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



## David

> *Conclusions*
> Marketplace introduction of infliximab has not yielded anticipated reductions in the population rates of IBD-related hospitalisations or intestinal resections, despite robust market penetration among patients with CD. Misguided use of infliximab in CD patients and underuse of infliximab in UC patients may largely explain our study findings.
> 
> This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial.


Source

Quite an interesting study.  Anyone have any opinions on it?


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## Jonny84

What were the anticipated reductions and how much did they fall short by?


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## kiny

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.''*_


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## kiny

The treatment in the West is much too reliant on immune suppression instead of fecal stream diversion (like one does as standard care in Japan). Chronic immune suppression leads to chronic disease.

Instead of trying to limit bacterial load in the intestine with fecal diversion and target AIEC with bacteriophages, Western doctors are preoccupied with the microflora and Western governments are spending billions on researching the microflora. Those billions have not helped one single person with crohn's disease.

Reducing the lumen content and lowering the bacterial load is why the intestine heals when you divert the fecal stream. Phagocytes, APC, and NK cells are no longer overwhelmed by a fecal stream with a high bacterial load, and the inflammation subsides because APC don't have to chronically initiate a T cell response.

(I argued that micriobiota transplantation would fail and make crohn's disease worse because you are introducing a fecal stream. Not surprisingly it worsens crohn's disease, to the surprise of doctors, but not to the surprise of researchers. ''_The risk of inflammatory bowel disease flares after fecal microbiota transplantation, Qazi T et al.  ...worsening in IBD activity (4.6%, (95% CI: 1.8-11%). _)

If you block the adaptive immune response and target cytokine that help control that response, you simply get a stronger and stronger chronic response from the body and a build-up of bacterial content in the intestine that is no longer being removed. The body eventually builds antibodies or infliximab simply stops working. Now patients have a lot of bacterial content in their intestine and of course many people simple relapse with worsening inflammation than before they started treatment.

The way immunesuppressants are used is irresponsible. They need to be used in acute phases, they should never be used chronically, because it will lead to chronic and worsening disease.

(Using immunosuppresants to lower acute inflammation is not new, it helps during infections to lower necrosis of tissue and lower nerf damage. It is stopped of course, because you don't want to hinder the body's immune system to clear the bacteria. It isn't stopped in crohn's disease, because doctors refuse to read scientific papers.)


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## kiny

Crohn's disease should be treated like Chronic granulomatous disease, also an innate immunodeficiency disease.

Crohn's disease is nothing like UC, has nothing to do with UC and should not be treated like UC.  People with UC don't have any immunodeficiency, they respond completely normal to infection, it is very very unlikely that UC is related to an inability to clear intestinal bacteria, the immune response to bacteria is completely normal in UC. Wound healing, blood flow and immune response is completely normal.

The immune response to an infection such as E Coli is completely *abnormal *in crohn's disease patients, Crohn's disease is related to *a very serious immunodeficiency of macrophages*.* Macrophages of crohn's disease patients secrete far too few cytokine like TNF**-α.* There is also a general lack of blood flow. Crohn's disease patients have an incredibly immunodeficient innate immune system, the adaptive response is completely normal however, but a lack of cytokine secretion by macrophages (TNF, IL-1, etc) will result in a delayed and inappropriate response. (the basis for this is of course genetic predisposition link in crohn's disease)



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

UC patients respond to bacterial infection like healthy controls. There is no difference, UC has nothing to do with bacterial infection, it is doubtful it has anything to do with bacteria at all.

However, Crohn's disease patients fail to clear bacteria properly and a persistent inflammation occurs. The innate immune response of macrohages is completley insufficient in crohn's disease patients.




_Andrew M. Smith 

Disordered macrophage cytokine secretion underlies impaired acute inflammation  and bacterial clearance in Crohn’s disease _

Again, completely normal response to bacterial infection in UC and Healthy Control, completely insufficient clearance in CD.

__

Just like CGD (chronic granulomatous disease), crohn's disease is an innate immunodeficiency (primarily of intestinal macrophages in crohn's disease), that results in a cascading adaptive immune response, specifically the cell-mediated immune response due to bacteria, fungi and fecal content that enter through the intestinal epithelial barrier that can't be cleared.

You don't treat primary immunodeficiency diseases with chronic immune suppression, because it often leads to more and more inflammation and bacterial load over time. It should be used to treat acute inflammation, and that's how infliximab used to be used, until they started using it chronically, which isn't a solution.


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## Jonny84

Kiny - what is your view on the treatment that Qu Biologics are currently developing?


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## kiny

Hi, I read the site. Not going to comment on the medication, I don't know how it works.

What they write is true.

It's true that Crohn's disease needs to be treated from a primary immunodeficiency standpoint, that should be the focus

I don't think the adaptive response is abnormal, it is delayed, but not abnormal. The adaptive immune system is simply responding to the (insufficient) secretion of TNF by macrophages and APC will keep triggering the adaptive immune system. The primary response is insufficient, the secondary response become chronic because macrophages failed to clear bacterial content that constantly invades the intestinal wall.

I also don't think it matters how crohn's disease is initiated. I think it's due to an initial infection. Many crohn's disease patients have nightsweats, fevers, and sometimes throw up early on. They got infected by a food borne infection, listeria, salmonella, yersinia or campylobacter. That infection left the intestine permeable, and bacteria and fecal content now chronically activating the immune system, which is why there is chronic inflammation. Because the immune system can't clear the bacteria, your inflammation persists. Removing the fecal stream or limiting it of course helps and lowers inflammation. I don't think the initial infection is still there either, it has long been cleared.

