Remicade anti-TNF therapy has not yielded expected declines in hospitalisation and intestinal resection rates in inflammatory bowel diseases

[Guerrero]

What about entyvio and stelara?

 

[kiny]

They have far lower remission rates and they need far longer to get people in remission. Interleukin are involved in inflammatory signaling, but aren't as relevant as TNF-α.

 

[kiny]

I think you'll also see people relapse faster on them, but they are so new there isn't much relevant data on it. That is ''new'', as compared to infliximab, which was the first biologic to treat crohn's disease.

There's a lot of data on infliximab, there's very little on newer biologics. I've noticed that early data on medication also tends to be a bit more ''positive' than larger scale studies later on.

 

[wild_one353]

Just want to say the term "limiting the fecal stream" and "fecal stream" is a very general term/oversimplification that does little justice to the details and mechanics of what is happening in the intestine. Feces after all can be 90% bacteria, so to disregard research into the human microbiome is to ignore alot of what is happening in the intestine. If you want to understand IBD and the intestine it would help to understand the microbiome.

This is just a joke, but I would like to redefine IBD as permanent diarrhea like opposed to acute diarrhea. We may have accumulated pathogens that we just cant get rid of, or remain susceptible to. So whenever we encounter them in the environment they either take us down for a moment or live inside us for a long time. I believe it is the loss of good microbes which are there as a defense system, that explain why. This is only one of many reasons why Fecal microbiota transplant makes sense to me.

 

[kiny]

Fecal microbiota transplant makes sense to me.

Primum non nocere. Do not harm the patient.

 

[Crohn2357]

This came out just a few days ago: https://www.nbcnews.com/health/heal...t-containing-drug-resistant-bacteria-n1017426

 

[Crohn2357]

Giving people with Crohn’s FMT is akin to putting fuel on fire. Especially when you take into consideration the facts that bacterial load is the most important cause of inflammation; also the innate immunodeficiency, the chronic use of immunosuppressants, the intestinal permeability problem etc. in Crohn’s patients.

 

[Crohn2357]

Relevant: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2036.1987.tb00635.x

As a slde note, this article also discusses the topic of EN in a favourable way, if I remember correctly. It’s been some time since I read the whole paper.

 

[wild_one353]

Primum non nocere. Do not harm the patient.

View attachment 3702

I am generally aware that people can develop flares from FMT. I guess the question in this study is what exactly is meant by worsening, I generally suspect it means temporary worsening perhaps similar to a flare. But many people find improvement too!! Results may depend on the quality of the donors stool, stool is like an unstandardized drug formulation, you really never know what your going to get, but that's why the science must advance, it's the beginning stages.

 

[kiny]

Relevant: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2036.1987.tb00635.x

As a slde note, this article also discusses the topic of EN in a favourable way, if I remember correctly. It’s been some time since I read the whole paper.

If you introduce bacteria in mice with deficiencies relevant to crohn's disease you cause antigenic stimulation and you can create, or at least mimmick, crohn's disease in mice.

If on the other hand, you use a sterile environment, you can not, mice with genetic deficiencies relevant to crohn's, only get sick if you actively introduce bacteria.

Not only do they get sick if you introduce pathogenic bacteria, they also get sick if you introduce bacteria found in human stool that are harmless in mouse without the deficiencies, but cause inflammation in the KO mice with crohn's deficiencies.

If those irresponsible doctors experimenting with microbiota transplantation had read a singly study, they would have never tried microbiota transplanation where patients got worse instead of better.

You don't try your eperiment on humans when it causes disease in a mouse model, you don't introduce bacteria in people who have issues clearing bacteria. It is no wonder people with crohn's disease flare after micriobiota transplanation. How was this treatment even considered, let alone used. Thank god those experiments on crohn's disease patients seeemed to have all but stopped now.

If they want to try it in other diseases, that is their choice, but not in crohn's disease patients. They are patients, not test subjects.

 

[Crohn2357]

If you introduce bacteria in mice with deficiencies relevant to crohn's disease you cause antigenic stimulation and you can create, or at least mimmick, crohn's disease in mice.

If on the other hand, you use a sterile environment, you can not, mice with genetic deficiencies relevant to crohn's, only get sick if you actively introduce bacteria.

Not only do they get sick if you introduce pathogenic bacteria, they also get sick if you introduce bacteria found in human stool that are harmless in mouse without the deficiencies, but cause inflammation in the KO mice with crohn's deficiencies.

If those irresponsible doctors experimenting with microbiota transplantation had read a singly study, they would have never tried microbiota transplanation where patients got worse instead of better.

You don't try your eperiment on humans when it causes disease in a mouse model, you don't introduce bacteria in people who have issues clearing bacteria. It is no wonder people with crohn's disease flare after micriobiota transplanation. How was this treatment even considered, let alone used. Thank god those experiments on crohn's disease patients seeemed to have all but stopped now.

If they want to try it in other diseases, that is their choice, but not in crohn's disease patients. They are patients, not test subjects.

I share your views on this.

 

[Crohn2357]

Speaking of TNF inhibitors...

 

[Jonny84]

Speaking of TNF inhibitors...

I often hear people use the word conspiracy to describe this sort of thing. Its not a conspiracy - its a business. These are commercial companies who are responsible first and foremost to their shareholders not patients. The aim is to maximise profit and shareholder value. Its no different to if they were selling oil, weapons or any other commodity/product.

That's why I'm so excited about the work of Qu Biologics - they are going to come along and eat big phara's lunch which something cheaper, safer and more effective that may only require one course of treatment.

 

[D Bergy]

Even if they get the results they are hoping for, its a long uphill battle to unseat the giants selling their numerous temporary fix products.

The profit motive will encourage Qu biologics to develop their product as it is not replacing a more profitable product they have already.

However the pharmaceutical giants certainly are aware of the ramifications for their temporary fix medications if the new products are effective. They are not going to just sit by and let this tiny company take away their market share. They have all the power to crush whoever they want and they do it regularly.

I don’t know how it will occur, there are so many possibilities, but its no slam dunk even if its the best treatment in the world. Doesn’t work that way. It hasn’t for about a hundred years.

Dan

 

[Jonny84]

Even if they get the results they are hoping for, its a long uphill battle to unseat the giants selling their numerous temporary fix products.

The profit motive will encourage Qu biologics to develop their product as it is not replacing a more profitable product they have already.

However the pharmaceutical giants certainly are aware of the ramifications for their temporary fix medications if the new products are effective. They are not going to just sit by and let this tiny company take away their market share. They have all the power to crush whoever they want and they do it regularly.

I don’t know how it will occur, there are so many possibilities, but its no slam dunk even if its the best treatment in the world. Doesn’t work that way. It hasn’t for about a hundred years.

Dan

I know what you are saying but I am an optimist and I believe, while it may be a struggle, this will make it and it will change lives. I'll be with them every single step of the way and so will many, many patients around the world who have been given hope with the news of this treatment.

I don't know if, at this stage, big pharma's arrogance blinds them. I've seen no indication that the GI establishment are aware of this treatment. I believe, when Qu get to the phase three results it will be front page news - in Canada at least.

While I take you point and I agree - its not unheard of for a small company to come through with a disruptive piece of technology and gain a high market share.

Also I would have thought if the powers that be has a very serious problem with this it would have been stopped at the patent stage.

 

[Jonny84]

I do absolutely take your point tho. I guess they'll pull out all the stops given that this product has the potential to have a very significant impact on the demand for their current drugs and all drugs that are currently in development.

 

[D Bergy]

There are very few GI’s aware of Low dose naltrexone either. Not because its any worse than any other treatment but because there are no drug reps promoting it. In this case its too cheap for any pharmaceutical company to even bother with. It would replace more profitable drugs.

Treatments you never hear about are not going to help many people.

I hope you are right, but the odds are not good.

Dan

 

[Jonny84]

There are very few GI’s aware of Low dose naltrexone either. Not because its any worse than any other treatment but because there are no drug reps promoting it. In this case its too cheap for any pharmaceutical company to even bother with. It would replace more profitable drugs.

Treatments you never hear about are not going to help many people.

I hope you are right, but the odds are not good.

Dan

I had the most awful experience on LDN - its was a total disaster for me. I know it works for some people but I regret trying it more than I can put into words.

 

[Scipio]

"That's why I'm so excited about the work of Qu Biologics - they are going to come along and eat big phara's lunch which something cheaper, safer and more effective that may only require one course of treatment."

If Qu Biologics manages to eat big pharma's lunch with a miracle cure they will pretty soon become wildly successful. In other words they will become a big pharma company themselves - with all the big money and big pharma mindset that goes along with that.

Actually, I think that if their product shows great results then a far more likely scenario is not that Qu will suddenly grow big or that big pharma will crush them but that big pharma will buy them. Dangle a couple of billion dollars in front of the current Qu owners' noses and even the most virtuous and altruistic medical crusaders will almost always take the money and run. All of the recent miracle breakthrough drugs have followed that path - the Hep C cures, the checkpoint inhibitor anti-cancer drugs, and so on. All of them. They get started at some small start-up, and if they get great data then one big pharma or another moves in and buys them.

In a way, getting bought is pretty much required in order to get a revolutionary new drug to market. It takes a lot of know-how and incredible amounts of money to conduct all the many clinical trials it takes to get a drug approved by FDA. Little start-ups almost never have enough of either one to pull it off on their own.

 

[Crohn2357]

Big pharma can use their power on regulatory institutions, political and judiciary system, media etc. to prevent the marketing of the Qu’s vaccine (assuming it will be a success). They may also buy the vaccine, and then it will be forgotten, or “the new data (or new analyses)” will show lack of effectiveness or safety concerns about the vaccine.

Qu biologics can also turn this into a lifelong treatment to maximise their profit. I don’t know how the treatment is designed and thought of now by them.

 

[Jonny84]

Big pharma can use their power on regulatory institutions, political and judiciary system, media etc. to prevent the marketing of the Qu’s vaccine (assuming it will be a success). They may also buy the vaccine, and then it will be forgotten, or “the new data (or new analyses)” will show lack of effectiveness or safety concerns about the vaccine.

Qu biologics can also turn this into a lifelong treatment to maximise their profit. I don’t know how the treatment is designed and thought of now by them.

The treatment (QBECO) is designed to activate an organ specific immune response. In this case by injecting elements of killed e'coli subcutaneously every second day. QBECO recruits activated innate immune cells into the intestinal mucosa, restoring innate immune competency, clearing dysbiosis and bacterial infection, removing the underlying trigger for the adaptive immune overreaction, resulting in disease resolution.

That's what I mean - its on a different planet to what is currently available. It is so far beyond the other treatments. It's a new way of thinking. Can you imagine being newly diagnosed and getting straight onto QBECO?

Qu are currently running a phase two trail that has two stages. The first stage is a 20 patient open label trial which is aim at developing an understanding of the optimum amount of time give QBECO. This will be followed by 150 double blind, placebo controlled trail which will start next year and recruit internationally as well as in Canada.

 

[Scipio]

Big pharma can use their power on regulatory institutions, political and judiciary system, media etc. to prevent the marketing of the Qu’s vaccine (assuming it will be a success). They may also buy the vaccine, and then it will be forgotten, or “the new data (or new analyses)” will show lack of effectiveness or safety concerns about the vaccine.

Qu biologics can also turn this into a lifelong treatment to maximise their profit. I don’t know how the treatment is designed and thought of now by them.

It's pretty clear that big pharma is obsessed with big profits - to the point that it's fair to call them excessively greedy. But I think people are often too quick to assign to them an unwarranted level of evil and bad intentions. If the Qu vaccine or any other new product works great they won't want to crush it. They will want to own it. They will want to be the only company offering this exciting new product. They will want to reap the rewards of Qu's cleverness and hard work.

