work as well as its fans say.  I'm a Crohn's sufferer myself.  I'd love to be rid of this disease.  And I want the MAP research to continue.  But I don't want people to think that it's already proven, and that's it's only due to the perfidy of bad people that we don't already have a wonder drug available.


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## irishgal (Jun 16, 2017)

Scipio - I partially agree with what you are saying in that as soon as MAP is proven the Big Pharmas will be all over it. Some medium companies are working on theories like that already: RedHill, Qu, and Dr. Faustman's BCG study at Mass General for T1D. If you actually talk to the bulk of the MAP researchers, you will hear that they have been denied over and over for grants and funding that will settle this question. There are a few "industry experts" who are funded by large pharmaceutical companies to stick with the status quo, which is why you don't see change of opinion even when the data is clear (see H. pylori.) A researcher had to actually infect himself because he was so desperate to show the world that he had a cure. That should never have to happen. This happens in just about every area of medicine. It's very clear that there are questionable conflicts of interest in the Pharma industry and how they sell their product. Europeans are amazed when the watch US TV and see all the Pharma ads - which are banned in most other countries. Money and power rule that industry, and we've seen numerous lawsuits where they've put these values over human health. I don't demonize them, and they produce many products which have saves countless lives, but I think the model needs some overhauling to keep some distance between the companies and the providers.

Here's also something interesting: About a year ago Nestle quietly started investigating a way to kill MAP in infant formula via a steam injection method. They did it with a Swiss lab. Now, Nestle are no dummies, and I think they've been watching MAP research and seeing it gain validity despite the lack of funding. If they were smart, they'd figure out a solution to the problem before being ordered to do so by the governments of the world so they could be the first company to slap the "MAP free" label on their product. I guess we'll have to wait and see.

Another thing - the world experts (like 70 docs) on this topic gathered in Philly a few months ago, and almost unanimously agreed that there is enough evidence to declare MAP as zoonotic under the precautoinary principle. Personally, I'm not a doctor, so I defer to the experts. They didn't spend 30-40 year of their careers studying this bug to be questioned by someone like me with little experience. I know other docs say otherwise, but they're not MAP experts. 

I doubt MAP is the one critical factor that will make everyone with CD well, but I do think it plays a role. Why not figure all of that out? Wouldn't it be nice to have this debate settled? In the next few months, look for three pieces of information to read: the interim RedHill results, Otakaro's publications and the Consensus article from the Philly conference. I think they all may shed more light on this.


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## wildbill_52280 (Jun 17, 2017)

OleJ said:


> Wildbill - the articles you refer to are very interesting to read. One of your links leads to a "forbidden"  article (PG_Jan09_DharmarajanArticle.pdf).
> Do you have an alternate source for that?


The link is working for me, but this was the title and abstract of the paper:



> Antibiotic Associated Hemorrhagic Colitis: The Need to Distinguish from Clostridium difficile Colitis!
> 
> Presented is a case of bloody diarrhea developing within days of taking amoxicillinclavulanate for sinusitis; both diarrhea and bleeding subsided completely shortly after discontinuing the antibiotic. Although Clostridium difficile colitis was the initial consideration, no single test confirmed the diagnosis. This report substantiates the sporadic case reports linking hemorrhagic colitis to the use of antibiotics such as amoxicillinclavulanate
> and the need to differentiate the entity from C. difficile colitis, as treatment
> and prognosis differ.


I used this paper as an anecdotal observation to support the concept of antibiotics, specifically amoxicillin, being associated or potentially causing colitis or diarrhea. I suggest it is possible that it may lead to crohn's which is a form of permanent colitis or diarrhea perhaps from the permanent elimination of good bacteria which now other studies support.


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## Mommabear (Jun 20, 2017)

Scipio-Do you know what they base this on? Is it the Shelby study? "The current official Crohn's treatment guidelines published by the American College of Gastroenterology specifically calls out anti-MAP as an ineffective therapy, and they assign a Grade A rating (meaning highest scientific quality) to the evidence against it."


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## Scipio (Jun 20, 2017)

They cite Selby and several other papers too, including a meta-analysis of 5 additional studies.  The relevant sections of the guideline are quoted below:

"Ileal, ileocolonic, or colonic disease has commonly been treated in clinical practice with oral mesalamine 3.2–4 g daily (grade C) or sulfasalazine for ileocolonic or colonic disease as 3–6 g daily (grade A) in divided doses. Despite the use of oral mesalamine treatment in the past, new evidence suggests that this approach is minimally effective as compared with placebo (grade A) and less effective than budesonide or conventional corticosteroids (grade A). Alternatively, metronidazole at a dose of 10-20 mg/kg/day has been used in a proportion of patients not responding to sulfasalazine (grade C). Controlled ileal release budesonide (9 mg/day) is effective when active disease is confined to the ileum and/or right colon (grade A). *Anti-tuberculous therapy has not been effective for either induction of remission or maintenance of remission in patients with CD (grade A)."*