I agree with what they write, just not all specifics, but I don't think those specifics matter for crohn's disease patients, it doesn't matter how the disease is initiated years ago to current patients. (it matters to avoid new cases of crohn's disease, and it's important, but it doesn't matter or affect me personally so I don't focus too much on that) What matters is how to maintina remission. .


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## kiny

(I also don't think it's helpful to lump crohn's disease and UC together. I have said many times these two disease are unrelated. What you see in crohn's disease is what you see in chronic granulomatous disease. Crohn's disease needs to be classified and treated as a primary immunodeficiency of macrphages. Response to bacteria is normal in UC, it is not normal in crohn's disease.

Hopefully they also stop wasting billions on microbiome research. 10 years of research that has never helped a single person with crohn's disease. The immune system in crohn's disease is clearly being triggered by the fecal stream which is high in bacterial load, and a handful of bacteria and fungi, not by harmless commensal bacteria.

If you give people with crohn's disease fecal transplants, they get worse, niether have probiotics ever helped. 

If you instead remove the fecal stream with parental or elemental nutrition instead, the intestine heals of course, since you removed or limited the fecal stream, which lowers the bacterial load, and which lowers the load on the compromised immune system in crohn's disease.)


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## kiny

kiny said:


> I don't think the adaptive response is abnormal, it is delayed, but not abnormal.


While I'm ranting. The innate immune response is very abnormal, but the adaptive response is normal. In the intestine of crohn's disease patients there are normal levels of T4 and T8. The thymus  works normal in crohn's disease.

It becomes abnormal once people with crohn's disease are on chronic immunsuppressants. You see CD4 drop dramatically and you see Lymphopenia as a side effect of inflixmab treatment. Which of course impact the disease because you need CD4 helper cells if you want phagocytes to destroy microbes. It takes a long time before the immune system recovers from chronic immunosuppressive therapy.


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## David

I'm so pleased to see you back @kiny -- your knowledge has obviously improved dramatically. 

I was going to ask if your statement of, "Removing the fecal stream or limiting it of course helps and lowers inflammation" is why so many do well with enteral nutrition but you shared that two posts above.  Is entertal nutrition the primary treatment option in Japan?


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## Crohn2357

Welcome back kiny. It’s nice to see you again.


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## kiny

David said:


> I'm so pleased to see you back @kiny -- your knowledge has obviously improved dramatically.
> 
> I was going to ask if your statement of, "Removing the fecal stream or limiting it of course helps and lowers inflammation" is why so many do well with enteral nutrition but you shared that two posts above.  Is entertal nutrition the primary treatment option in Japan?


Hi David.

Yes and yes. Adults are routinely put on EN in Japan. Fecal stream diversion and limiting the fecal stream is an important but neglected therapy in the West, especially for adults. The fecal stream evokes chronic inflammation, if you remove the fecal stream the inflammation subsides.

The reason EN works is because it simply limits the fecal stream, EN has high bioavailability. It does not work because there is something particular in EN, not because it changes the composition of the microbiome (it does, but that's normal after inflammation subsides), it simply works because it lowers fecal content.

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


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## David

Which would explain why many on juicing diets do well as well.

Many have reported improvement with paleo and SCD diets.  Do you think there could be something in that fecal stream from western diets that may be the underlying cause?  And those diets either don't negatively affect something with the innate immune system OR don't allow certain bacteria to proliferate?


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## David

Kiny, do you think those who take immunosuppressants long term still have the opportunity to benefit from fecal stream diversion or is the damage already done?

I know Qu Biologics sees the best result in those who have not taken biologics.


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## kiny

David said:


> Do you think there could be something in that fecal stream from western diets that may be the underlying cause?


The initial cause is probably an infection. Either with a foodborne bacteria like yersinia or listeria, or salmonella or campylobacter.

People who have had a salmonella or campylobacter infection are far more likely to develop crohn's disease after.  https://www.ncbi.nlm.nih.gov/pubmed/19361507

This explains why people who develop crohn's disease suffer from high fevers, night sweats, they tend to throw up before diganosis, it all points to food borne bacteria and infections.

This infection likely subsides, but it leaves a permeable bowel behind. That permeable bowel is then chronically being invaded by bacterial content from the fecal stream, and certain bacteria like AIEC, fungi, and others, exploit a chronic inflammatory environment.

(this results in dysbiosis, but this is not the reason for the inflammation, it is a secondary event, intestinal inflammation lead to dysbiosis)

Due to macrophage deficiencies, the intestine can not properly clear the high bacterial load in the intestine, it is especially difficult with a high bacterial load from the fecal stream. In a second phase,the innate immune system then chronically stimulates the adaptive immune and
antigen-presenting cell keep recruiting lymphocites, and you get cascading inflammation.



David said:


> Many have reported improvement with paleo and SCD diets.  Do you think there could be something in that fecal stream from western diets that may be the underlying cause?  And those diets either don't negatively affect something with the innate immune system OR don't allow certain bacteria to proliferate?


If diets have a beneficial impact, it is probably because they are low residue and reduce fecal matter. SCD removes complex carbohydrates which would increase the bioavailability of the diet. I don't think they have any effect on the innate immune system, nor that they have a significant effect on bacterial composition in the lumen.


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## Crohn2357

Kiny, I think a few corrections/elaborations are needed for your posts. I am currently in a hospital bed, with a picc line on my right hand. First, I am dropping this thread from HW. My nickname is xy123 there.