One often heard criticism is that big pharma deliberately suppresses cures in favor of chronic treatments to keep the money flowing long term. But the example in recent years of hepatitis C puts the lie to that notion. They had expensive, chronic treatments for Hep C going for years and years with interferon in combo with the anti-viral drug ribavirin. It was expensive and didn't work very well. Then the new Hep C drugs were developed that are outright cures - miracle cures. Nobody sought to suppress these cures. It's been a revolution. No more chronic treatments. The long term money stream has stopped. So instead the pharma companies simply charge a fortune for the new Hep C cure drugs.

Big pharma LOVES new products. They spend many billions searching for new and exciting drugs. If Qu's technology works they'd be foolish to buy up Qu and then hide it under a bushel. It would be far better for them and much better aligned with their current business model buy it up, lock up its technology with as many patents as they can possibly obtain, and then charge an arm and a leg for it.

 

[Jonny84]

It's pretty clear that big pharma is obsessed with big profits - to the point that it's fair to call them excessively greedy. But I think people are often too quick to assign to them an unwarranted level of evil and bad intentions. If the Qu vaccine or any other new product works great they won't want to crush it. They will want to own it. They will want to be the only company offering this exciting new product. They will want to reap the rewards of Qu's cleverness and hard work.

One often heard criticism is that big pharma deliberately suppresses cures in favor of chronic treatments to keep the money flowing long term. But the example in recent years of hepatitis C puts the lie to that notion. They had expensive, chronic treatments for Hep C going for years and years with interferon in combo with some anti-virals. It was expensive and didn't work very well. Then the new Hep C drugs were developed that are outright cures - miracle cures. It's been a revolution. No more chronic treatments. The long term money stream has stopped. So instead the pharma companies simply charge a fortune for the new Hep C cure drugs.

Big pharma LOVES new products. They spend many billions searching for new and exciting drugs. If Qu's technology works they'd be foolish to buy up Qu and then hide it under a bushel. It would be far better for them and much better aligned with their current business model buy it up, lock up its technology with as many patents as they can possibly obtain, and then charge an arm and a leg for it.

Good post and many excellent points.

I agree they will be falling over themselves to get a hold of this. Can you imagine the impact on share price when the news breaks of owning a possible Crohn's cure? They'll be wetting themselves.

In the mean time IBD patients themselves must be the greatest advocated for this research. I'd encourage folk to spread the word.

 

[D Bergy]

Taking one of the current treatments is far more profitable in the long run. You are never done with them as they are not curative.

There are many possible outcomes but one is they are bought out and get the patents and sit on it.

Dan

 

[Jonny84]

But even the current treatments will be replaced. We are talking 5-7 years before QBECO hits the market. In that time there will be a number of new treatments available.

Its no more than a question of time - drugs like infliximab may be extremely profitable but they are also very effective in bringing severe inflammation under control. Infliximab is far from perfect but its a big step forward from what was available before. Its patent has now expired - there is always a gap in the market and it can only be filled by coming up with something that is better than what's come before.

 

[Crohn2357]

It's pretty clear that big pharma is obsessed with big profits - to the point that it's fair to call them excessively greedy. But I think people are often too quick to assign to them an unwarranted level of evil and bad intentions. If the Qu vaccine or any other new product works great they won't want to crush it. They will want to own it. They will want to be the only company offering this exciting new product. They will want to reap the rewards of Qu's cleverness and hard work.

One often heard criticism is that big pharma deliberately suppresses cures in favor of chronic treatments to keep the money flowing long term. But the example in recent years of hepatitis C puts the lie to that notion. They had expensive, chronic treatments for Hep C going for years and years with interferon in combo with the anti-viral drug ribavirin. It was expensive and didn't work very well. Then the new Hep C drugs were developed that are outright cures - miracle cures. Nobody sought to suppress these cures. It's been a revolution. No more chronic treatments. The long term money stream has stopped. So instead the pharma companies simply charge a fortune for the new Hep C cure drugs.

Big pharma LOVES new products. They spend many billions searching for new and exciting drugs. If Qu's technology works they'd be foolish to buy up Qu and then hide it under a bushel. It would be far better for them and much better aligned with their current business model buy it up, lock up its technology with as many patents as they can possibly obtain, and then charge an arm and a leg for it.

If you re-read my post you may see that the content is all about all about possibilities. I believe what you say is also a possibility.

As for the big pharma and the establishment, I have nothing positive to say. The mechanism is economically clear: maximisation of profits, increase of capital as the sole value and direction. This is capitalism as we know it; but there’s also a political ideology running along with it, which is not that clear, and is part of what is going on in our lives, which includes seemingly mechanistic economical decisions and even our illnesses.

How many natural treatments have been suppressed, banned by the fda and governments, highly inflenced (controlled) by the big pharma and the whole political-economical establishment? How many scientists’ lives ruined because they want to explore other possibilities, create and pursue new hypotheses, and realise/practice their ideas that could have helped many?

Just for a simple example think about the lies about saturated fats, eggs, cholesterol, seed oils etc... All of them are always political-economical. Sickness is needed for the machinery to run, both economically and politically. Of course contextuality is the most important when making judgements; not generalisms.

About some people’s inclination towards blindly assigning the big pharma bad intentions in every instance (if that’s what you meant), I would agree that’s not a healthy way of approaching phenomena.

 

[Jonny84]

You describe the situation very accurately Crohn2357. That is the way thing are in the world - it's a reflection of who we are collectively as human beings.

I believe that an important part of the next phase of our (spiritual) evolution will be rethinking the way we do business. Its happening already with the rise of social enterprise, B corporations, social entrepreneurs, community based initiatives etc. One day people will look back and scratch their heads as to why we thought the profit dominated, share holder value driven world of the large multinational corporations was the right way to do business. Especially regarding those corporations that produce medicines, food etc.

 

[D Bergy]

There is nothing inherently wrong or bad in a profit driven system. Its basically like gravity in that it is a force that is naturally there. It is a matter of having the incentives for profit put in the proper place and a truly free marketplace of ideas and products. One where small companies can innovate without the threat of being stepped on in the process. Where cheap treatments are allowed to exist without interference.

No one but big pharma can complete with big pharma. Only because they control virtually every aspect of treatment via their control of the FDA, media, scientific journals, etc. They answer to themselves for the most part.

It shows in our second rate health care system that politicians refer to as best in the world. Its not even in the top ten in the U.S. We have some good aspects of healthcare but overall it’s not nearly what it could or should be.

Ok. We are way off topic now but I truly hope that something better is coming because the current mainstream treatments are nothing to brag about. I am doing fine myself but there tens of thousands not as fortunate.

Dan

 

[Jonny84]

There is nothing inherently wrong or bad in a profit driven system. Its basically like gravity in that it is a force that is naturally there. It is a matter of having the incentives for profit put in the proper place and a truly free marketplace of ideas and products. One where small companies can innovate without the threat of being stepped on in the process. Where cheap treatments are allowed to exist without interference.

No one but big pharma can complete with big pharma. Only because they control virtually every aspect of treatment via their control of the FDA, media, scientific journals, etc. They answer to themselves for the most part.

It shows in our second rate health care system that politicians refer to as best in the world. Its not even in the top ten in the U.S. We have some good aspects of healthcare but overall it’s not nearly what it could or should be.

Ok. We are way off topic now but I truly hope that something better is coming because the current mainstream treatments are nothing to brag about. I am doing fine myself but there tens of thousands not as fortunate.

Dan

Treatment gets better incrementally - are things perfect now? Absolutely not but are they better than they were 20 years ago? Definitely. Will they be even better in another 20 years? Of course. As much as its strong medication and there are risks, I'd be without a colon if it wasn't for the biologics..

As much as I wish with all my heart the QBECO was available now, its great that as Crohn's patients that there is something in development for us that will lead to a very significant step forward in treatment. I always remind myself of that. Its frustration and its years away but there is light at the end of the tunnel.

 

[Crohn2357]

I truly hope that something better is coming because the current mainstream treatments are nothing to brag about.

I agree with that. We need more treatment options, better or worse. Here’s a list of clinical trials for Crohn’s that are currently recruiting patients:

https://www.clinicaltrials.gov/ct2/...Search=Apply&recrs=a&age_v=&gndr=&type=&rslt=
Here’s another list:

https://trials.crohnscolitisfoundation.org/
——————

https://www.niddk.nih.gov/health-information/digestive-diseases/crohns-disease/clinical-trials
This is the main webpage:

https://www.clinicaltrials.gov/

 

[Crohn2357]

These are currently recruiting phase 3 and phase 4 studies for Crohn’s, all around the world:

https://www.clinicaltrials.gov/ct2/...ndr=&type=&rslt=&phase=2&phase=3&Search=Apply

By applying filters we can see different lists.

 

[Crohn2357]

There’s also this website:

https://ibdnewstoday.com/

 

[Jonny84]

Looks like there are many more options in the pipe line. Is there anything that it not an immune suppressant?

 

[Crohn2357]

Just from a quick glance I have seen stem cell and EN studies.

 

[Jonny84]

Also on the subject of big pharma research - why has there not been more of an effort to find a replacement for pred?

I would have thought this would be one of the highest priorities of IBD research given that in some cases pred can have a worse effect on the body than the disease itself.

 

[Delta_hippo]

This has been such an interesting thread to read, thank you to everyone who has contributed. Looking at the studies underway there is hope that one of the new directions will pan out: different antibiotic combinations; the anti-map vaccine; restoring the innate immune system; phages; diet; so that we won't have to choose between immunosuppresant drugs or uncontrolled inflammation.

In the here and now though, what to do? I'm on entyvio at the moment after failing to tolerate the other immunosuppresant pills and remicade. I also started the perfect health diet around the time remi failed and haven't exactly felt well but haven't had to take time off sick since I started.

What are people's thoughts about "natural" antimicrobial herbs to try and help keep bacteria under control. I'm conscious entyvio decreases what might already be an inadequate innate immune response but reluctant to just come off it as I'm terrified of getting a perforation/ sepsis again. And I can't start antibiotics without a doctor authorising and if I could would you go for an anti-map combo or anti- e coli.

Interesting what kiny said about night sweats, this happened to me a couple of months before I got seriously ill.

 

[Crohn2357]

What are people's thoughts about "natural" antimicrobial herbs to try and help keep bacteria under control.

I think one of the most important supplements Crohn’s patients can take is vitamin D3. Regarding herbs, I know a person who has colonic CD and a positive MAP culture (blood), he has used oil of oregano (mixed with thyme oil, high carvacrol) with success. He used to be active in HW’s Crohn’s forum. I think that might be worth a try.

Herbs generally work much better for UC patients. With Crohn’s, you have deep transmural inflammation, which makes you require a more systemic effect to resolve the inflammation (through whatever mechanism), as opposed to the more local effects herbs have on UC. Not to mention the different pathogenesis.

 

[Crohn2357]

@David, what do you think about Qu’s vaccine, and its potential for the future?

Also, what are your thoughts on the upcoming Crohn’s MAP Vaccine trial that will start recruiting Crohn’s patients at the end of this year (estimation)?