(Further down the page)


"Thus, although antibiotics are widely used in clinical practice for the treatment of CD (see perianal disease), controlled trials have not consistently demonstrated efficacy in the setting of luminal disease. Two small placebo-controlled trials of anti-mycobacterial therapy in combination with corticosteroid taper (after a steroid-induced remission) demonstrated efficacy for the maintenance of remission in patients receiving either clofazimine monotherapy or combination therapy with clofazimine, ethambutol, rifampicin, and dapsone (110, 111). In contrast, five placebo-controlled trials using combinations of anti-mycobacterial agents alone without concurrent conventional corticosteroids have not demonstrated short- or long-term efficacy using varying combinations of medications, including rifampin, ethambutol, isoniazid, sulphadoxine, pyrimethamine, and rifabutin. The results of these studies are summarized and incorporated into a recent meta-analysis (112). A recently reported, large Australian study also failed to demonstrate long-term benefits from anti-mycobacterial therapy (113). *On the basis of the nearly uniform evidence in these controlled clinical trials, anti-mycobacterial therapy has no role in the treatment of patients with CD*."

The cited references:

110. Afdhal NH, Long A, Lennon J et al. Controlled trial of antimycobacterial therapy in Crohn’s disease. Clofazimine versus placebo. Dig Dis Sci 1991;36:449–53.
111. Prantera C, Kohn A, Mangiarotti R et al. Antimycobacterial therapy in disease: review of the clinicopathologic features and therapy. Inflamm Bowel Dis 2001;7:328–37.
112. Borgaonkar M, MacIntosh D, Fardy J et al. Anti-tuberculous therapy for maintaining remission of Crohn’s disease. Cochrane Database Syst Rev 2000, CD000299.
113. Selby W, Pavli P, Crotty B et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn’s disease. Gastroenterology 2007;132:2313–9.


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## Mommabear (Jun 21, 2017)

Thank you Scipio for including this info. 

I am really surprised and also quite dismayed that they would use the Selby trial as evidence against MAP and AMAT, as it has been shown to be highly flawed. Marcel Behr's critique of it is excellent. I am also quite surprised that they use three other studies to base their opinion yet, if you go onto the Redhill site they cite 14 studies that show it IS effective! 

It may be that in those three studies including the meta analysis that it seemed to not work, but is the combo of antibiotics and dosage the same? I don't believe so.

In the name of "evidence based science" or "evidence based medicine" there seems to be a huge double standard regarding the link between MAP and Crohn's. Why is it that the status quo (The American College of Gastrointerology) can use a flawed study, such as Selby along with three other studies which prove nothing, as PROOF that MAP is not to blame for at least a portion of Crohn's? Or that AMAT doesn't work. What about those 14 studies that do?

I can (sort of) accept the argument that more research needs to be done, but to dismiss it entirely based on flawed studies is really nauseating.

No wonder people start to lose faith in conventional medicine. I really, really do not want to be cynical and believe that most of them are in the pockets of big pharma, but I have to say, their "evidence" has a lot to be desired! 

I think once Redhill publishes their results, these guys are going to be forced to take a hard look at their role in preventing a true cure to happen sooner. At least I hope so!


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## wildbill_52280 (Jun 23, 2017)

OleJ said:


> Last year I attended a lecture series by a microbiologist, and he echoed what you are saying. I remember he showed an illustration of the types / numbers of bacteria they found in healthy humans, vs. the types and numbers found in IBD patients. The latter group had reduced diversity, and different kinds. I guess the critic would argue that why can it not be that some autoimmune condition destroys the gut wall, disrupting the microflora.


OleJ, i know this thread has become focused on the MAP issue, but I thought you asked a good question and wanted to discuss it more. Your question was along the lines of whether the differences in the microbiome composition between IBD patients and healthy controls was an effect of the disease, rather then the cause? Say perhaps if a genetic influence or something is the reason why these changes have occurred, which would render fecal microbiome transplants a mere temporary treatment and not a potential cure. Here is one study that suggests genetics have very little influence on microbiome composition, and for a genetic influence to be highly unlikely cause of dysbiosis or extinction of bacteria. http://biorxiv.org/content/early/2017/06/18/150540

So the likelihood of some genetic alteration to be responsible for a disturbance in the microbiome, or rather the "autoimmune disease" destroying the gut wall, or eliminating good bacteria or causing dysbiosis, it is very unlikely and more likely that something else in the environment has destroyed the good bacteria causing malfunctioning of the body/immune system which also suggest restoring the missing bacteria could be a permanent cure. I also recall studies done on nod2 gene, and many people who have this gene never develop crohn's disease even though it slightly increases the risk and severity of the disease, that's study suggests genes barely matter, and also twin studies all suggests the same thing. So far, evidence for causation is pointing towards the microbiome as the sole cause of the disease. 