						Top line results from Redhill's Triple Antibiotic for MAP study
					

RedHill Announces Positive Top-Line Results from Phase III Study of RHB-104 in Crohn’s Disease For any interested or that have been following. Here is...



					www.healingwell.com
				




I will write with my left hand on my iPad, it will take some time.


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## kiny

David said:


> Kiny, do you think those who take immunosuppressants long term still have the opportunity to benefit from fecal stream diversion


Yes, the goal should be to limit fecal content in the intestine so the bacterial load at the epithelial barrier is reduced.

I understimated the permeability of the intestinal epithelial barrier in the past. Mucosal healing does not mean the bowel is no longer permeable, a bowel is very permeable and fecal matter is a constant threat to the integrity of the mucus layer and intestine. The intestine is lined from top to bottom with macrophages to rid the intestine of bacterial content, crohn's disease inflammation can be deep and transmural. The intestine is the main point of entry for bacteria.


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## Crohn2357

There are other and very important possible reasons for the initiation and the chronicity of the intestinal permeability problem other than microorganisms. Some examples are the immunogenicity of the foods and liquids we consume, endocrinological state of the person (this is quite complex but the easiest you can look for is the direct relationship between elevated cortisol and the increased intestinal permeability), the energy metabolism of the person etc.

Fully elemental EN works, because it is not fermentable (massive reduction in the microbial load) AND it doesn’t contain immunogenic substances like casein; unlike non-fully elemental EN like modulen, which is casein based. Even if, theoretically, you get a sterile gut, if you keep putting immunogenic substances on your mouth and swallow, the inflammation will continue, though it will still be decreased a lot because of the non-existence of the microorganisms.

Fully elemental EN are amino acid based.

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.

Surgical diversion of the intestines is also effective, for the same reason: limiting the microorganism growth and stopping the immunogenic foods’ stream, also toxins in our foods, drinks etc. Not surprisingly, often quickly after the reversal of the diversion (anastomosis), crohns returns in patients.

Edit: fully elemental EN is quickly, efficiently and easily absorbed in the small intestines. That’s what I mean by the “not fermentable”. Compare it with starch for the fermentability issue. By the way, because of these, your nutritional and hormonal state, and energy metabolism improve from fully elemental EN. Which are also relevant mechanisms.

Edit 2: also, with the exclusion of hard, irritating, fermentable foods, intestinal serotonin decreases a lot. This is also relevant for the inflammation, functionality, healing. People with Crohns have elevated serotonin in their intestines.


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## kiny

David said:


> I know Qu Biologics sees the best result in those who have not taken biologics.


I don't know anything about this medication, I have simply read the site because people asked me to.

But like they said, the ideal solution would obviously be to correct the primary immunodeficiency. If you correct macrophage defficiencies (especially the lack of TNF secretion) you could treat the disease proactively, instead of reactively.

Stimulation of the innate immune response has been tried before with success in crohn's disease.

_Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor._









						Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor - PubMed
					

Treatment for Crohn's disease is aimed at immunosuppression. Yet inherited disorders associated with defective innate immunity often lead to development of a Crohn's-like disease. We performed an open-label dose-escalation trial (4-8 microg/kg per day) to investigate the safety and possible...




					www.ncbi.nlm.nih.gov
				




If it wasn't for the fact that Chronic granulomatous disease  is rather rare, Crohn's disease and Chronic granulomatous disease with intestinal involvement, would be incredibly hard to dintinguish. In fact, people with Chronic granulomatous disease, not surprisingly, have very high rates of Crohn's disease. So do people with Blau syndrome.


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## Crohn2357

@kiny, *this* is the only bacteriophage product I can find without added probiotics or other crap. Do you think it could be helpful for us? Or another phage product? Do you use bacteriophages?


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## kiny

Crohn2357 said:


> @kiny, *this* is the only bacteriophage product I can find without added probiotics or other crap. Do you think it could be helpful for us? Or another phage product? Do you use bacteriophages?


No, bacteriophages need to be specifically selected or modified before they are useful.

I don't doubt that product contains bacteriophages, because pretty much everything contains bacteriophages. The mucus layer in the intestine is full of bacteriophages, so is the human skin. Everywhere where there are bacteria, there are bacteriophages, if it wasn't for bacteriophages, life would quickly succumb to bacteria.

But no, that products is not helpful in any way, nor do I recommend anyone taking it.


What we will see is specifically designed bacteriophages that target specific bacteria found in crohn's disease. It will hopefully lead to more personalised therapy, where a stool sample or biopsy serves as a guideline to determine which bacteriophage might be useful.









						Bacteriophages Targeting Adherent Invasive Escherichia coli Strains as a Promising New Treatment for Crohn's Disease - PubMed
					

These findings demonstrate that bacteriophages are a new treatment option for targeting AIEC in CD patients and represent a strong basis for a clinical trial evaluation.




					www.ncbi.nlm.nih.gov
				




There are currently ongoing trial underway with bacteriophages to treat crohn's disease. It might be helpful in people who harbour invasive E coli.

What the benefit of bacteriophages is over antibiotics is of course their specificity, the fact they don't have any known side effects, and unlike antibiotics they don't suffer from resistance.

Broad spectrum antibiotics that are used currently, have no such specificity, and they create resistance.


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## Crohn2357

This is the current study. It’s interesting.

I thought supplementing the above product (on amazon) every day could reduce bacterial load, thus reduce intestinal inflammation; but I think you are saying the phages have always a much narrower spectrum, therefore it won’t be very useful - unlike antibiotics.