 

[Crohn2357]

I agree that claims and speculations about good and bad bacteria are bogus. Microbiota topic is highly complex with its interrelations with each other, the host, the environment, epigenetics etc. And the current knowledge about the topic is almost nil - compared to what needs to be known.

https://www.newscientist.com/articl...dition-may-be-triggered-by-good-gut-bacteria/

 

[Crohn2357]

Segal AW, Studies on patients establish Crohn's disease as a manifestation of impaired innate immunity

Abstract

The fruitless search for the cause of Crohn's disease has been conducted for more than a century. Various theories, including autoimmunity, mycobacterial infection and aberrant response to food and other ingested materials, have been abandoned for lack of robust proof. This review will provide the evidence, obtained from patients with this condition, that the common predisposition to Crohn's is a failure of the acute inflammatory response to tissue damage. This acute inflammation normally attracts large numbers of neutrophil leucocytes which engulf and clear bacteria and autologous debris from the inflamed site. The underlying predisposition in Crohn's disease is unmasked by damage to the bowel mucosa, predominantly through infection, which allows faecal bowel contents access to the vulnerable tissues within. Consequent upon failure of the clearance of these infectious and antigenic intestinal contents, it becomes contained, leading to a chronic granulomatous inflammation, producing cytokine release, local tissue damage and systemic symptoms. Multiple molecular pathologies extending across the whole spectrum of the acute inflammatory and innate immune response lead to the common predisposition in which defective monocyte and macrophage function plays a central role. Family linkage and exome sequencing together with GWAS have identified some of the molecules involved, including receptors, molecules involved in vesicle trafficking, and effector cells. Current therapy is immunosuppressant, which controls the symptoms but accentuates the underlying problem, which can only logically be tackled by correcting the primary lesion/s by gene therapy or genome editing, or through the development of drugs that stimulate innate immunity.

...

TREATMENT
Treatment of CD poses a problem. It would be logical to correct the underlying pathogenesis by enhancing innate immunity, however, no such drugs are currently available.
Immunostimulation might exaggerate ongoing bowel inflammation. However, if developed, such treatments, could be useful to maintain patients in remission after they had been cleared of disease by surgical resection, or through the use of non-immunosuppressant therapies such as elemental diets(119), They might also be useful as a prophylactic measure in subjects like siblings of patients or members of families with multiply affected individuals at high risk of developing the disease.
Past attempts to stimulate immunity with Levamisole were unsuccessful(120) and GM-CSF was modestly effective but was never adopted as an FDA approved treatment(121).
An alternative approach that is likely to be applied in the near future, given that most of the defective genes are in myeloid cells in the bone marrow, would be transplantation of autologous bone marrow transfected with the normal gene or altered by genome editing, into conditioned recipients.
There is evidence that allogeneic bone marrow transplantation can cure CD(122) but risk of death or major side effects precludes its routine use except in children with severe monogenic disease. It was hoped that autologous haematopoetic stem cell transplantation into conditioned patients might “reset” the immune system without correcting the underlying genetic lesion, but a randomised trial did not result in a statistically significant improvement and was associated with significant toxicity(123).
Specific correction of the causal genetic lesions appears logical and is becoming increasingly feasible. Gene therapy using viral vectors to transfect haemopoietic stem cells with the wild-type gene now provides standard clinical practise for several primary immunodeficiency diseases and other conditions(124). This approach should be currently applicable to treat CD where the causal gene defect is readily identifiable, for example in subjects with homozygous truncating mutations in NOD2. In the near future, improvements in gene editing technologies should lead to a personalised medicine approach with the correction of the genetic architecture of individual patients as the contributions to their disease by individual variants in genes regulating innate immunity become better defined and easier to identify.

10.1111/joim.12945

 

[Pangolin]

10.1111/joim.12945

Great find. This article really seems to be on the right track.

 

[Guerrero]

I guess many scientists and doctors don’t agree with this theory, otherwise they’d suggest different therapies, right?
Or they don’t event know about it??

 

[Crohn2357]

Or they don’t event know about it??

If they read the Wikipedia page of Crohn’s, they would see these:

While the cause of Crohn's disease is unknown, it is believed to be due to a combination of environmental, immune, and bacterial factors in genetically susceptible individuals.[6][7][8] It results in a chronic inflammatory disorder, in which the body's immune system attacks the gastrointestinal tract, possibly targeting microbial antigens.[7][9] While Crohn's is an immune-related disease, it does not appear to be an autoimmune disease(in that the immune system is not being triggered by the body itself).[10]The exact underlying immune problem is not clear; however, it may be an immunodeficiency state.[9][11][12]

References ([9][11][12]):

• Marks DJ, Rahman FZ, Sewell GW, Segal AW (February 2010). "Crohn's disease: an immune deficiency state". Clinical Reviews in Allergy & Immunology. 38 (1): 20–31. doi:10.1007/s12016-009-8133-2. PMC 4568313. PMID 19437144.
• Casanova JL, Abel L (August 2009). "Revisiting Crohn's disease as a primary immunodeficiency of macrophages". The Journal of Experimental Medicine. 206 (9): 1839–43. doi:10.1084/jem.20091683. PMC 2737171. PMID 19687225.
• Lalande JD, Behr MA (July 2010). "Mycobacteria in Crohn's disease: how innate immune deficiency may result in chronic inflammation". Expert Review of Clinical Immunology. 6 (4): 633–41. doi:10.1586/eci.10.29. PMID 20594136.

...


Cause
Risk factors

	Crohn's disease	Ulcerative colitis
Smoking	Higher risk for smokers	Lower risk for smokers[44]
Age	Usual onset between 15 and 30 years[45]	Peak incidence between 15 and 25 years

While the exact cause is unknown, Crohn's disease seems to be due to a combination of environmental factors and genetic predisposition.[46] Crohn's is the first genetically complex disease in which the relationship between genetic risk factors and the immune system is understood in considerable detail.[47] Each individual risk mutation makes a small contribution to the overall risk of Crohn's (approximately 1:200). The genetic data, and direct assessment of immunity, indicates a malfunction in the innate immune system.[48] In this view, the chronic inflammation of Crohn's is caused when the adaptive immune system tries to compensate for a deficient innate immune system.[49]

Genetics

NOD2 protein model with schematic diagram. Two N-terminal CARD domains (red) connected via helical linker (blue) with central NBD domain (green). At C-terminus LRR domain (cyan) is located. Additionally, some mutations which are associated with certain disease patterns in Crohn's disease are marked in red wire representation.[50]
Crohn's has a genetic component.[51] Because of this, siblings of known people with Crohn's are 30 times more likely to develop Crohn's than the general population.

The first mutation found to be associated with Crohn's was a frameshift in the NOD2 gene (also known as the CARD15 gene),[52] followed by the discovery of point mutations.[53] Over thirty genes have been associated with Crohn's; a biological function is known for most of them. For example, one association is with mutations in the XBP1 gene, which is involved in the unfolded protein response pathway of the endoplasmic reticulum.[54][55] The gene variants of NOD2/CARD15 seem to be related with small-bowel involvement.[56] Other well documented genes which increase the risk of developing Crohn disease are ATG16L1,[57] IL23R,[58] IRGM,[59] and SLC11A1.[60] There is considerable overlap between susceptibility loci for IBD and mycobacterial infections.[61]Recent genome-wide association studies have shown that Crohn's disease is genetically linked to coeliac disease.[62]

Crohn's has been linked to the gene LRRK2 with one variant potentially increasing the risk of developing the disease by 70%, while another lowers it by 25%. The gene is responsible for making a protein, which collects and eliminates waste product in cells, and is also associated with Parkinson's disease.[63]

Immune system
There was a prevailing view that Crohn's disease is a primary T cell autoimmune disorder, however, a newer theory hypothesizes that Crohn's results from an impaired innate immunity.[64] The later hypothesis describes impaired cytokine secretion by macrophages, which contributes to impaired innate immunity and leads to a sustained microbial-induced inflammatory response in the colon, where the bacterial load is high.[7][48] Another theory is that the inflammation of Crohn's was caused by an overactive Th1 and Th17 cytokine response.[65][66]

In 2007, the ATG16L1 gene has been implicated in Crohn's disease, which may induce autophagy and hinder the body's ability to attack invasive bacteria.[57] Another study has theorized that the human immune system traditionally evolved with the presence of parasites inside the body, and that the lack thereof due to modern hygiene standards has weakened the immune system. Test subjects were reintroduced to harmless parasites, with positive response.[67]

Microbes
It is hypothesised that maintenance of commensal microorganism growth in the GI tract is dysregulated, either as a result or cause of immune dysregulation.[68][69]

A number of studies have suggested a causal role for Mycobacterium avium subspecies paratuberculosis (MAP), which causes a similar disease, Johne's disease, in cattle.[70][71]

NOD2 is a gene involved in Crohn's genetic susceptibility. It is associated with macrophages' diminished ability to phagocytize MAP. This same gene may reduce innate and adaptive immunity in gastrointestinal tissue and impair the ability to resist infection by the MAP bacterium.[72] Macrophages that ingest the MAP bacterium are associated with high production of TNF-α.[73][74]

Other studies have linked specific strains of enteroadherent E. coli to the disease.[75] Adherent-invasive Escherichia coli (AIEC), are more common in people with CD,[76][77][75] have the ability to make strong biofilms compared to non-AIEC strains correlating with high adhesion and invasion indices[78][79] of neutrophils and the ability to block autophagy at the autolysosomal step, which allows for intracellular survival of the bacteria and induction of inflammation.[80] Inflammation drives the proliferation of AIEC and dysbiosis in the ileum, irrespective of genotype.[81] AIEC strains replicate extensively inside macrophages inducing the secretion of very large amounts of TNF-α.[82]

Mouse studies have suggested some symptoms of Crohn's disease, ulcerative colitis, and irritable bowel syndrome have the same underlying cause. Biopsy samples taken from the colons of all three patient groups were found to produce elevated levels of a serine protease.[83] Experimental introduction of the serine protease into mice has been found to produce widespread pain associated with irritable bowel syndrome, as well as colitis, which is associated with all three diseases.[84] Regional and temporal variations in those illnesses follow those associated with infection with the protozoan Blastocystis.[85]

The "cold-chain" hypothesis is that psychrotrophic bacteria such as Yersinia and Listeria species contribute to the disease. A statistical correlation was found between the advent of the use of refrigeration in the United States and various parts of Europe and the rise of the disease.[86][87][88]

There is an apparent connection between Crohn's disease, Mycobacterium, other pathogenic bacteria, and genetic markers.[89][90] In many individuals, genetic factors predispose individuals to Mycobacterium avium subsp.paratuberculosis infection. This bacterium then produces mannins, which protect both itself and various bacteria from phagocytosis, thereby causing a variety of secondary infections.[91]

Still, this relationship between specific types of bacteria and Crohn's disease remains unclear.[92][93]

There is a tentative association between Candida colonization and Crohn's disease.[94]

https://en.m.wikipedia.org/wiki/Crohn's_disease

I guess many scientists and doctors don’t agree with this theory, otherwise they’d suggest different therapies, right?

Most scientists and doctors are puppets of the drug industry. It’s not up to them to decide on treatments. Most of the scientists and doctors are content with their earnings and social status. Ignorance, and lack of questioning and of responsibility makes this system run smooth for them.

 

[Pangolin]

This thread, the impaired immunity paper, and the Qu Biologics trials are making me wonder if there's any role for pyrotherapy (inducing a fever) in Crohn's treatment. Has that been tested?

 

[Guerrero]

https://www.medicalnewsbulletin.com/the-role-of-macrophages-in-the-treatment-of-crohns-disease/

 

[Crohn2357]

This thread, the impaired immunity paper, and the Qu Biologics trials are making me wonder if there's any role for pyrotherapy (inducing a fever) in Crohn's treatment. Has that been tested?

I remember that’s been discussed a few times in HW forum. I think I read about artificially inducing and maintaining fever through hot showers in one of those discussions too. It’s risky, to say the least. It can cause brain damage. You can search for it in HW’s UC forum if you are really interested; though I am not sure if you can find those threads easily. Old Mike wrote in them.

 

[Crohn2357]

When I say ''crohn's disease'', I too strictly mean ileal disease, with no or negligeable colon involvement. I know far more about the ileum and peyer's patches than I do about the colon.