These are a few more reasons why the focus on one pathogen like MAP is not as important to understanding the cause and cure as other aspects of the microbiome and genetics. Many other diseases also correlate with MAP presence so that's more evidence suggesting it's not necessarily the cause. that bacteria alone couldnt explain all these different diseases where you find it, there has to be something more unique to explain the more unique features of all those diseases. The absence of a single or certain class of good bacteria may be more of a unique feature to explain the cause of IBD or all those diseases, and the accumulation of the same pathogen at different sites on the body might explain the presence of any degree of pathogens allowed to persist. Adherent invasive e.coli also has been considered as a cause of IBD and is more frequently found in crohn's but I also recall its found in UC too. Perhaps in mice experiments these pathogens given at a high dosage could cause major dysbiosis leading to colitis, but I'm not sure that's how it happen in real life nor explains all cases of IBD. But then the question remains, if one pathogen can outcompete the good bacteria, then i suppose it could still be equally possible for an FMT with good bacteria to outcompete   the bad and cure the disease? This would still make Fecal Transplants a promising therapy.


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## Deleted member 431298 (Jun 25, 2017)

Scipio:
Thank you for supplying the statement from the American College of Gastroenterologists (ACG). MAP as a pathogen is certainly not a hypothesis they support, I see that. The main conclusion, which is AMAT has no role in the treatment of CD, comes from five studies:

_ In contrast, five placebo-controlled trials using combinations of anti-mycobacterial agents alone without concurrent conventional corticosteroids have not demonstrated short- or long-term efficacy using varying combinations of medications, including rifampin, ethambutol, isoniazid, sulphadoxine, pyrimethamine, and rifabutin.
_

Looking through the studies (ref.1) used to draw that conclusion, I can see two problems:

First problem: 
They were all conducted before 1998, meaning it is rather old data. A newer meta-study of placebo-controlled trials exists (ref. 2) which draw the following conclusion:
_Long-term treatment with nitroimidazoles or clofazimine appears to be effective in patients with
Crohn’s disease._

Interestingly, that study concludes that the Selby study demonstrated superiority of antibacterial treatment over placebo, as Mommabear pointed out in a post above.. (look for odds ratio > 1 in this illustration from the study):






Second problem:
None of the five studies used to conclude that AMAT has no role in CD include the currently used combination of clarithomyzin, clofazimine, and rifabutin. In fact, many studies used completely different drugs. The one study which did include two of the three AMAT drugs (Prantera 1994) used a very poor analysis method: (outcomes: "remission induction and maintenance - failure defined as need for steroids, other drug therapy or surgery based on clinical symptoms and signs"). The studies were also underpowered (under 50 participants)

For these reasons I think it is unscientific of the ACG to be so dismissive of the role of AMAT in CD.


REFERENCES:

1)Borgaonkar et. al 1999, Anti-tuberculous therapy for maintenance of remission in Crohn's disease
2) M.Feller et. al 2010, Long-Term Antibiotic Treatment for Crohn’s Disease: 
Systematic Review and Meta-Analysis of PlaceboControlled Trials


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## Deleted member 431298 (Jun 25, 2017)

wildbill: thank you for the thoughts and the link discussing environmental factors vs. genetics influencing the microbiota. 
That reference does indeed support that the altered microbiota can be linked to disease, as opposed to alterations in the microbiota happening after some autoimmune destruction of the intestinal mucosal layer.
Still, in finding out the roles of genes, is hard for me to understand what data has the most gravity - I have heard microbiologists talk about that NOD2 mutations lead to increased mycobacterium susceptibility in mouse models. But that does not mean the same is true in humans... 
Anyway - your reference and many other studies published these years demonstrate a connection between the microbiome and disease. Other studies demonstrate that the microbiome is altered based on diet, so as a CD patient it makes alot of sense to eat a healthy diet.
Can infection with one pathogen (eg. MAP or E.coli) lead to altered microbiota? Hard to tell I guess? I wonder if the H.Pylori bacteria infection results in an altered microbiome- I tried to search for litterature, but did not find anything.