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## ncman

Some really great info here, I just wanted to highlight the summary from AW Segal's 2016 work:



> *"Future treatment options*
> Treatment of CD poses a conundrum. The logical approach to correcting the underlying problem would be to develop means of enhancing innate immunity, although at present no such range of drugs is currently available. It would be dangerous to attempt to do this in the presence of ongoing bowel inflammation but it could be useful to maintain patients in remission after they had been cleared of disease by surgical resection, or through the use non-immunosuppressant therapies such as elemental diets. This approach was attempted with levamisole as the immunostimu-lant, with varying results. One problem with this form of treatment is that it is important to ensure that the patients are in remission before it is commenced; otherwise it is likely to exacer-bate the inflammation. In two studies levamisole induced a severe reversible polyarthropathy, indicating that the drug was in fact altering the immunological/inflammatory axis, and providing clues as to IBD associated arthritis, and to the immunopathology of the idiopathic arthritides in general. Current drug and biological treatments are largely immunosup-pressant. This, to varying degrees of efficiency, dampens down the secondary inflammation induced by the retained foreign material within the tissues. Anti-TNF treatments can be very helpful but do not provide a comprehensive answer. Only one third of patients will be in remission after one year on these treatments. Immuno-suppressant treatment further compromises the underlying innate immune deficit to mucosal damage, thereby increasing the like-lihood of further infection and the influx of bowel contents into the tissues, possibly converting CD from a sporadic to a chronic condition. The primary pathology in most case of CD appears to affect macro-phages recruited from the blood as monocytes. Advances in gene editing with the CRISPR-Cas technology make the correc-tive treatment of CD a real possibility in the relatively near future. Once a primary causal mutation has been identified, and validated in animal models, bone marrow could be extracted, edited and rein-fused into a conditioned patient in much the same way as is being applied to gene therapy for primary immunodeficiencies."
> 
> Source: https://iris.ucl.ac.uk/iris/publication/1204875/1


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## kiny

It's quite difficult for people and even doctors, to wrap their heads around crohn's disease being an innate immunodeficiency state.

_''if it is an immunodeficiency state, why is there all this inflammation?''_

What happens in an immunocompetent person who doesn't suffer from immunodeficiency is something like this....

...this is how a normal reaction takes place in an immunocompetent person:

00:00
*1) *the epithelial barrier was compromised, a bacteria has entered through the epithelial barrier (main entry points of the body for bacteria are the skin, intestine and lungs)

00:00-6 hours
*2)* phagocytes like macrophages and NK cells waiting behind the epithelial barrier mount the primary immune response, macrophages start to secrete cytokine

*3)* if the bacteria was not killed by the initial macrophage response (a tuberculosis infection for example), the much slower but much more competent and specific adaptive immune system is called upon

12 hours later
*4) *dendritic cells from the innate immune system form the link between the innate and adaptive immune system, they migrate to the lymph nodes and contact T cells, they do this by presenting antigen (they are antigen-presenting cells), T cells are now activated and mount the adaptive response

1 day later
*5)* T cells have now recognized the bacteria thanks to antigen presentation, they migrate to the bacteria, they activate macrophages and order them to kill phagocytosed microbes, other T cells kill infected cells to destroy intracellular microbes

2 days later
*6)* the invader is defeated, some immune cells were killed, some survived and will serve as memory cells, the inflammation subsides


The problem with crohn's disease is that first of all, that the epithelial barrier is compromised. The second problem is that innate response is insufficient, bacterial content is not properly cleared, crohn's disease is a primary immunodeficiency disease, and the result is that the adaptive immune system is chronically activated which leads to chronic inflammation.


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## kiny

If crohn's disease was an ''overreactive immune system'', that would actually be great, we would be immune to infections and never get a cold during the winter.

That's sadly not what is going on. We are immune deficient, our innate immune system is unable to clear bacterial content in a correct manner, our adaptive immune system is chronically activated to compensate as a result. Stopping the adaptive immune system from activating is what immunosuppressant drugs try to do, and they work great to limit damage to the bowel initially. But they don't solve the underlying problem, they don't remove bacterial content, and if you use immunosuppression chronically, you might actually be promoting chronic disease instead.

Crohn's disease needs to be categorized as a primary immunodeficiency disease, just like Chronic granulomatous disease.


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## ncman

Kiny, I wondered what your thoughts were on food intolerances?

Is my thinking correct: we know that EN works because it reduces the bacterial flora - the two ways we know how to change the flora are antibiotics and diet. And if by eating a 'wrong' food, you are increasing the bacteria which then cannot be cleared from the intestinal wall and therefore causes inflammation and therefore causes symptoms - thereby allowing the patient to identify it as a 'wrong' food.

In my case, my intolerances are increasing i.e. a previously safe food is now causing issues.

What would be a logical next step?  Probiotics possibly, but I just feel probiotics sit better with UC than CD.


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## kiny

ncman said:


> Is my thinking correct: we know that EN works because it reduces the bacterial flora


It lowers bacterial load because it reduces the fecal stream and fecal retention, likely due to its high bioavailability.

Fecal content is high in bacterial load (why is smells bad, why we have aversion to it, and why we throw up if the body notices we ingested it, the body is trying to avoid you come into contact with it due to how loaded with bacteria it is)

Which bacteria are responsible for the immune response isn't known, but I kinda doubt it is commensal bacteria from the gut flora. It's possible, but it is more likely pathogenic bacteria like invasive E coli,  opportunistic bactera, foodborne bacteria, fungi, etc.