Some info on Peyer’s patches:

Haven't been on a lot, saw tag late.

Peyer's patches are normal to begin with, it's just a feature of the small intestine, it is the inflammation of them that is a sign of an issue.

Peyer's patches are tissue with immune cells. They're only found in the small intestine, you can see them with the naked eye through an endoscope, they look like little domes. The little dome bump is caused by the immune cells, the follicle. They're right on the surface of the intestinal wall, covered by M cells. I posted pictures of inflamed peyer's patches before. Peyer is from the person who discovered them, patches is because they're spread out like a patch. They're like mini lymph nodes in a way. Most people learn about lymph nodes long before they hear about peyer's patches so it's common to compare them to a lymph node.

Peyer's patches are like sensors, they're like the guards of the small intestine checking if everyone who is present in the small intestine is allowed to be there. If peyer's patches is the police station of the small intestine, then M cells are the gate that opens and closes. M cells are right on the surface, they actually aren't covered with mucus, and the guards at the M cells call in thousands of particles and antigens in to check for questioning in the peyer's patch.

The peyer's patch is filled with lymphocytes and dendritic cells. The immune system consists of the innate immune system and adaptive immune system. Dendritic cells awaken the adaptive immune cells if something has gone wrong (such as a salmonella infection), it's the alarm bell that will awaken those lymphocytes (B and T cells). They're often called antigen presenting cells, APC, since they present antigen to immune cells from the adaptive immune system as evidence that something is going horribly wrong in the body and they need new recruits to help, they're the alarm bell. Not only that, since those peyer's patches are conected to the lymphatic system, it will start recruiting more and more immune cells until the threat is over.

Anyway, why the peyer's patches are interesting in crohn's disease. Is because they are specific to the small intestine, if inflamed they are the first signs with an endoscope of crohn's disease, they are most active during teen years (crohn's is most diagnosed during those years) and we know AIEC invades peyer's patches through those M cells (AIEC is associated with crohn's disease).

Why does Crohn's disease usually occur in terminal ileum?
Renzo Caprilli
Journal of Crohn's and Colitis, Volume 2, Issue 4, December 2008, Pages 352–356, https://doi.org/10.1016/j.crohns.2008.06.001
Published: 01 December 2008

Abstract
Crohn's disease can affect any part of the gastrointestinal tract, but terminal ileum is the most frequent localization. The reason why Crohn's disease is primarily located in the distal part of the ileum remains unexplained.

In this article it has been attempted to provide a compelling explanation why Crohn's disease usually occurs in terminal ileum. Recent data indicate that some individuals are genetically predisposed to develop ileal Crohn's disease. Two genetic alterations, the polymorphism of Caspase Associated Recruitment Domain (CARD15) and Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACM6), favour the colonization of terminal ileum by entero adherent-invasive Escherichia coli (AIEC). The adhesion of these bacteria to epithelial intestinal cells depends on Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 expression in ileal epithelial cells and on the reduced ileal defensins expressed in a CARD15 dependent manner. Genetic defects in Authophagy-related 16-like gene (ATG16L1) and Immunity-related Guanosine Triphospatase (IRGM) recently found in ileal CD patients lead to a reduction of bacterial killing by macrophages and consequent continuous immunological upstimulation, cytokine secretion, chronic inflammation of the ileum and tissue injury. On the basis of all these data Crohn's disease of the ileum seems to be a subset of the disease mainly genetically determined.

https://academic.oup.com/ecco-jcc/article/2/4/352/489613

Our findings pose an important question: does the CD lesion selectively originate from the Peyer’s patch? In this regard, Lockhart-Mummery and Morson[2] reported in 1960 that the earliest microscopic change in CD was ulceration of the lymphoid follicles and Peyer’s patches in the terminal ileum. Since then, several investigators have reported that CD initially occurs as tiny aphthoid lesions at the sites of mucosal lymphoid follicles in the gastrointestinal tract[3-5]. Recently, Fujishima et al[3-5] investigated ultrastructurally the epithelium covering solitary lymphoid nodules using biopsy samples obtained from the colorectum during colonoscopy, and indicated that the red halo appearance of such epithelia seemed to precede visible aphthoid ulcers. They suggested that ulcerations in CD might originate from the follicle-associated epithelium (FAE), possibly related to its role as a portal entry for potentially pathogenic agents. These studies have led to the concept that CD could originate from GALT including Peyer’s patches and lymphoid follicles in the terminal ileum[3-8]. With this concept[3-7], one can explain the reason for the occurrence of the skip lesions and the frequent involvement of the terminal ileum in CD.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572213/
Histopathology of Crohn’s disease and ulcerative colitis
http://www.forpath.org/workshops/minutes/0411/Crohn_s_disease_and_ulcerative_colitis.pdf
https://en.m.wikipedia.org/wiki/Peyer's_patch
https://en.m.wikipedia.org/wiki/Microfold_cell
https://en.m.wikipedia.org/wiki/Gut-associated_lymphoid_tissue
https://en.m.wikipedia.org/wiki/Lamina_propria

 

[kiny]

Antigen-related Cell Adhesion Molecule 6 (CEACM6), favour the colonization of terminal ileum by entero adherent-invasive Escherichia coli (AIEC).

A few years ago, I made an extensive AIEC index once when I was bored. If anyone wants to read about AIEC, the studies are all ordered by chronological order. I hand picked all the significant studies and added some compelling images to the thread.

https://crohnsforum.com/threads/aiec-index.52198/#post-660861

 

[kiny]

If they read...

Three quarter of all lymphocytes are in mucosal tissue. The intestine is the main entry point of bacteria.

Considering crohn's disease is an innate immunodeficiency of macrophages, crohn's disease patients should not just be seen by a gastro, but by a gastro and an immunologist.

When world renowned Institut Pasteur is categorically classifying crohn's disease as innate immunodefficiency and is trying to treat it with bacteriophages, it is time for some gastros to take a step back and start accepting what immunologists are writing.

And the ones who continue the peddle to ''autoimmunity, stress, we simple don't know (and don't care)'' theories, should be questioned for negligence.

 

[Guerrero]

Is there any treatment we could already received from immunologists?

 

[kiny]

The reason I said that crohn's disease patients should also be followed by immunologists is because the innate immunodefficiency is why people with crohn's disease develop extraintestinal manifestations like aphthous ulcers, uveitis, secondary infections, why some have lymphopenia, etc.

Most (if not all) of the common extraintestinal manifestations are simply a consequence of innate immunodeficiency, that are also seen in other innate immunodeficiency diseases. People who specialize in innate immunodeficiency diseases such as immunologists, understand and can properly treat those manifestations, gastros often don't understand why these secondary symptoms present themselves.

 

[kiny]

gastros often don't understand why these secondary symptoms present themselves.

To be more specific.

a gastro who still believes that crohn's disease is an autoimmune disease (a completely discredited theory, there's no self-antigen response in CD) is not going to be able to explain:

-why the patient develops aphthous ulcers
-why the patient develops uveitis
-why the patient has secondary infections
-why the inflammation is granulomatous inflammation
-why the patient responds to antibiotics or EN

But if you show those symptoms to an immunologist. Well, they recognize them, they have seen them in chronic granulomatous disease patients, they have seen them in blau syndrome patients, they have seen them in a whole host of diseases and they know how to treat them.

 

[Guerrero]

Very interesting points kiny.
Waiting for our gastros to wake up then.. but in the meantime is there a natural/medicinal way to boost our immunity or macrophage activity?

 

[kiny]

natural/medicinal way to boost macrophage activity?

Well, ''natural'' is keeping optimal levels of Vitamin D. Vitamin D impacts macrophage function and beta-defensins production.

(people with CD also often carry VDR anomalies, another reason why vitamin D matters in CD

people in northern regions also have far more cases of CD, the only reasonable explanation anyone has come up for this so far, is that they get less sunshine and less vitamin D, kids who play in the sunshine also have less chance to develop CD than kids who stay inside)

''medicinal'' is GM-CSF, Granulocyte-macrophage colony-stimulating factor, but it wasn't approved by the FDA for crohn's disease. It worked reasonably well in kids with CD, but not good enough in adults.

 

[Guerrero]

What would be an optimal level of vitamin D you think? I checked my levels this year and last year and they were around 35-40, so not low but not high...

Regarding the GM-CSF i've found studies and trials... don't seem to be miraculous so far, but they probably need to work on it and find the right combinations.

 

[Crohn2357]

''medicinal'' is GM-CSF, Granulocyte-macrophage colony-stimulating factor, but it wasn't approved by the FDA for crohn's disease. It worked reasonably well in kids with CD, but not good enough in adults.

I think rapamycin might also be worth looking in the same vein.

New insights provided by the results of genome-wide association scanning in Crohn's disease highlight autophagy, a cellular process implicated in the clearance of intracellular bacteria, as a key process in Crohn's disease pathogeneses. Sirolimus (rapamycin) is a drug used to upregulate autophagy in cell culture in the laboratory, and in clinical practice to prevent rejection following organ transplantation due to independent immunosuppressive action.

Use of sirolimus (rapamycin) to treat refractory Crohn's disease. - PubMed - NCBI

Mohamed Mutalib, Osvaldo Borrelli, Sarah Blackstock, Fevronia Kiparissi, Mamoun Elawad, Neil Shah, Keith Lindley, The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children, Journal of Crohn's and Colitis, Volume 8, Issue 12, 1 December 2014, Pages 1730–1734, https://doi.org/10.1016/j.crohns.2014.08.014

https://clinicaltrials.gov/ct2/show/NCT02675153

What would be an optimal level of vitamin D you think? I checked my levels this year and last year and they were around 35-40, so not low but not high...

I have been taking 5000 IU vitamin d3 every day for years.

https://www.vitamindcouncil.org/why-does-the-vitamin-d-council-recommend-5000-iuday/
https://www.tandfonline.com/doi/full/10.1586/eci.10.31
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285235/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1728007
https://www.hindawi.com/journals/bmri/2015/470805/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360635/
http://onlinelibrary.wiley.com/doi/10.1111/j.1462-5822.2010.01491.x/full

There are many studies that show correlations between vitamin d levels and disease severity, treatment-refractoriness, resection and remission rates, inflammatory markers etc. The researchers are still doing research on vitamin d and Crohn’s, you can even see two of them from this link:

These are currently recruiting phase 3 and phase 4 studies for Crohn’s, all around the world:

https://www.clinicaltrials.gov/ct2/...ndr=&type=&rslt=&phase=2&phase=3&Search=Apply

 

[Crohn2357]

Three quarter of all lymphocytes are in mucosal tissue. The intestine is the main entry point of bacteria.

Considering crohn's disease is an innate immunodeficiency of macrophages, crohn's disease patients should not just be seen by a gastro, but by a gastro and an immunologist.

The reason I said that crohn's disease patients should also be followed by immunologists is because the innate immunodefficiency is why people with crohn's disease develop extraintestinal manifestations like aphthous ulcers, uveitis, secondary infections, why some have lymphopenia, etc.

Most (if not all) of the common extraintestinal manifestations are simply a consequence of innate immunodeficiency, that are also seen in other innate immunodeficiency diseases. People who specialize in innate immunodeficiency diseases such as immunologists, understand and can properly treat those manifestations, gastros often don't understand why these secondary symptoms present themselves.

This is a comment written recently by John Aitken, after someone shared this paper by Marcel Behr:

 

[kiny]

Yes, Marcel Behr and Tony Segal are brilliant people. I have read and linked their studies countless times. Even though Behr now writes about TB mostly. The team from Clermont-Ferrand and Institut Pasteur is brilliant too.

Without these people (which is a small group of people), we would still be debating if crohn's disease is caused by stress, diet, or by the fairy princess.