PS: wildbill, maybe you will find this article interesting, it describes how
harmful biofilms can form in the gut when the "right" bacteria and fungi are present (C. tropicalis, S. marcescens, and/or E. coli )
http://mbio.asm.org/content/7/5/e01250-16.full


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## Deleted member 431298 (Jun 28, 2017)

UPDATE: I just recieved the results of MAP culture testing. It came back positive. The amount and types of cells found in my blood matches what they typically see in CD patients in remission and on prolonged therapy. Two times good news I think:
1) For the first time I have a probable cause of my CD.
2) Even though the infection is there, it seems to be somewhat suppressed at the moment. They were able to culture viable MAP, both dormant, mother and daughter cells meaning I have live MAP bacteria in the white blood cells, and they multiply. That could explain why I get worse if I try to come off methotrexate, which has an anti-MAP therapeutical effect. In the analysis I got the microbiologist wrote that I am wise to stay away from dairy products. 

The fact that MAP causes Johne's disease in animals which is the same kind of intestinal inflammation as Crohn's, combined with the fact that I have live MAP bacteria in my white blood cells make me believe MAP causes Crohn's.
My advice to all who read this: do not eat any food items that come from dairy cows - it can aggrevate your disease. You can get protein from eggs, fish and veggies instead, same with calcium.

My next step will be to try to get a consult with a specialist who has expirience with treating CD patients with a MAP infection to get advice if I should try the atypical antibiotics treatment regimen or not.


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## wildbill_52280 (Jun 28, 2017)

OleJ said:


> UPDATE: I just recieved the results of MAP culture testing. It came back positive. The amount and types of cells found in my blood matches what they typically see in CD patients in remission and on prolonged therapy. Two times good news I think:
> 1) For the first time I have a probable cause of my CD.
> 2) Even though the infection is there, it seems to be somewhat suppressed at the moment. They were able to culture viable MAP, both dormant, mother and daughter cells meaning I have live MAP bacteria in the white blood cells, and they multiply. That could explain why I get worse if I try to come off methotrexate, which has an anti-MAP therapeutical effect. In the analysis I got the microbiologist wrote that I am wise to stay away from dairy products.
> 
> ...


Maybe you are already familiar with this but I vaguely recall that MAP is an intracellular bacteria that can persist inside a cell and autophagy is a natural defense our cells have to eliminate bacteria inside of a cell, among other functions. Autophagy stimulation has been proposed as one therapeutic target for crohn's not much experiments on this that i recall though maybe like one or two on humans with some positive results. Whether this is an effective antimap strategy I'm not sure, but I do take things to stimulate autophagy and while im not "cured" the stuff does help a bit i think. I take a herb that is high in resveratrol japanese knotweed but very small amount because it can be toxic in high amounts and also eat aged, one year old cheese which is very high in spermidine. Lithium also stimulates autophagy I've tried it but its pretty toxic stuff. I eat aged cheese every day for spermidine and take resveratrol everyday also. Ceylon cinnamon has a substance proanthocyanadin that inhibits a specific enzyme like cranberries  that inhibits AEIC , and i take that everyday as well in my oatmeal!! Those are the two bacteria that are suspected pathogens in Crohn's I think.


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## Deleted member 431298 (Jun 29, 2017)

Thanks for sharing that knowledge wildbill. I have reviously watched the videos from the MAP conference and some of the speakers discussed how to stimulate autophagy. I will look into your suggenstions on how to boost that phenomenon. cheers. 

Also, allow me to share this cool picture of a proud MAP mother which has been hosted by yours sincerely and her daughters, bred in the culture medium (real test tube babies ). Dangerous ones too, I might add, as far as I understand they are the ones producing antigens that the immune system pick up and react to.


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## wildbill_52280 (Jun 30, 2017)

OleJ said:


> Thanks for sharing that knowledge wildbill. I have reviously watched the videos from the MAP conference and some of the speakers discussed how to stimulate autophagy. I will look into your suggenstions on how to boost that phenomenon. cheers.
> 
> Also, allow me to share this cool picture of a proud MAP mother which has been hosted by yours sincerely and her daughters, bred in the culture medium (real test tube babies ). Dangerous ones too, I might add, as far as I understand they are the ones producing antigens that the immune system pick up and react to.


I don't fully understand what you are showing us, did you grow a MAP bacteria yourself? 

Here is a study that found said stimulating autophagy seems to overcome MAP infection. http://www.sciencedirect.com/science/article/pii/S0092867404011067


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## Deleted member 431298 (Jul 1, 2017)

I appriciate the reference, thank you. Very interesting stuff, that I will look more into. I also started reading up on if exercise stimulates autophagy.

No, I did not culture the blood myself. I sent two blood samples off to a laboratorium. The picture of the mother and daughter cells were in the analysis report that i got back on Tuesday.


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## wildbill_52280 (Jul 1, 2017)

OleJ said:


> I appriciate the reference, thank you. Very interesting stuff, that I will look more into. I also started reading up on if exercise stimulates autophagy.
> 
> .