If the commensal gut flora isn't directly involved in evoking the immune response, it would explain why probiotics aren't useful in crohn's disease.

That's not to say that probiotics are completely useless, bacteria compete for space in the intestine, commensal bacteria prevent adhesion of pathogenic bacteria to the intestinal wall, and they affect biofilm formation of those bacteria. But the effect of probiotis is probably extremely limited.



ncman said:


> antibiotics


Antibiotics can be very useful in crohn's disease. But they come with their own problems.

Several of the antibiotics that are effective in crohn's disease and macrophage penetrating, are very broad spectrum, which might leave the patients in a worse situation.

Antibiotics create resistance, cipro is very effective against invasive E Coli but AIEC become resistant very quickly.



ncman said:


> And if by eating a 'wrong' food, you are increasing the bacteria which then cannot be cleared from the intestinal wall


There's probably some foods that don't help. Avoiding maltodextrin and emulsifiers is probably a good idea. Maltodextrin will increase the growth of E Coli and emulsifiers cause bacteria to migrate into intestinal epithelia. Otherwise I don't know if diets help in any meaningful way.


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## kiny

Just to add. When research papers, especially older research papers, use the word ''crohn's disease'', they are often referring to the strict definition of crohn's disease as described by Dalziel. Chronic enteritis, inflammation of the ileum in the form of patchy granuloma.

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.

EN has been shown to help in standard classic crohn's disease, where the disease is restricted to the ileum. It especially helps if there is stenosis present or wall narrowing, which might restrict the normal flow of regular food.

EN doesn't work nearly as well if there is colonic involvement, which makes sense, because stool forms in the colon where water is absorbed, not in the small intestine.


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## my little penguin

So I am following the innate immunodeficiency 
-some researchers in the US feel strongly this is behind veo ibd kids (Ds has this version of crohns )

But....
If een helps calm why does inflammation come back the minute it’s stopped  
Is the time period too short ???
Kids typically get 6-8 weeks of een 
At least Ds has 
And then he continued with 50% supplemental en (amino acid based ) 
He goes back to een as needed 

Inflammation still comes back 
Even before he started immunosuppressants of any sort 
He did een first .

Ivig helps immunodeficiency 
Ds tried this as well 
Didn’t help either 

Do adults stay on een for life ???
I know some US pediatric ibd hospitals 
Use 90%een/10% food 
Or 
80%een/20% foid
Long term 
This didn’t work for my kiddo but works for a lot of kids


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## kiny

my little penguin said:


> But....
> If een helps calm why does inflammation come back the minute it’s stopped
> Is the time period too short ???


A full immune response is mounted over a few days. Lymphocytes have to recognize antigen, they expand and then effector cells eliminate the antigen.

All these steps happens over a number of days, it doesn't strike me as unreasonable that inflammation comes back within weeks, or even days, if the person drops EN. Remission isn't going to last if EN is dropped.

People do seem to relapse more slowly after stopping immunosupressants, but these powerful immmunosupressants results in a weaked immune system that takes a long time to recover. One of the common side effects of infliximab is lymphopenia for example. By the time people relapse on immunosuppressants (they all only work for a few years before people relapse), the medication has probably stopped working for a long time,  it takes the immune system a while before it recovers.

The body has a whole host of mechanics to circument these type of medications and reintroduce an inflammatory response, people without antibodies to infliximab relapse too. It just takes the body a while before it understand how, but everyone relapses on infliximab after a few years, which is why this study isn't that surprising. Chronic immunosuppression isn't a long term solution, the body will find ways to circumvent the medication.  And the main problem, namely bacteria getting past the intestine's epithelial barrier and not being removed by the immune system in a correct manner, isn't being dealt with, so you just stimulate chronic disease.


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## kiny

What is not widely known is that the chronic use of infliximab is not how this medication was originally used to treat crohn's disease. It was given as a one-off treatment to limit the more acute forms of inflammation.

(it also isn't known by hospitals that only started using this medication later on)

It was used to induce remission, but it wasn't a therapy to maintain remission. Treatment was stopped after one IV, and people went back to their maintenance therapy after, their corticosteroids, imuran, antibiotics, mesalamine, EN, whatever they were using as maintenance therapy back then (there wasn't a lot of choice, infliximab was the only biologic on the market).

The idea of giving people this medication every 8 or 10 weeks was introduced years after the medication had been on the market and actively used to treat crohn's disease.

When researchers started warning that chronic use of immunosupressants might lead to  chronic disease, it was a response to doctors suggesting that this medication should be used chronically to avoid antibody development. The consequence of chronic use of this medication were never a problem initially, because it wasn't used chronically.


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## Crohn2357

@kiny, have you seen this paper?






						Anti-MAP Therapy Support Group
					

Regarding rifabutin, there may have been some confusion early on about rifabutin vs. rifampin dosage. I clarified with Dr. Chamberlin recently, and he said it was generally 300 mg daily rifabutin, 600 mg daily of rifampin. Patients take one or the other. However, he also mentioned RedHill would...



					crohnsforum.com
				




A review of it: https://crohnsforum.com/threads/anti-map-therapy-support-group.82362/post-1020294

"In cattle, inoculating against MAP has proved remarkably effective, according to a study published in October 2014 in Veterinary Research. The vaccine trains cows’ immune systems to kill off MAP in their guts, in many cases leading to permanent relief. The tantalizing question: Might it also work for people?"