 

[kiny]

Behr and Segal also pointed out that there needs to be some kind of initial and rather catastrophic event to initiate the disease.

The intestinal mucosa is very good at regulating inflammation, it is in a constant state of minor chronic inflammation in ''healthy'' people.

It is constantly playing a balancing act between effector T cells that increase inflammation, and suppressor T cells that lower inflammation. It is constantly balancing CD8+ and CD4+ responses in the epithelium and lamina propria.

Unlike other parts of the body, the intestine is being confronted with antigen 24/7, and is constantly regulating inflammation.

For such a competent system to go so catastrophically out of control, you need a serious initial acute infection with a bacteria. (which is what people with crohn's disease show, the weeks or days leading up to diagnosis people with crohn's disease have fevers, they have night sweats, they throw up, they are going through an acute infection)

What initiated the immune response, and compromised the intestinal mucosa...and what maintains the inflammation...are probably two distinct and different events.

The age of onset in ileal crohn's disease being around puberty, can easily be explained by the activity of peyer's patches being highest in puberty. Many foodborne bacteria exploit M cells.

 

[kiny]

Crohn's disease is widespread in the West. The pathogens responsible for that initial infection need to be widespread also, and they need to target the ileum.

People with CD predisposition are vulnerable to mycobacteria and intracellular bacteria that invade the ileum. That limits the potential bacteria to just a few.

Foodborne infections are still incredibly common in the West. Salmonella, campylobacter, yersinia, listeria, e coli. Millions are infectioned in the West on a yearly basis.

(I put salmonella in the front of the list, because salmonella is particularly good at invading M cells in the ileum, the niche of this bacteria is how it can exploit peyer's patches, and how it exploits immunocompromised individuals)

Studies have consistently shown that people infected with those bacteria, are much more likely to develop CD after.

(But like Segal points out, this initial infection is probably no longer responsible for the chronic inflammation, you don't find those bacteria in stool of CD patients, however, it is needed to initiate the disease)

 

[kiny]

(that's not to say that because I believe, like Segal argues, that the initial infection is probably overcome and cleared, that people can't be reinfected

several studies have made the case that salmonella infections in crohn's disease could not just initiate the disease, but people with CD could also be chronically reinfected
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329042/

foodborne infections are so common in the West, that it is highly likely that at least a subset of people with crohn's disease will simply be reinfected with a bacteria like salmonella again

this also again argues for the use of EN of course, since it removes the potential of reinfection

however, you don't find salmonella in stool in patients with crohn's disease on a consistent basis, people with CD are able to overcome a salmonella infection, but probably much slower, and with much more damage to the epithelial barrier than immunocompetent people...the chronic inflammation is simply kept alive by the fecal stream and opportunistic bacteria like AIEC that thrive in inflammatory conditions)

 

[kiny]

Regarding the search for the bacteria that caused the onset of crohn's disease.

If the bacteria was cleared, then it's no longer important to us patients which bacteria it was. If you use EN you avoid reinfection and it doesn't matter anymore if it was salmonella or campylobacter or some other bacteria.

It matters only if you want to study the incidence of crohn's disease and do demographic studies or want to support the cold-chain hypothesis.

(it doesn't even matter as a preventative matter. How could you possibly use this knowledge to prevent new CD cases. Screen everyone for NOD2 mutations and tell them to stop eating poultry and put them on EN to avoid them developing a salmonella infection? It would never work.)

What the studies that showed that people with salmonella and campylobacter infections are more likely to develop CD, did...was solidify the immunodeficiency case. But me as a patient, don't care what that initial bacteria was, it doesn't help me knowing if the bacteria was cleared.

What matters far more is knowing what is causing the chronic inflammation in people with CD, studies about AIEC, fungi, fecal stream, etc.

 

[Crohn2357]

Well, ''natural'' is keeping optimal levels of Vitamin D.

Vitamin D Deficiency Predisposes to Adherent-invasive Escherichia coli-induced Barrier Dysfunction and Experimental Colonic Injury
Amit Assa, MD Linda Vong, PhD Lee J. Pinnell, MSc Jaana Rautava, DDS, PhDNaama Avitzur, BSc Kathene C. Johnson-Henry, BSc Philip M. Sherman, MD
Inflammatory Bowel Diseases, Volume 21, Issue 2, 1 February 2015, Pages 297–306, https://doi.org/10.1097/MIB.0000000000000282
Published: 14 January 2015

Background
Adherent-invasive Escherichia coli (AIEC) colonization has been strongly implicated in the pathogenesis of Crohn's disease. Environmental triggers such as vitamin D deficiency have emerged as key factors in the pathogenesis of inflammatory bowel diseases. The aim of this study was to investigate the effects of 1,25(OH)2D3 on AIEC infection-induced changes in vivo and in vitro.

Methods
Barrier function was assessed in polarized epithelial Caco-2-bbe cells grown in medium with or without vitamin D and challenged with AIEC strain LF82. Weaned C57BL/6 mice were fed either a vitamin D–sufficient or –deficient diet for 5 weeks and then infected with AIEC, in the absence and presence of low-dose dextran sodium sulphate. Disease severity was assessed by histological analysis and in vivo intestinal permeability assay. Presence of invasive bacteria was assessed by transmission electron microscopy.

Results
Caco-2-bbe cells incubated with 1,25(OH)2D3 were protected against AIEC-induced disruption of transepithelial electrical resistance and tight-junction protein redistribution. Vitamin D–deficient C57BL/6 mice given a course of 2% dextran sodium sulphate exhibited pronounced epithelial barrier dysfunction, were more susceptible to AIEC colonization, and showed exacerbated colonic injury. Transmission electron microscopy of colonic tissue from infected mice demonstrated invasion of AIEC and fecal microbiome analysis revealed shifts in microbial communities.

Conclusions
These data show that vitamin D is able to mitigate the deleterious effects of AIEC on the intestinal mucosa, by maintaining intestinal epithelial barrier homeostasis and preserving tight-junction architecture. This study highlights the association between vitamin D status, dysbiosis, and Crohn's disease.

 

[kiny]

yes, AIEC abuses impaired autophagy of macrophages in crohn's disease. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1462-5822.2009.01381.x

What Vitamin D does is partly restore the defective autophagy in CD patients (polymorphisms in genes ATG16L1 and IRGM) by acting on NOD2, which constrains the proliferation of AIEC.

But there are limits with using vitamin D as a form of treatment, you can only strive for optimal vitamin D levels, you can't use too high doses, patients would get hypercalcemia and lots of other issues. But it's very important to have adequate levels of vitamin D. They have tried very high doses of vitamin D to treat CD, it's not any better as normal doses, what they do consistently find, is that people with too low vitamin D, are much sicker than people with optimals levels of vitamin D.

 

[kiny]

(reason why you can have studies that show 6 out of 10 of people with CD with AIEC in stool and biopsies...and 1 in 10 of healthy controls also showing AIEC...is because AIEC doesn't cause major issues in those healthy controls, they don't have polymorphisms in autophagy genes, they don't have immunodefficiencies, they can competently control the bacteria...the AIEC seen (rarely) in healthy controls, are also far less virulent types)

 

[kiny]

AIEC competes for nutrients like any other bacteria....that's why bacteriophages are interesting, you want to kill AIEC, but you don't want to kill everything with a broad spectrum antibiotic, you'll just enable AIEC to proliferate that much faster once it gets resistent.

Bacteriophages can now be genetically modified, so the defensive mechanisms against viruses that bacteria use (see CRISPR, the immune system of bacteria) are no longer useful.

Anti-CRISPR phages will revolutionize treatment. AIEC also use their disgusting biofilms to protect themselves, but that so far hasn't been an issue, phages seem to have no issue penetrating biofilms and injecting their genome.

 

[kiny]

Segal et al. detailing diminished acute inflammation in crohn's disease when challenged with E Coli. Comparing inadequate immune response in CD, and normal response in UC.

I wrote some TNF-α and IFN-y information. Lack of acute TNF-α secretion by macrophages in CD patients will severely limit the acute inflammatory response. Neutrophils recruitment is insufficient and delayed in CD.

TNF-α = potent inflammatory orchestrator, recruitment of neutrophils and monocytes, induction of fever
(produced by macrophages, NK cells anc T cells)

IFN-y = macrophage activation, MHC expression
(produced by T cells and NK cells)

Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease.

Department of Medicine, University College London

http://jem.rupress.org/content/206/9/1883.long

 

[kiny]

The wording ''bacterial load'' why use that word. Segal et al. keep using it, why not just ''bacteria''.

Crohn's disease patients can effectively clear minor infections, acute response might be delayed but it is resolved competently.

But crohn's disease patients don't effectively clear areas with high ''bacterial load''. Bacterial load is extremely high in the ileum and colon (much much less so higher up the GI tract, bacteria are in the ileum and colon, not higher up). Bacterial load seems to matter, a delayed acute immune response isn't a problem as long as the immune system is not overwhelmed, but it can get easily overwhelmed in the ileum and colon, especially if you add a fecal stream.

When you have a compromised epithelial barrier in the ileum or colon , bacterial load is extremely high, leading to a chronic adaptive response to compensate for a lack of acute response.

What fecal stream diversion does, is lower bacterial load. Resolution will still be delayed, but happen with much more competence, because the actue phase response is no longer overwhelmed.

 

[kiny]

Fecal stream diversion and broad spectrum antibiotics like cipro and flagyl their action includes a large decrease in ''bacterial load''.

(note studies that show cipro and flagyl are far more effective in CD patients if taken orally, and not very effective IV)
(antibiotics related to secondary infections should be IV)

Fecal transplantation worsen's crohn's disease. It is not surprising at all. It is a massive increase in bacterial load. Doctors who try this on crohn's disease patients should lose their license.

 

[Guerrero]

What about Rifaximin? Seems a good treatment option too.

 

[kiny]

What about Rifaximin? Seems a good treatment option too.

It's a very interesting antibiotic because rifaximin is gut-specific, it doesn't have potential side effects like cipro does, you can give it for longer. Cipro is very effective in inducing remissions in CD, but you can't give this antibiotic long term, cipro needs to be stopped after a while to avoid serious side effects, it's not a long term solution.

AIEC is sensitive to rifaximin (which is no wonder, it was invented to treat traveller's d. caused by E Coli), but AIEC are bacteria that adhere to and invade the epithelial barrier. I don't think we know why specifically rifaximin helps people with CD. Just because it acts on AIEC in vitro doesn't mean that it is doing that in crohn's disease patients. It might just be lowering bacterial load, rifaximin is not macrophage penetrating like cipro is. You would have to check presence of AIEC in stool before and after rifaximin treatment to know, and I don't think there are studies like that.

But yes, rifaximin is very interesting because it is gut-specific, which is why it has so few side effects.

 

[kiny]

(The fact antibiotics can cause remission in CD, was enough to 100% disqualify the autoimmune theory.

You need one single patient with CD who improves on antibiotics, and it disqualifies autoimmunity. If the inflammation shuts off when you remove bacteria, autoimmune theory is done. The immune system was responding to bacteria, not self-antigen.

If you have studies that show 40-60% induction of remission in CD patients on cipro, autoimmune theory is dead. The immune system in crohn's disease patients is responding to bacteria and fungi, not self-antigen. Autoimmune theory in crohn's disease is dead.

Dalziel knew it was caused by bacteria in 1913. Somewhere around the 90s it became a trend to start calling every inflammatory disease without a known cause autoimmune, even if there was no proof of this, you didn't need to present a self-antigen response.

Thank God those days are over, you actually need to present evidence nowadays. The evidence is completely on the side of bacterial involvement, you can't even mimmick crohn's disease in sterile environment without bacteria. There is zero evidence for autoimmunity, zero.