There are some studies that show exercise does stimulate autophagy and makes contributions to basal autophagy and so does all versions of fasting like intermittent fasting/caloric reduction. Fasting supposedly stimulates autophagy in the brain like alot, and exercise mainly in the muscle. Inositol inhibits autophagy and is included in some b vitamins and its pretty toxic stuff. This is One reason I think the vitamin industry should have stricter regulations. Supposedly the mechanism by which lithium stimulates autophagy is enhancing an enzyme that breaks down inositol, so you might see why a higher inositol status in the body might be a dangerous thing and taking inositol supplements are probably a bad idea and especially a bad idea when ATG protiens/genes are involved in crohn's as well as nod2 which all related to killing intracellular pathogens and autophagy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502774/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2171537/


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## Deleted member 431298 (Jul 2, 2017)

Thanks for the reference wildbill. I will share back my bedtime read for tonight: 

A Therapeutic Role for Diet in the Treatment of Crohn’s Disease? By Dr. Gilles Monif  (PDF)


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## Jakefriesz1 (Jul 2, 2017)

It's true the mycobacterium about subspecies is a huge problem for 95% or crohns patients. And it lives in the Lymph system as well. So even when you kill it in the gut it can hold out for years in your lymph


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## Crohn2357 (Jul 6, 2017)

Take a good look at this.

In addition, you may want to read kiny's posts about MAP and Crohn's. They're very informative.


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## wildbill_52280 (Jul 6, 2017)

Crohn2357 said:


> Take a good look at this.
> 
> In addition, you may want to read kiny's posts about MAP and Crohn's. They're very informative.


Didn't know Vit d played a role in autophagy, but its a "vitamin/hormone" so I'm not surprised that it does as most vitamins play a role in almost every process, to varying degrees. I will also add that taking higher doses of vitamin d is something I will testify to helping me gain greater control over my Crohn's. It would be the #1 supplement I'd recommend.


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## Deleted member 431298 (Jul 7, 2017)

I also did not know that, I was once treated by a GI at a university hospital who told me about a research project he had done where they gave CD patients Vitamin D, and registered the efficacy (using the CDAI score I think). He told me they concluded Vitamin D was as efficient in maintaining remission as the high dose of 5-ASA.

They did not study the mechanism, but reeding through the PubMed links you sent, it seems stimulating autophagy would be the reason. 
So - does any of the established drugs like the biologics, Methotrexate and glucocorticosteroids have an impact on autophagy?

#WARNING: lengthy reply with lots of references.. :runaway:

I found a very interesting article, Autophagy: a new target or an old strategy for the treatment of Crohn's disease?

quote:

"_ Interestingly, as well as the promising introduction of direct autophagic modulators, several drugs already used in the treatment of Crohn's disease might exert at least part of their effect through the regulation of autophagy. However, *whether this phenomenon contributes to or rather counteracts their therapeutic use, remains to be determined and might prove to be highly compound-specific *. Here we review the complex and emerging role of autophagy modulation in the battle against Crohn's disease. Moreover, we discuss the potential benefits and deleterious effects of autophagic regulation by both new and clinically used drugs."_

unfortunately the full article is not available without subscription.

Below are some articles I found dealing with autophagy and specific CD drugs. They sometime use the word "Apoptosis"  which is also a programmed cell death and an important mechanism in the elimination of infected cells. It sounds a bit like autophagy, but I read that they can also be opposites, ind that autophagy can block the induction of apoptosis. 

apoptosis and infliximab:
Downregulation of epithelial apoptosis and barrier repair in active Crohn’s disease by tumour necrosis factor α antibody treatment

In conclusion, we have shown a significant decrease in
epithelial cell apoptosis in CD patients after TNF-a antibody
therapy which was accompanied by an increase in epithelial
resistance. Tight junction protein expression did not contribute
to this barrier repair.

note: could this mean anti-TNFa drugs, while suppressing the inflammatory response and thus inducing a clinical improvement ("the parking lot effect" - patients getting infusions, and feeling improvement already when they exit the hospital), actually at the same time inhibit the body's attempts to clear an infection (eg. with AIEC or MAP?).