"'If it does in humans what it did in preclinical animal trials, the vaccine could have significant benefits for people with Crohn’s disease,' Hermon-Taylor says."

From: https://www.everydayhealth.com/crohns-disease/treatment/cure-crohns-disease-how-hopeful-should-we/

This is the link to the animal study: https://veterinaryresearch.biomedcentral.com/articles/10.1186/s13567-014-0112-9

What do you think about the immunisation approach against MAP for Crohn’s?


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## Crohn2357

Regarding the vet study, they gave the vaccine prior to the MAP infection in calves, and found it an effective preventative. How will this translate into treating already infected humans? Even if it stimulates the successful killing of the MAP in the patients by their immune system, will this actually help their Crohn's?

The study published by Jenner institute was done on healthy adult volunteers, and the vaccine was found to be immunogenic (look at the section 3.3. [Immunogenicity] in the paper for more information). Whether it will actually help Crohn's patients, or, more importantly, whether Crohn's is caused by MAP or not remains to be seen.

From the study article:

"The vaccine antigen consists of a fusion construct from the AhpC, Gsd, p12 and mpa MAP genes, which are present in all MAP strains. The antigen was named HAV and has been described elsewhere [34]."

"Prior to vaccination, responses to HAV antigens were low, with a geometric mean response of 109 (95% CI 79–151) spot-forming cells (SFC) per million PBMC, which increased to a geometric mean of 250 SFC (95% CI 107–583) at day 28 taking an average across all dose groups (Figure 3a).

Responses were highest at day 28 in participants immunised with 2.5 × 1010 vp and were significantly increased after vaccination only in this dose group (p < 0.05, Kruskall-Wallis test with Dunn’s multiple comparison test compared with D0 responses). Responses were detected to all antigens at day 28 with geometric mean responses ranging as follows; AhpC- 56 SFC, Gsd-41SFC, p12-64 SFC, mpa-52 SFC per million PBMC (Figure 3b)."


----------



## kiny

I think it's possible that MAP is at least partially responsible for inflammation in a subset of crohn's disease patients.

But for every argument that speaks in favor of MAP being a causative agent, there are just as many that put them in doubt.

MAP infection in cattle looks quite similar to Crohn's disease in humans. The digestive track of cattle is different than that of humans, but the part that is relevant here is the ileum, and that is not that different. Cattle feature the exact same peyer's patches as humans, the inflammation results in patchy granuloma that are exactly like you find in humans.

Genetic predisposition in crohn's disease leaves patients particularly vulnerable to mycobacteria infections. It makes sense that would leave someone very vulnerable to MAP infection.

But then there are arguments against MAP too.

Why don't farmers have higher rates of crohn's disease, they should have spectacularly higher rates of crohn's disease but they don't. Why don't people who drink lots of milk have higher rates of crohn's disease.

MAP is slow dividing and has a long incubation period in cattle, crohn's disease isn't like that, crohn's disease is rather acute, patients initially suffer from what seems to be an infection like salmonella or campylobacter, they throw up, they have acute fevers with night sweats (this later subsides, most likely because the initial infection is overcome), but those aren't symptoms of a MAP infection.


----------



## kiny

Improvements after administration of antibiotics cocktails that target MAP might just be lowering bacterial load instead of suppressing MAP.

One should also keep in mind that MAP is a gram positive mycobacteria that is very different from the cell wall you find in gram negative E coli and other foodborne pathogens like yersinia you often find in crohn's disease patients.

If you give those antibiotics to someone who is actually harbouring invasive E Coli, you might be creating resistance and making something that is effective against e coli, like cipro, less effective due to the resistance you created with those broad spectrum cocktails.

Before you administer those cocktails, you need to be sure that the patients harbours MAP, and that it is behind the inflammation.


----------



## Crohn2357

The vaccine group is very self-confident that their vaccine will be “the cure” for the majority/all crohns patients. In their estimation, at the end of this year, the clinical trial with actual crohns patients will start.

Here’s their FAQ page: http://www.crohnsmapvaccine.com/faq/

Regardless of this, the rhb-104 trial result was disappointing.

About cipro: anti-map abx combination usually consists of clarithromycin, rifabutin, and clofazimine. Cipro is very rarely used. I for one wouldn’t touch that drug, after reading and experiencing its high toxicity. For me to use it, I must have absolutely no other options. You can read many horror stories about people’s experiences with cipro online. Terrible, seemingly permanent effects.

I agree with you about the reduction of “commensal” gut bacteria (bacterial load) being the possible reason for the anti-map cocktail’s effectiveness. I wrote about it in the HW forum thread I posted above. Let’s not forget also that, antibiotics have actually anti-inflammatory effects independent of their antibacterial effects. Low dose tetracyclines’ anti-inflammatory effect is a well known example. This is also a possible mechanism.


----------



## kiny

Crohn2357 said:


> About cipro: anti-map abx combination usually consists of clarithromycin, rifabutin, and clofazimine. Cipro is very rarely used.


Right. The point is that quinolones like cipro are antibiotics that have shown to be effective in crohn's disease and they are quite effective against E Coli. But quinolones increasingly run into resistance, E coli develop drug resistant mutations.

My worry is that if doctors use clarithromycin, rifabutin, and clofazimine, drugs that are not very effective in treating gram negative bacteria like invasive E coli, they are likely creating resistant E coli and might be impairing more effective treatments like cipro.