When world renowned Institut Pasteur gets involved in crohn's disease, you can burry the autoimmune theory, because all the evidence shows bacterial involvement.)

 

[kiny]

Anti-TNF like infliximab, were also not developed for crohn's disease. It was developed to treat infections, to manage inflammation from septic shock.

That's why infliximab used to be given once and discontinued when it was first used for crohn's disease.

Trying to limit the damage to tissue and organs during acute phases of inflammation is beneficial. But chronically shutting down the adaptive inflamatory response by blocking cytokine responsible for orchestrating that inflammation, will be deterimental long term and lead to chronic disease because you're overwheling an already compromised innate immune system.

That's why those biologics, when used chronically, ''mysteriously stop working'' after a year for most people, they stop working because you're stimulating chronic disease like Segal his team warned.

That's why you get these results from Canada.

Maybe if those clinicians opened a book instead of taking money from pharma companies, they wouldn't be so shocked at those depressing results from their clinic.

 

[kiny]

It's also increasingly difficult to make any sense of studies about new biologics that came out after infliximab.

They're clearly far less effective, some take months before they show any improvement.

We went from reliable high sensitivity CRP, ASCA, symptom and biopsy testing for infliximab, where the measuring stick was mucosal healing within weeks.

To studies relying on faecal calprotectin to prove a new biologic does anything. You can send the same stool sample to two different labs, and get vastly different faecal calprotectin results. And measuring sticks for mucosal healing went from weeks, to months.

What's the goal, to put people on infliximab for a few years, get depressing results like those Canadian hospitals, then put them on other biologics that might or might not work, and if they do work, it is maybe in 4 to 8 months in 20% of patients.

Spending billions on inventing new interleukin blockers, medication that is less and less effective. Without knowing a clue what half of those interleukin actually do and what possible side effects the medication might cause?

That is not a solution for patients, you need to start treating the underlying cause of the inflammation.

 

[Hopeful girl]

Crohn's disease is an immunodeficiency state where the innate immune system (especially the macrophages in the intestine) are unable to clear luminal content that has entered the intestinal wall. The initial lack of secretion of inflammatory cells, causes a chronic response from the adaptive immune system, T cells are chronically being recruited by APC like dendritic cells.

What remicade (and all other anti-inflammatory medication used for CD) does is block that secondary immune response.

This leads to lowering of inflammation. But the problem is that lumen content (mostly from the fecal stream) that has entered the intestinal wall, is now not cleared at all, because medication is actively blocking the immune response.

Infliximab never used to be chronically administered in the past, it was used a single time to stop inflammation. If you chronically administer infliximab like they do now, you are just going to stimulate the underlying lesions over time.


''The Lancet, 2006 Feb
Department of Medicine, University College London

Defective acute inflammation in Crohn's disease: a clinical investigation.

INTERPRETATION:
In Crohn's disease, a constitutionally weak immune response predisposes to accumulation of intestinal contents that breach the mucosal barrier of the bowel wall, resulting in granuloma formation and chronic inflammation. Polymorphisms in CARD15 do not underlie this phenotype, but incapacitate the NOD2 pathway that can compensate for impairment of innate inflammation. Current treatment of secondary chronic inflammation might exaggerate the underlying lesion and promote chronic disease.''

This is such a great thread, if a little confusing to us non-scientists.

Are you saying that Crohn’s is a state where the immune system is too weak to clear intestinal contents that have entered the lining of the intestines? A secondary response by the immune system causes inflammation. The body is producing the inflammation to try and clear the foreign particles within the lining of the intestines. Remicade puts down that inflammation. However, the original problem of intestinal contents within the lining of the intestines remains. the body’s response to clear the foreign particles is damped down by the medication hence over time the situation gets worse.

If that is correct, then after that I am totally confused. I cannot work out what exactly a fecal stream is. Is it the passage of food from throat to anus? If so how can something like that possibly be diverted? There is only one way down.

And how does the foreign particles enter the lining of the intestines in the first place? Is this the leaky gut problem? Is the particles themselves or bacteria that are somehow attached to the particles that are the problem? Is the solution to strengthen the immune system while healing the gut lining?

Appreciate your advice.

 

[Guerrero]

Kiny, thank you again for your very interesting replies. However you are maybe a bit unfair with some of the new biologics. entyvio takes months to work, cause if i’m not wrong it binds new lymphocytes T to activate inside the gi tract... so for months the old ones will still be activated causing possibly damages. It takes time to replace all the T cells. That’s grossly what I understood....

Regarding efficacy, they are not that bad, considering you using them on patients that already failed an anti-tnf so on situations and mucosa already compromised.
Clearly entyvio has slightly lower efficacy results, but I think i read somewhere stelara had comparable results than anti tnf.
I think stelara could still be usefull then, especially if you failed the anti tnf... regarding safety you may be right, we dont have the 20 years experience on side effects we have for infliximab...

 

[kiny]

Are you saying that Crohn’s is a state where the immune system is too weak to clear intestinal contents that have entered the lining of the intestines?

The acute innate immune response is insufficient. There are deficiencies at the macrophage level, which leads to insufficient neutrophil response.

We know this because we can see in tests that response to heat killed E Coli in CD patients for example, is delayed. We also know this because the genetic mutations and genetic predispositions in CD tell us.

A secondary response by the immune system causes inflammation.

Right, the weak innate immune system keeps chronically activating the adaptive immune system to compensate. Activation of the adaptive (or secondary) response is primarily done through dendritic cells that will present antigen to T lymphocytes.

In crohn's disease, this activation of the adaptive response becomes chronic due to the constant failures at the macrophage level to clear pathogens.

The body is producing the inflammation to try and clear the foreign particles within the lining of the intestines. Remicade puts down that inflammation. However, the original problem of intestinal contents within the lining of the intestines remains. the body’s response to clear the foreign particles is damped down by the medication hence over time the situation gets worse.

right

If that is correct, then after that I am totally confused. I cannot work out what exactly a fecal stream is. Is it the passage of food from throat to anus?

right

If so how can something like that possibly be diverted? There is only one way down.

Fecal stream is diverted in several different ways, you have surgical faecal stream diversion, and nonsurgical faecal diversion.

The first time people started to notice that fecal stream diversion lead to healing of the intestine, was during surgeries in the 90s. If you did a surgery on a CD patient, you are forced to do at least a partial fecal stream diversion. To doctor's surprise, the parts of the intestine that didn't any longer come into contact with fecal matter, healed.

That was surprising, this lead to the support of nonsurgical faecal diversion to actually treat active crohn's disease, nutrition administered through an IV, avoiding the whole intestine.

This also lead support to the use of EN. While EN isn't the same as faecal diversion, it most likely works in a similar way, EN limits the faecal stream due to its high bioavailability (EN contain medium chain triglycerides, sucrose and glucose, it optimizes the uptake of nutrients).

And how does the foreign particles enter the lining of the intestines in the first place? Is this the leaky gut problem?

The intestine, especially the ileum, is permeable by design. Not just so it can uptake nutrients, but because it contains peyer's patches. M cells from peyer's patches are completely exposed to lumen content (by design).

Of course people with crohn's disease also simply have a breakdown of the intestinal barrier itself, which causes activation of immmune cells in the epithelium and lamina propria. It's not just peyer's patches being activated, but they are heavily involved in ileal CD.

Is the particles themselves or bacteria that are somehow attached to the particles that are the problem?

It's a persistent antigen response, most likely bacterial, fungi, and particles that cause a response.

Is the solution to strengthen the immune system while healing the gut lining?

Strengthening the immune system would be nice and probably the ultimate goal. But there are very few options. You can correct the immuno defficiencies through genetic intervention (which has actually cured people with CD), but the goal should of course be a drug that corrects the macrophage defficiency without having to resort to gene modification.

 

[kiny]

To elaborate on the insufficienct neutrophils response I mentioned.

The healthy intestine contains macrophages, dendritic cells, CD4, CD8 T cells (also plasma and mast cells).

But the healthy (non-infected) intestine does not contain large portions of neutrophils. However, when the intestine is challenged with an infection, neutrophils will, within minutes, start migrating en masse to the intestine.

This does not happen sufficiently in CD patients. This is not due to the neutrophils themselves, neutrophils are completely competent in CD patients, but due to defective acute response of macrophages. (people who actually have hereditary deficiencies in neutrophils can get really sick due to infections, neutrophils are very important immune cells).

Macrophages and neutrophils are partners in crime, they rely heavily on each other to set up the acute response. While macrophages will be the first that encounter the invading pathogen, they will very quickly be accompanied by thousands of neutrophils. Somehow this does not happen sufficiently enough in crohn's disease.

Segal and Loewi discovered this in 1976 (it was published in the lancet).

 

[kiny]

To add regarding neutrophils. I once posted that they tried viagra to treat crohn's disease.

Why...

I said neutrophils aren't present in the healthy intestine. They are in blood. When a doctor does a WBC count test, they are testing circulating leukocytes. One of those are neutrophils.

They can migrate to tissue, but for that they need a signal.

One of the earliest cytokine release during an infection is TNF-α.

TNF-α is an extremely important pro-inflammatory cytokine. What isn't immediately apparent, is that TNF-α affects capillaries, unless you start to read about diseases related to blood flow.

One of the things cytokine released by macrophages do, is dilate those blood vessels. It allows those neutrophils to migrate into tissue easily.

Neutrophils start to migrated from blood into tissue in response to chemical signaling from macrophages that have been activated in response to a bacteria or fungi.

Because of the dilated blood vessels, you also get fluid entering the tissue, nutrients and oxygen. But specifically neutrophils. This is the acute inflammatory response...this is what you see when you see a wound and you see it swell and get red.

Normally macrophages are capable of dealing with most issues at the epithelial border, macrophages can clear bacteria on their own without needing an adaptive response most of the time.

But in crohn's disease that acute response is stunted. Macrophages don't response correctly, cytoke response is stunted, therefore blood flow is stunted and neutrophil recruitment is stunted, and now the innate immune system is chronically activating the adaptive immune response.

That is why they tried viagra in crohn's disease. Viagra improves blood flow.

 

[Hopeful girl]

The acute innate immune response is insufficient. There are deficiencies at the macrophage level, which leads to insufficient neutrophil response.

We know this because we can see in tests that response to heat killed E Coli in CD patients for example, is delayed. We also know this because the genetic mutations and genetic predispositions in CD tell us.



Right, the weak innate immune system keeps chronically activating the adaptive immune system to compensate. Activation of the adaptive (or secondary) response is primarily done through dendritic cells that will present antigen to T lymphocytes.

In crohn's disease, this activation of the adaptive response becomes chronic due to the constant failures at the macrophage level to clear pathogens.




right




right



Fecal stream is diverted in several different ways, you have surgical faecal stream diversion, and nonsurgical faecal diversion.

The first time people started to notice that fecal stream diversion lead to healing of the intestine, was during surgeries in the 90s. If you did a surgery on a CD patient, you are forced to do at least a partial fecal stream diversion. To doctor's surprise, the parts of the intestine that didn't any longer come into contact with fecal matter, healed.

That was surprising, this lead to the support of nonsurgical faecal diversion to actually treat active crohn's disease, nutrition administered through an IV, avoiding the whole intestine.

This also lead support to the use of EN. While EN isn't the same as faecal diversion, it most likely works in a similar way, EN limits the faecal stream due to its high bioavailability (EN contain medium chain triglycerides, sucrose and glucose, it optimizes the uptake of nutrients).




The intestine, especially the ileum, is permeable by design. Not just so it can uptake nutrients, but because it contains peyer's patches. M cells from peyer's patches are completely exposed to lumen content (by design).