Another article, however, concludes the opposite, namely that infliximab increases apoptosis:

Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease

conclusions:
Conclusions: Our data indicate that infliximab treatment causes a rapid and specific increase in apoptosis of T lymphocytes in the gut mucosa. These findings may explain the rapid and sustained therapeutic effects of infliximab in Crohn's disease.
Infliximab induced activation dependent apoptosis of Jurkat T lymphocytes, possibly altering the Bax/Bcl-2 ratio. In patients with Crohn's disease, infliximab rapidly increased the number of apoptotic T cells in the inflamed mucosa, without affecting peripheral blood mononuclear cells. These data indicate that infliximab functions, in part, as an “immunotoxin” that specifically targets the mucosal T lymphocytes that are involved in the pathogenesis of Crohn's disease



On apoptosis and Methotrexate:

One way MTX works is that it is a competitive inhibitor of many enzymes that use folates, inhibiting synthesis of DNA, RNA, thymidylates, and proteins.
The article Autophagy induction contributes to the resistance to methotrexate treatment in rheumatoid arthritis however, concludes that MTX also upregulates autophagy, at least in patients with rheumatoid arthritis:

Results:
MTX-induced apoptosis was increased in OA-FLS compared with RA-FLS. However, MTX stimulated the autophagy response in RA-FLS by inducing autophagosome formation, but not in OA-FLS. In RA-FLS, transfection with Beclin-1 small interfering RNA inhibited autophagy and increased susceptibility to MTX, which induces cell death. MTX upregulated autophagy through its ability to enhance the expression of HMGB1 and Beclin-1 rather than through the Akt/mTOR pathway.

Conclusions:
Autophagy induction contributes to resistance to MTX treatment in fibroblasts from patients with rheumatoid arthritis. 



Another study on MTX that describe apoptosis:

Increased sensitivity to apoptosis induced by methotrexate is mediated by Jun N-terminal kinase

Results:
MTX does not directly induce apoptosis but rather ‘primes’ cells for markedly increased sensitivity to apoptosis via either mitochondrial or death receptor pathways by a Jun N-terminal kinase [JNK]-dependent mechanism. Increased sensitivity to apoptosis is mediated, at least in part, by MTX-dependent production of reactive oxygen species, JNK activation and JNK-dependent induction of genes whose protein products promote apoptosis. Supplementation with tetrahydrobiopterin blocks these methotrexate-induced effects. Subjects with rheumatoid arthritis on low-dose MTX therapy express elevated levels of the JNK-target gene, JUN.

Conclusions:
Our results support a model whereby methotrexate inhibits reduction of dihydrobiopterin to tetrahydrobiopterin resulting in increased production of ROS, increased JNK activity and increased sensitivity to apoptosis. The finding of increased JUN levels in subjects with RA taking low-dose MTX supports the notion that this pathway is activated by MTX, in vivo, and may contribute to efficacy of MTX in inflammatory disease.


Glucocorticosteriods (Prednisone) and apoptosis :

Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease

From the abstract:
Glucocorticoid hormones (GCH) induce apoptosis in PHA-primed peripheral blood T lymphocytes (PBL) and down-regulate membrane-bound proteins involved in the immune response.

Another one on glucocorticosteroids:

Recent insights into the mechanism of glucocorticosteroid-induced apoptosis

From the abstract:
Glucocorticosteroid hormones induce apoptosis in lymphocytes. Therefore, glucocorticoids are commonly used as immunosuppressive and chemotherapeutic agents

In summary, it does not seem far fetched to propose that upregulating autophagy and/or apoptosis may explain why usual CD drugs help inducing remission. Further, it makes the case for investing natural ways of stimulating these processes, to see if it can be done without the need for these drugs, in order to avoid the side effects.

*Please note*: I realise I may be mixing pears and apples in citing studies that describe either Autophagy or Apoptosis. Any thoughts on this?

Also, I realise I could be causing thread drift into the topic "CD and autophagy / apoptosis". Should we maybe start a new thread on this?? Kiny started one in 2012, but it is re. a specific article on autophagy and AIEC. http://www.crohnsforum.com/showthread.php?t=44825


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## Crohn2357 (Jul 7, 2017)

There's more. There are animal model studies showing that the deletion of VDR gene strongly correlates with an increased disease severity.


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## wildbill_52280 (Jul 7, 2017)

Another thought is how a pathogen would ever get as far as reaching the epithelial surface of the gi tract because it has to get past alot of protective layers , I think the mucus layer and all the good bacteria that are supposed to be protecting and limiting pathogen invasion in the first place. or even when pathogens gain access to immune cells which are supposed to be able to kill them, microbiome also can affect immune cell functions too, lack of signals from microbiome that limit autophagy might allow a pathogen to persist intracellularly.

I don't recall the specifics of GI anatomy at the moment, but before we talk about problems with intracellular bacteria, we also have to address other weaknesses that allowed a bacteria to get that far, it makes you wonder which came first and which is more important. Maybe autophagy and pathogens are all minor details to IBD, at least that's kind of how I feel now. It's the protective factors and perhaps all the beneficial functions of the microbiome. My current opinion is still that genes and pathogens don't matter much in regards to what causes the disease, microbiome might explain it all and possibly not just bacteria but viruses and fungus too.