If someone has a positive PCR test for MAP (mine were always negative), and you can show that MAP is not an innocent bystander but responsible for the inflammation, then maybe it's justified to use those antibiotics cocktails. But if you don't find MAP, can't prove MAP is causing inflammation, then you will be doing more harm than good by using antibiotics that haven't been shown to be particularly effective in crohn,s disease. And you might create bacteria that become resistant to antibiotics that have shown to be of some success in crohn's disease, like cipro or flagyl.


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## Crohn2357

kiny said:


> If you use clarithromycin, rifabutin, and clofazimine, drugs that are not effective in treating gram negative bacteria, you might be creating resistant E coli and might be impairing more effective treatments like cipro.


Because you are decreasing the number of competitor bacteria in the gut by using those three?


----------



## my little penguin

> All these steps happens over a number of days, it doesn't strike me as unreasonable that inflammation comes back within weeks, or even days, if the person drops EN. Remission isn't going to last if EN is dropped.


Kiny
So is the standard of care to stay on een for life ?
And not eat any solid foods ever again in Japan ?
Since your saying they don’t use immunosuppressants /biologics and going off een brings back inflammation


----------



## kiny

Crohn2357 said:


> Because you are decreasing the number of competitor bacteria in the gut by using those three?


Each time you use antibiotics and you don't manage to kill the bacteria, you create a more resistant strains. Antibiotics always come with strong advisory to keep taking the antibiotic as prescribed, stopping too soon will just create resistant strains.

The invasive E Coli found in ileal crohn's disease, AIEC, are highly resistant bacteria (the  reside in biofilms, they exploit inflammatory conditions, and they are highly resistant to most antibiotics).

There are few antibiotics effective against AIEC, but cirpo is quite effective, as long as you didn't create prior resistance with other antibiotics. The danger is of course that if you start using anbiotics that target MAP, and the patient actually harbours invasive E Coli (which is very common in CD patients), you will create resistant AIEC strains and mace cipro ineffective.



			http://www.medsp.umontreal.ca/IRSPUM_DB/pdf/26755.pdf


----------



## Crohn2357

Otakaro Pathways in New Zealand accepts blood samples of crohns patient all around the world. Cultures them, and mostly finds the samples positive. Mine came back positive. The big question is, is MAP the cause, and whether its successful eradication (or something close to that) will result in any improvements in Crohn’s.


----------



## kiny

my little penguin said:


> Kiny
> So is the standard of care to stay on een for life ?
> And not eat any solid foods ever again in Japan ?
> Since your saying they don’t use immunosuppressants /biologics and going off een brings back inflammation


Immunosuppressants are used, not everyone responds to EN, people who respond best are those with ileal disease, especially those with stenosis.

For adults, EN is far more standard care in Japan than it is in the West. Before biologics EN was also standard care for adults in the West, there are large studies from the 90s where EN was used to induce remission, in adults. Now it's only used primarily in children, which is a shame, because it is an effective way to treat people.

If patient compliance is good, you stay on it as long as you can. There is no reason why anyone needs to go off EN, it has all the nutrients people need.


----------



## Crohn2357

kiny said:


> The danger is of course that if you start using anbiotics that target MAP, and the patient actually harbours invasive E Coli (which is very common in CD patients), you will create resistant AIEC strains and mace cipro ineffective.


I thought the 3 abx cocktail for MAP does not target e.coli, so they can’t create antibiotic-resistant e.coli.


----------



## kiny

Crohn2357 said:


> I thought the 3 abx cocktail for MAP does not target e.coli, so they can’t create antibiotic-resistant e.coli.


E coli resistance to quinolones has increased in the last decades, it is likely due to the indescriminate use of antibiotics, including antibiotics that are not E coli specific.

Using antibiotics against MAP should include the identification of MAP in a biopsy and a positive PCR test. Just testing antibiotics cocktails will likely do more harm than good.


----------



## Guerrero

Hi Kiny, are you a scientist studying crohn's disease? or you are just a patient like us doing some research?


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## kiny

Guerrero said:


> Hi Kiny, are you a scientist studying crohn's disease? or you are just a patient like us doing some research?


Hi, I'm just a crohn's disease patient. When I joined this forum years ago (I was barely an adult back then), I knew nothing about the disease or about the immune system. Reading is a form of therapy for me, a family member is a toxicologist who started to help me with the basics of immunology.


----------



## Crohn2357

@kiny, could the immunodeficiency in Crohn’s be secondary, acquired? Only a subset of patients have genetic mutations pointing to immunodeficiencies. Genome-wide association studies for Crohn’s have not shown a meaningful, generalisable evidence for genetic mutations.  We might be overlooking the impact of environmental factors, epigenetics. What do you think?


----------



## Jonny84

@kiny Here is a really concise video that explains Qu's approach to treating Crohn's disease - would be interested to hear your views on this....









						Qu Biologics' Goal: Curing Crohn's Disease by Restoring Innate Immunity | Human Paratuberculosis Foundation
					

Dr. Hal Gunn is the founder & CEO of Qu Biologics. Learn more about Qu Biologics' research and their currently recruiting Phase 2 RESTORE Crohn's Disease Trial!




					humanpara.org


----------



## kiny

Jonny84 said:


> Qu Biologics' Goal: Curing Crohn's Disease by Restoring Innate Immunity | Human Paratuberculosis Foundation
> 
> 
> Dr. Hal Gunn is the founder & CEO of Qu Biologics. Learn more about Qu Biologics' research and their currently recruiting Phase 2 RESTORE Crohn's Disease Trial!
> 
> 
> 
> 
> humanpara.org


Thanks. They are not very forthcoming about how the medication works. I haven't read anything about site specific stimulation of macrophages. Granulocyte-macrophage colony-stimulating factor has been used, but it's not site specific, but it does seem to correct innate immunodeficiencies.