Of course people with crohn's disease also simply have a breakdown of the intestinal barrier itself, which causes activation of immmune cells in the epithelium and lamina propria. It's not just peyer's patches being activated, but they are heavily involved in ileal CD.




It's a persistent antigen response, most likely bacterial, fungi, and particles that cause a response.



Strengthening the immune system would be nice and probably the ultimate goal. But there are very few options. You can correct the immuno defficiencies through genetic intervention (which has actually cured people with CD), but the goal should of course be a drug that corrects the macrophage defficiency without having to resort to gene modification.

Thank you so much for your detailed response.

 

[Crohn2357]

Do you use antibiotics as needed or chronically?

As needed through an IV (they're not given orally, antibiotics should ideally always given through IV in CD patients, to spare their intestine, unless there it is a localised antibiotic of course, like rifaximin).

About antibiotics, could you elaborate on “sparing the intestines”? What happens to the intestines when you take the abx orally?

You just want to kill the bacteria that have entered the lamina propria, the wall of the intestine. Antibiotics are broad spectrum, you don't want to indescriminately kill all the bacteria in your intestine, that's why bacteriophage therapy is so interesting, it's specificity.

—————

Fecal stream diversion and broad spectrum antibiotics like cipro and flagyl their action includes a large decrease in ''bacterial load''.

(note studies that show cipro and flagyl are far more effective in CD patients if taken orally, and not very effective IV)
(antibiotics related to secondary infections should be IV)

(Taken from the salmonella and IBD article you posted.)

Kiny, in your own opinion, when a Crohn’s patient has a flare up, should he/she receive the antibiotics treatment orally or intravenously? (The purpose of using the antibiotics in this context is to get the patient back into remission.)

 

[Crohn2357]

And how does the foreign particles enter the lining of the intestines in the first place? Is this the leaky gut problem?

Even though I don’t agree with some of paleo diet’s claims, I think Sarah Ballantyne has made good, simplified explanations on this topic.(just ignore the ads on the page):

https://www.thepaleomom.com/what-is-leaky-gut-and-how-can-it-cause/
Here’s another simple explanation:

http://www.clevelandclinicmeded.com...tations/Leaky Gut and Inflammation Powell.pdf
Here’s a relevant figure, taken from the salmonella article kiny posted:



You can find more detailed articles on the intestinal permeability problem/epithelial barrier dysfunction in pubmed.

Avoiding NSAIDs, constipation, gluten (1) and other problematic foods, chronic stress (2); consuming gelatin (from bone broth, gelatinous cuts of animals, supplements), maintaining adequate nutrition are just some of the things that can be done to prevent leaky gut problem from happening/worsening.

(1): On the relationship between gluten and leaky gut:

https://www.crohnsforum.com/threads...asano-on-gluten-autoimmunity-leaky-gut.84503/
(2):

https://www.physiology.org/doi/full/10.1152/ajpgi.2001.280.1.G7
https://www.sciencedirect.com/science/article/pii/S0301051118303302
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432792/

 

[Crohn2357]

https://paleoleap.com/leaky-gut-demystified/

 

[Crohn2357]

Kiny, while I understand the theoretical basis of your stance on the current medications to treat Crohn’s, I am not sure if I understand your stance on what we as Crohn’s patients should do to manage this disease in practice.

If left untreated (i.e. not taking immunosuppressants chronically), Crohn’s would kill many of us. EN simply wouldn’t work for many Crohn’s patients, antibiotics are not effective for the long term. I understand why you say immunosuppressants are actually making Crohn’s even more problematic and more chronic.

We share the same opinions on where the research and development on treatment should focus, but that is mostly beyond our control (it is even beyond the control of researchers for the most part).

What should Crohn’s patients do, now, to manage their Crohn’s? Could you elaborate your thoughts on this by addressing these problems?

 

[Crohn2357]

bacteriophages

 

[Hopeful girl]

Thank you for all the material in non technical English Crohns2357. It’s very helpful.

 

[kiny]

Kiny, while I understand the theoretical basis of your stance on the current medications to treat Crohn’s, I am not sure if I understand your stance on what we as Crohn’s patients should do to manage this disease in practice.

If left untreated (i.e. not taking immunosuppressants chronically), Crohn’s would kill many of us. EN simply wouldn’t work for many Crohn’s patients, antibiotics are not effective for the long term. I understand why you say immunosuppressants are actually making Crohn’s even more problematic and more chronic.

We share the same opinions on where the research and development on treatment should focus, but that is mostly beyond our control (it is even beyond the control of researchers for the most part).

What should Crohn’s patients do, now, to manage their Crohn’s? Could you elaborate your thoughts on this by addressing these problems?

All I can say is that two major things changed in regards to treatment of CD patients in the last decade.

-gastros went from therapy escalation (mesalamine -> EN -> corticosteroids -> 6MP -> biologics), where biologics were given as a last resort, to a top down approach where you start with biologics sooner and they started giving biologics chronically
-gastros and pharma companies argued that biologics should instead of being used once, be used chronically

Gastros made the big promise that early and chronic use of biologics would decrease the amount of hospitalisations, even though there were warnings from prominent researchers that chronic use of biologics could lead to chronic disease due to the further weakening of the immune system.

We now increasingly see that hospitalisations have not decreased with the use of biologics.

Bacterial infections, fungi infections, histoplasmosis, neutropenia, lymphopenia, are all increasingly common side effects of biologic immunosuppressants. If you get patients with all sorts of side effect, you better be able to show that your medication is decreasing hospitalisations.

There are plenty of studies testing early results of biologic treatment and far far too few that study what happens with patients a year down the road when they fail biologic therapy. What is the hospitalisation rate of those people, what is the rate compared to people who didn't go on biologic therapy. This is the first one I read, and it does not bode well for the argument gastros made ten years ago.

The promise made by gastros and pharma companies was decreased hospitalisations due to the advent of biologics. Gastros have a lot of explaining to do. Gastros need to start explaining and discussing these depressing results coming out of Canada with patients. Canadian politicians are starting to ask questions regarding these results, so should patients.

 

[Crohn2357]

I should clarify that, by “immunosuppressants”, I meant thiopurines, mtx, and biologics all together. It’s well known that the rate of loss of response to biologics is substantial. There have been proposed mechanisms for that, as you well know.

As far as I know, loss of response rates are a lot less (at the very least least it takes longer) for thiopurines in the management of Crohn’s, compared to biologics. There are many patients who have been in remission for decades by using thiopurines (or combination therapy) for their Crohn’s.

I agree and support your views on the need for questioning by all sides of this problem. I certainly acknowledge the problem and think everyone should do so. There’s been an urgent need for change - morally, economically, socially, theoretically-scientifically, politically, medically etc. for a long time, but the circumstances of our lives make us need to be realistic and take immediate action for our lives.

I am saying that, taking the immunosuppressants chronically has been the only option for most of us; for the other option is painful death from CD. We need to use whatever we can use right now. Do the immunosuppressants make the Crohn’s more problematic and chronic because of CD’s aetiopathogenesis? Maybe they do. Do most Crohn’s patients have an alternative? I don’t think they do. Even if all of us lived a mostly stress-free life with a very restricted diet (to prevent dietary causes of the worsening of CD) with good supplements and natural treatment methods etc. most of us would still require the addition of immunosuppressants as maintenance drugs. That’s because of the aggressive, stubborn and fatal nature of CD.

I agree with you about their side effects, their lack of success etc. but most of the CD patients still need to take the current drugs regularly.

 

[kiny]

I argued that micriobiota transplantation would fail and make crohn's disease worse because you are introducing a fecal stream.

another case of failed microbiota transplantation in crohn's disease

december 2018

https://www.ncbi.nlm.nih.gov/pubmed/30643841

Department of Internal Medicine, University of California Los Angeles, Los Angeles, California

Severe Ileocolonic Crohn's Disease Flare Associated with Fecal Microbiota Transplantation

We present a case of mild ileocolonic Crohn's disease in a patient treated with Fecal Microbiota Transplantation for recurrent CDI who subsequently developed severe steroid-refractory flare requiring surgical intervention 1 week post-FMT. Greater understanding of risk factors associated with post-FMT IBD flare is indicated.

 

[Jonny84]

I should clarify that, by “immunosuppressants”, I meant thiopurines, mtx, and biologics all together. It’s well known that the rate of loss of response to biologics is substantial. There have been proposed mechanisms for that, as you well know.

As far as I know, loss of response rates are a lot less (at the very least least it takes longer) for thiopurines in the management of Crohn’s, compared to biologics. There are many patients who have been in remission for decades by using thiopurines (or combination therapy) for their Crohn’s.

I agree and support your views on the need for questioning by all sides of this problem. I certainly acknowledge the problem and think everyone should do so. There’s been an urgent need for change - morally, economically, socially, theoretically-scientifically, politically, medically etc. for a long time, but the circumstances of our lives make us need to be realistic and take immediate action for our lives.

I am saying that, taking the immunosuppressants chronically has been the only option for most of us; for the other option is painful death from CD. We need to use whatever we can use right now. Do the immunosuppressants make the Crohn’s more problematic and chronic because of CD’s aetiopathogenesis? Maybe they do. Do most Crohn’s patients have an alternative? I don’t think they do. Even if all of us lived a mostly stress-free life with a very restricted diet (to prevent dietary causes of the worsening of CD) with good supplements and natural treatment methods etc. most of us would still require the addition of immunosuppressants as maintenance drugs. That’s because of the aggressive, stubborn and fatal nature of CD.

I agree with you about their side effects, their lack of success etc. but most of the CD patients still need to take the current drugs regularly.

Good post and I agree. Most of us don't have any choice.

The thing that I find most frustrating is that there is hope on the horizon - Qu BIologics being a prime example. In some ways, I am grateful for the biologics as I would be without a colon without them. On the other hand in say 5-10 years I believe we will be in a much better position in terms of the range, quality and side effect profile of available treatments.

I guess that's just the nature of how treatment develops - things improve incrementally. People who were diagnosed 20 years ago didn't have anywhere near the options we have now, but the same will be true we look back at this time in the future.

 

[Crohn2357]

The immune system:



—



—







—

https://m.youtube.com/watch?v=CeVtPDjJBPU
https://en.m.wikipedia.org/wiki/Immune_system

 

[kiny]

Macrophages respond to bacteria and fungi, but they also interact with inorganic (dead) particles. Particles that contain titanium dioxide, nickel, chromium and other metals are somteimes found in macrophages isolated from peyer's patches of crohn's disease patients.

In the past people argued that there was probably not a lot of uptake of those particles, but we know that isn't true now. Peyer's patches do a lot more than just uptake bacteria, in fact drug companies are increasingly interested in how drugs are taken up by peyer's patches.

What happens with those inorganic particles, we don't really know. They enter through M cells, interact with macrophages, then they probably end up somewhere in the serosa and end up in the lymphatic.

How do these metallic particles enter the body of crohn's disease patients. Food mostly, toothpaste and probably also from medical instruments, coated colonoscopy instruments, etc.

Is interaction with inorganic particles as important as interaction with bacteria and fungi...probably not, but there has been little research about this.

 

[kiny]

I also don't want to reinforce an argument to eat ''organic'' or ''natural'' foods. Because that's what people did when I posted a study about peyer's patches responding to inorganic particles. ''Natural'' doesn't mean it is good for you, maybe it contains less titanium dioxide particles, but that same ''natural'' food contains millions of bacteria. Those ''natural'' fruits and vegetables from ''natural'' soil are a breeding ground for millions of bacteria.

The reason the mucosal immune system in the intestine is so complex, why the intestine is covered in macrophages and why most lymphocytes reside in the intestine, is because all those ''natural" things found in soil and food tried to kill us.