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## Deleted member 431298 (Jul 12, 2017)

Exciting news from Redhill: in the beginning of August they will announce the result of an interim analysis of the efficacy of their antibiotics regimen for atypical mycobacterium infection.
Redhill RHB-104 news (12 July, 2017)


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## Deleted member 431298 (Jul 21, 2017)

My proposal for a dream study: 
1000 crohn's patients in a current state of active disease, confirmed by elevated calprotectin, measured each month for six month(say, average above 200 mg/kg). All of them confirmed positive for MAP infection by culture and PCR, and tested for gut bacteria diversity and - count. 500 remain on their current treatment, 500 participants are put on a treatment that:

a) strengthen the immune system by boosting vitamin and mineral consumption and omega-3 fats intake. 
b) adds live, good bacteria to the diet through the consumption of fermented foods (probiotics), along with foods for those bacteria (Prebiotics)
c) reduce the risk of MAP exposure.
d) stimulate autophagy / apoptosis to help the body deal with the infection.

Such a diet treatment could be: 
All unprocessed foods. Almost exclusively organic fruit and vegetables, nuts and berries, unheated honey as sweetener, good sources of fatty acids such as coconut and hemp oil, a little fish, a little wholegrain. Fermented foods (such as kimchi and sauerkraut). Prebiotics (such as jerusalem archichokes). Vitamin D supplements.
No processed foods, no dairy, no meat from cows.
Three days of cycling per week, 10km each time.

Then after six month and one year the trends in calprotectin, MAP incidence, and gut bacteris diversity are compared between the two groups. 

Who will fund a study like that I wonder. Heck, we should to it here in the forum!
Who wants to join

Even though such a study can never be done blinded I still think the results would tell alot about whether MAP, gut bacteria, and food plays a role in CD.

Regarding antibiotics, by the way,  an article recently published on this topic:

Resolution of Crohn's with antibiotics - What are the next steps?

Excerpt:

_
1) The first step should be for the medical and research communities to move forward in unison with the recognition that Map is another zoonotic mycobacterial pathogen similar to M. tuberculosis

2) The second step should be reevaluation of methods for diagnosis of patients infected with Map. Diagnostic tests have not been standardized for use in humans. Current methods of testing for the presence of Map in blood and other tissues should be improved and should be robust and sensitive. The current diagnostic tests in humans are not approved by the US FDA and are probably relatively insensitive. Based on prevalence studies such as Naser’s culture of blood samples from CD patients, it is estimated that at least 50% of CD patients are infected with Map

3) The third step should be implementing a study on the effects of all antimycobacterial antibiotics (current and experimental) on Map. Numerous clinical trials of antibiotics in CD [... references ...] have been conducted on the theory that Map or some other bacterium is the etiologic agent. Several meta-analyses of controlled trials comparing antibiotics to placebo have concluded that antibiotic therapy has a significant effect of superiority to placebo

4) Although a large randomized controlled clinical trial is under way sponsored by RedHill Biopharma Limited, Tel Aviv, Israel, ‘[...] there is an urgent need for a trial without restrictions on evaluating different combinations of antibiotics for treatment of clinically ill patients infected with Map. The focus of the RedHill trial is on the use of a proprietary drug formula RHB-104. [...] Many of the parameters of the trial would overlap those of the RedHill trial, but the trial would be restricted to patients clearly infected with Map

_


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## Ih8crhns (Jul 21, 2017)

This may sound silly but i think my crohns was brought on by a heavy dose of antibiotics. Had cellulitis. multiple shots in the rear. and 2 or 3 oral antibiotics. Was not 2-3 months later my symptoms started. Anything? First time post


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## Crispix73 (Jul 22, 2017)

Ih8crhns said:


> This may sound silly but i think my crohns was brought on by a heavy dose of antibiotics. Had cellulitis. multiple shots in the rear. and 2 or 3 oral antibiotics. Was not 2-3 months later my symptoms started. Anything? First time post


I don't think that's silly at all. I'm convinced that mine was caused by overuse of antibiotics. I had chronic sinus problems in my late teens and early twenties and was given 2-3 courses of antibiotics per year. I was diagnosed with IBD at 24. 

I wish I had known better and requested an evaluation from an ENT to explore the constant sinus problems, rather than just taking the antibiotics my GP prescribed. I was always sensitive to the antibiotics. I would end up having cramping and diarrhea with almost every one I took. I definitely think the frequent courses of antibiotics over a long period of time triggered by Crohn's. 

What's done is done, I can't do anything to reverse it now, but I do stay away from antibiotics when possible. And it's definitely something I'll be conscious of with my daughter. Antibiotics will only be used when absolutely necessary.


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## Deleted member 431298 (Jul 22, 2017)

I agree, it would make sense that the usually given antibiotics would erradicate some of the good bacteris and thus protective layers in the gut. 
MAP, AIEC and other pathogen bacteria would then have the conditions needed to multiply and cause inflammation which destroy the protective layers of the gut wall. Maybe, because of the gut wall damage, partially digested food items are able to reach the deeper layers of the gut wall where they and no supposed to be, causing even more inflammation.
This would explain why enteral nutrition works - then the latter mechanism stops.

One of the important questions is if antibiotics against intercellular bacteria such as MAP will have a similar effect? It would be very interesting to hear from someone on Anti-MAP therapy.


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## Crohn2357 (Jul 22, 2017)

OleJ, as I said earlier, you may want to read kiny's posts about the pathogenesis of Crohn's Disease, and related topics.

This.

Read the whole of this article, published in 2009.



> Although CD is immune mediated, it is not an autoimmune disease, as the immunological process appears to be triggered by the content of the gut lumen rather than a self-antigen.





> To date, CD is widely accepted as a genetically determined immunological disease that manifests principally in the gut and is triggered by bowel contents. But this is as far as scientific consensus and certainty go.





> The first breakthrough toward an understanding of the pathogenesis of CD came in 1976 when Anthony Segal demonstrated impaired influx of granulocytes into skin windows in CD patients (Segal and Loewi, 1976), a finding that was confirmed and extended to the gut in 2006 (Marks et al., 2006). As CD is an inflammatory disease, it was hard to imagine a more paradoxical and provocative finding than impaired inflammation (Korzenik, 2007). Moreover, although CD is principally localized to the gut, these studies claimed that the inflammatory defect was systemic and affected various tissues, such as the skin, that were not affected clinically. However, as the Hungarian physiologist Albert Szent-Györgyi pointed out, “a discovery is a discovery because it is at variance with accepted knowledge.”
> 
> In a clinical investigation reported by Smith et al. (2009) in this issue, Segal's group studied inflammation in response to skin wounded with heat-killed bacteria. Consistent with their past studies, patients with CD had impaired inflammation at the wound site, as demonstrated by tracking intravenously injected, radio-labeled granulocytes. Clearance of Escherichia coli at the sites of injection was also impaired in patients with CD, but not in those with another inflammatory disease, ulcerative colitis, or in healthy subjects. Notably, impaired bacterial clearance was evident for high, but not low, bacterial doses. Overall, these experiments suggest a causal link between impaired inflammation and impaired bacterial clearance. The intestine was not wounded with bacteria, but the skin defect was proposed to be systemic and to involve the gut in particular. In fact, E. coli was chosen for these studies because of its abundance in the intestinal flora. It is important to reiterate that the defect was seen only with high bacterial loads, given that the highest bacterial load in the human body is found in the intestinal tract, which is the primary target of CD. Impaired bacterial clearance presumably results in chronic inflammatory responses, accompanied by accumulation of granulomas consisting of macrophages and T lymphocytes. Therefore, in this model, excessive inflammation is the consequence of an underlying immunodeficiency rather than the primary cause of CD pathogenesis





> Macrophages from the patients are intrinsically defective, with impaired secretion of cytokines that are normally translated but internally degraded. Because of insufficient production of cytokines and chemokines, there is impaired attraction of granulocytes to mucosal breaches. Impaired acute, granulocytic inflammation results in impaired clearance of bacteria and debris from the gut wall, itself resulting in chronic, granulomatous inflammation.


and so on...

Read the discussions in these topics, for example:
http://www.crohnsforum.com/showthread.php?t=71588
http://www.crohnsforum.com/showthread.php?t=65923
http://www.crohnsforum.com/showthread.php?t=47428
http://www.crohnsforum.com/showthread.php?t=45026

There are many others that might be of interest to you.


On a side note, I agree with kiny on the fecal transplants; and not only that, I think it may be very dangerous for someone with Crohn's Disease, considering the immunodeficiency hypothesis, the use of immunosuppressants, leaky gut, impaired gut flora, malnutrition etc...



> "and do you believe fecal transplants are worth trying?"
> 
> I think they are worthwile for C Difficile and perhaps UC. If crohn's disease is related to AIEC or MAP they wouldn't be very effective, AIEC are present in submucosa and both are intracellular, fecal transplants wouldn't be an effective treatment for them.


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## Deleted member 431298 (Jul 22, 2017)

thanks Crohn2357. There is some very interesting discussion points and knowledge in those threads.


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## Deleted member 431298 (Jul 31, 2017)

another announcement from Redhill just came out. I wonder if this is their interim safety/efficacy report due in august 2017? If so I am a little disappointed, nothing is revealed about the efficacy of their antibiotics-regimen RHB-104, as far as I can see..

31th JULY 2017:
RedHill Biopharma Announces Unanimous Positive DSMB Recommendation for Continuation of the Phase III Study with RHB-104 for Crohn’s Disease


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