We have acquired defense mechanism against them, but that doesn't mean they are now ''good bacteria''. Some help us because they outcompete more invasive and pathogenic species for nutrients, but to say these bacteria are now ''good for us'' and that crohn's disease patients should be shugging them down in probiotics, I have my doubts.

Supposedly completely harmless and ''good'' Lactobacillus you find in probiotics are upregulated during flares of CD patients...not because they have invasive characteristics, but because all sorts of bacteria will be able to enter the luminal wall during inflammation, I still need to find the first study that shows any bacteria or probiotic has any positive effect in crohn's disease. Primary immunodefficiency diseases means keeping every bacteria as far away from you as possible...you can not mimmick crohn's disease in sterile environments.

 

[kiny]

Macrophages respond to every bacteria. Macrophages don't care which bacteria it is, the innate immune system (unlike the adaptive) is non-specific. If supposedly ''good bacteria'' get through the epithelium, a macrophage in the lamina propria is going to respond. TLR will activate the macrophage and it will try to kill the bacteria, it doesn't care if it's ''good bacteria'' from a probiotic drink you just drank, or if it's a salmonella infection. This idea that there are ''good and bad bacteria'' only works as long as these bacteria don't enter tissue. When a bacteria enters tissue, those good bacteria are now pathogens and will cause inflammation.

Just because a healthy person without intestinal issues is able to drink down a million bacteria from a probiotic drink, doesn't mean a crohn's disease patient with a compromised epithelial barrier and an innate immunodeficiency of macrophages should be trying it.

 

[Crohn2357]

How do these metallic particles enter the body

Is interaction with inorganic particles as important as interaction with bacteria and fungi...probably not, but there has been little research about this.

https://www.functionalps.com/blog/2011/10/22/3169/
https://christiane-volkheimer.com/en/gerhard-volkheimer/#persorption
Pathologe. 1993 Sep;14(5):247-52.
[Persorption of microparticles].
[Article in German]
Volkheimer G.
Abstract
Solid, hard microparticles, such as starch granules, pollen, cellulose particles, fibres and crystals, whose diameters are well into the micrometre range, are incorporated regularly and in considerable numbers from the digestive tract. Motor factors play an important part in the paracellular penetration of the epithelial cell layer. From the subepithelial region the microparticles are transported away via lymph and blood vessels. They can be detected in body fluids using simple methods: only a few minutes after oral administration they can be found in the peripheral blood-stream. We observed their passage into urine, bile, cerebrospinal fluid, the alveolar lumen, the peritoneal cavity, breast milk, and transplacentally into the fetal blood-stream. Since persorbed microparticles can embolise small vessels, this touches on microangiological problems, especially in the region of the CNS. The long-term deposit of embolising microparticles which consist of potential allergens or contaminants, or which are carriers of contaminants, is of immunological and environmental-technical importance. Numerous ready-made foodstuffs contain large quantities of microparticles capable of persorption.

https://www.ncbi.nlm.nih.gov/pubmed/8415433
https://www.europeanmedical.info/drug-delivery/persorption.html
Gastrointestinal persorption and tissue distribution of differently sized colloidal gold nanoparticles
Abstract
The gastrointestinal uptake of micro‐ and nanoparticles has been the subject of recent efforts to develop effective carriers that enhance the oral uptake of drugs and vaccines. Here, we used correlative instrumental neutron activation analysis and electron microscopy to quantitatively and qualitatively study the gastrointestinal uptake and subsequent tissue/organ distribution of 4, 10, 28, and 58 nm diameter metallic colloidal gold particles following oral administration to mice. In our quantitative studies we found that colloidal gold uptake is dependent on particle size: smaller particles cross the gastrointestinal tract more readily. Electron microscopic studies showed that particle uptake occurred in the small intestine by persorption through single, degrading enterocytes in the process of being extruded from a villus. To our knowledge this is the first report, at the ultrastructural level, of gastrointestinal uptake of particulates by persorption through holes created by extruding enterocytes.

Hillyer, J.F., and Albrecht, R.M. 2001. Gastrointestinal persorption and tissue distribution of differently sized colloidal gold nanoparticles. J. Pharm. Sci. 90:1927-1936.

 

[Crohn2357]

another case of failed microbiota transplantation in crohn's disease

december 2018

https://www.ncbi.nlm.nih.gov/pubmed/30643841

Case Report
A 35-year old man with a history of refractory ileocolonic Crohn’s disease with primary sclerosing cholangitis and recurrent CDI presented with watery diarrhea and abdominal pain. His medical history included refractory Crohn’s disease, first diagnosed at age 28, requiring multiple diverting ileostomies complicated by disease flare upon ileostomy takedown and non-response to multiple therapies, including thiopurines, methotrexate, infliximab, adalimumab, and vedolizumab. Despite counseling, the patient was not amenable to colectomy throughout his disease course. His disease course had been complicated by at least 7 episodes of CDI with positive C. difficile polymerase chain reaction (PCR) tests over the past 7 years corresponding to worsening of clinical symptoms, ultimately requiring long courses of suppressive antibiotic therapy with vancomycin and consideration for FMT in the past. He had negative C. difficile PCR studies between episodes.

Four months prior to this presentation, the patient was on ustekinumab maintenance therapy every 8 weeks with colonoscopy demonstrating mucosal healing and no histological evidence of active disease. An ileostomy takedown was performed at this time (Figure 1). Subsequent colonoscopy 2 months after takedown revealed mild colonic recurrence with few scattered aphthous ulcers noted in the sigmoid and descending colon; biopsies showed only mild histologic activity in the rectum. During this month, he also had an episode of
CDI (positive C. difficile PCR) that was subsequently treated with oral vancomycin.



Two months later, the patient had mild tenderness in the lower abdomen. He was afebrile with elevated inflammatory markers (C-reactive protein 2.2 mg/dL; erythrocyte sedimentation rate 35 mm/hr), and C. difficile PCR and stool bacterial pathogens studies were negative. With the intention to prevent future CDI recurrences after his recent episode and history of recurrent 7 prior episodes, FMT was performed via colonoscopy, which revealed mild pancolitis (Figure 2). He received ustekinumab the night following the FMT, which was four weeks after his previous dose, due to evidence of recurrent disease despite standard ustekinumab dosing.



Two days later, the patient was readmitted with fever, abdominal pain, and frequent bloody stools. C-reactive protein and erythrocyte sedimentation rate were elevated to 12.7 mg/dL and 58 mm/hr, respectively. Stool studies were negative for infection. Sigmoidoscopy 1 week after FMT demonstrated punched-out ulcerations in the sigmoid and descending colon (Figure 3). Biopsies for cytomegalovirus were negative. Albumin decreased from 4.0 g/dL on presentation to 2.1 g/dL. Intravenous solumedrol was given for 5 days with initial improvement, but due to worsening symptoms and continued C-reactive protein elevation upon transition to oral steroids, the patient requested diverting ileostomy for colonic healing while continuing on ustekinumab therapy. At follow-up 2 weeks later, he reported feeling well with no abdominal pain or fevers with healthy weight gain, and he was weaned off steroids. He has not experienced further CDI relapse and is currently continuing ustekinumab maintenance therapy every 4 weeks to maintain remission after ileostomy takedown.

Even though the antibiotics were effective in every instance of CDI for him, AND there was no evidence of CDI at that time, the doctors decided to perform FMT on him, “with the intention to prevent future CDI recurrences”.

This is malpractice, plain and simple.

Giving people with Crohn’s FMT is akin to putting fuel on fire. Especially when you take into consideration the facts that bacterial load is the most important cause of inflammation; also the innate immunodeficiency, the chronic use of immunosuppressants, the intestinal permeability problem etc. in Crohn’s patients.

If those irresponsible doctors experimenting with microbiota transplantation had read a singly study, they would have never tried microbiota transplanation where patients got worse instead of better.

 

[kiny]

The uncontrollable flares you see in crohn's disease patients after a fecal microbiota transplantation seem to happen 1 or 2 days after the transplantation. Which is exactly the time the adaptive immune system requires to mount a full response.

The FMT studies to treat crohn's disease has got to be some of the most ridiculous studies I have ever read.

Although this is a close second https://www.ncbi.nlm.nih.gov/pubmed/27215921

Adding stool full of bacteria didn't work.
Adding worms didn't work.
Maybe these same doctors will try treating their patients with salmonella, just to see what happens.

 

[Crohn2357]

The uncontrollable flares you see in crohn's disease patients after a fecal microbiota transplantation seem to happen 1 or 2 days after the transplantation. Which is exactly the time the adaptive immune system requires to mount a full response.

The FMT studies to treat crohn's disease has got to be some of the most ridiculous studies I have ever read.

Although this is a close second https://www.ncbi.nlm.nih.gov/pubmed/27215921

Adding stool full of bacteria didn't work.
Adding worms didn't work.
Maybe these same doctors will try treating their patients with salmonella, just to see what happens.

Yeah, I got your point, but I think making a distinction between clinical trials - institutionally backed medical treatments and self experimentation is necessary here.

I actually find the editor’s note and the fact that this journal decided to publish this article quite good. Sometimes those with the craziest ideas make the greatest contributions to science, they are even often behind the scientific revolutions.

And if you read the full text of his article, you might see that his plan was not as crazy and disgusting as it looks on the title. He swallowed the eggs (mixed into plain water), which are not visible to the naked eye (he confirmed their existence with a “plastic toyshop microscope” before swallowing). He says he had been living with CD for half his life, since he was 12, and nothing had worked for him thus far, and he had read a study where researchers found this treatment might be effective. He had two friends with CD who were self-dosing with helminths before him. He told his plan (which involves a more benign kind of helminths than the helminths his friends were taking) to his gastroenterologist, and his GI agreed to monitor his health and provide care (his GI neither recommended nor condemned his treatment plan). He tried to design his plan scientifically. In the end, he became better than he was, although it is admitted that this result might not be related to his experiment at all.

Theoretically, it is dangerous and maybe even stupid; but theories are just that - theories. Nothing is absolutely certain, including the innate immunodeficiency hypothesis. It’s important to keep an open-mind and avoid dogmatism in scientific enquires.

Also, being miserable and hopeless can sometimes make you do the craziest things in life, as you may know.

 

[Hopeful girl]

The immune system:



—



—







—

https://m.youtube.com/watch?v=CeVtPDjJBPU
https://en.m.wikipedia.org/wiki/Immune_system

Brilliant! Thanks again!

 

[Crohn2357]

Good post and I agree. Most of us don't have any choice.

The thing that I find most frustrating is that there is hope on the horizon - Qu BIologics being a prime example. In some ways, I am grateful for the biologics as I would be without a colon without them. On the other hand in say 5-10 years I believe we will be in a much better position in terms of the range, quality and side effect profile of available treatments.

I guess that's just the nature of how treatment develops - things improve incrementally. People who were diagnosed 20 years ago didn't have anywhere near the options we have now, but the same will be true we look back at this time in the future.

I have tried to raise awareness about Qu Biologics’ vaccine trial for Crohn’s by creating and updating these two threads in HealingWell’s CD and UC forums.

https://www.healingwell.com/community/default.aspx?f=17&m=4087960&r=x
https://www.healingwell.com/community/default.aspx?f=38&m=4087962&g
I think you participated in the first thread, with the nickname “Jonny_Murray”.

Personally, I currently see five different experimental treatment plans for the future of Crohn’s that are at least interesting: RHB-104 trial, Crohn’s Map Vaccine, Qu’s SSI Vaccine, bacteriophages that target specific bacteria, and stem cell therapies.

I am not fanatical about any of them, but I want them to be known and discussed by the Crohn’s community.

I don’t keep my expectations too high, but I maintain a positive outlook for the future of CD treatments. You can’t live for long without any hope.