The underlying premise to correct the innate immune deficiencies and clear the infection is an attractive way to treat crohn's disease because it would lead to sustained improvement and should have far less side effect than stopping inflammation by blocking the adaptive response.

All you really need is a competent macrophage reaction, our immune system is completely capable of shutting down inflammation after an infection subsides, effector cells of the adaptive immune system don't live very long, they die by apoptosis and all that's left is memory cells.

If you correct the innate immune response, a secondary infection would also be cleared more competently since you would have more competent adaptive immune system and more competent memory cells. It should in theory lead to sustained improvement.

The rate of improvement in the graph is what  you would expect to see in a sustained but competent immune response that eventually subsides.


----------



## kiny

Crohn2357 said:


> @kiny, could the immunodeficiency in Crohn’s be secondary, acquired?


It's the adaptive immune system that is developed during life, it adapts. The innate immune system is non-specific and relies primarily on evolutionary factors, it is innate. The innate immune system in the intestine probably evolved together with the microbiome during evolution. 

So to answer the question, no I don't think the innate immunodeficiencies are acquired. 

There's the hygiene hypothesis, but that also involves the adaptive immune system. The idea that somehow our own immune system lost tolerance to bacteria. I don't believe in it, I think our immune system is competent enough to not mount an inflammatory response against its own flora just for the heck of it at some random date in time. No.



Crohn2357 said:


> Only a subset of patients have genetic mutations pointing to immunodeficiencies.


NOD2 mutations in crohn's disease result in loss of function NOD2, a very large portion of CD patients in the West carry the muation. It's seeen in other diseases too like Blau syndrome (people with Blau syndrome have lots of crohn's disease).

There are also defects in autophagy competence (ATG16L1 and IRGM), which again point to innate immunodefficiency.

Vitamin D receptor defects again point to innate immunodeficiency.



Crohn2357 said:


> We might be overlooking the impact of environmental factors, epigenetics. What do you think?


Well, crohn's disease is distributed along a Y axis on a map, people in the north have lots of crohn's disease, people in the south much less.

The explanation has been that northern regios have different standards of living, different socio-economic status, and somehow this plays a role. Maybe people from higher economic status freeze their food more, which might result in more foodborne infections.

Another explanation, which could simply tie in to the first explanation, is that people in the North receive less sunlight, and we know vitamin D status affects the innate immune system.


----------



## kiny

If the question was how relevant the primary immunodeficiency is. Extremely relevant I would say, I don't think there are crohn's disease patients who don't have a primary immunodeficiency.

Crohn's disease patients are consistently shown to have weak immune responses, the adaptive immune system is competent, the innate is incompetent, specifically macrophage competency is hindered by autophagy and signaling protein defficiencies.

(UC doesn't show any of those deficiencies)


----------



## Chrons Ma

Crohn2357 said:


> Otakaro Pathways in New Zealand accepts blood samples of crohns patient all around the world. Cultures them, and mostly finds the samples positive. Mine came back positive. The big question is, is MAP the cause, and whether its successful eradication (or something close to that) will result in any improvements in Crohn’s.


Son was tested by Otakaro Pathways, and subsequently became a patient of Prof. Tom Barody (CDD, Sydney), using anti-biotic anti-map therapy. Unfortunately,  our son is not one of the success stories, but there are many for whom this treatment does work. Research does back the theory, with the para-physiology of Johnnes in cattle identical to Crohns in humans. Toms "poster" patient is a woman now in her 30's, living a full life in complete remission for years. Kimberly was 17 when she became one of Tom's first patients, when anti-map was in its infancy. She had been told she needed a total colectomy as her lower GI was beyond repair, and she would never have children. A remarkable success story indeed.

I am pleased we partook in the treatment, for though it was unsuccessful for our son, if we had not tried, it would always have been a "what-if" for us. (And I do wonder whether there were other factors involved in his particular lack of success with the treatment, but this is another story all together)

The research into gut bacteria and the implications on our health is being more widely researched now, with strong links to other diseases, including the likes of Parkinsons, Alzheimers and even cardio-vascular implications


----------



## Crohn2357

@kiny, Is the immunodeficiency in Crohn’s caused solely by genetic predispositions for all Crohn’s patients?

Also, why do you exclude colonic Crohn’s from your conception of Crohn’s disease?



> It is also notable that 60–70% of CD patients do not have any of the commonly associated _NOD2_variants; further highlighting the complexity. Subphenotype analyses have shown a replicable association between these _NOD2_ variants and stricturing, ileal disease [13].


James C. Lee, Miles Parkes, Genome-wide association studies and Crohn’s disease, Briefings in Functional Genomics, Volume 10, Issue 2, March 2011, Pages 71–76, https://doi.org/10.1093/bfgp/elr009


----------



## Jonny84

Anti-MAP does not seem particularly impressive from what I have read.

For me the really exciting treatment is QBECO which is being developed by Qu Bioligcs.  We are talking about the potentially moving from immune suppressing treatments to immune restoring treatments - that is a paradigm shifting change. That's why I am surprised Big Pharma have not taken more notice of QBECO - once its approved there will surely be a significant drop in demand for their expensive immune suppressing treatments of which there are several on the market and more in the research phase as we speak. The whole identify a molecule and block it big pharma extravaganza could be coming to an end!


----------



## kiny

Jonny84 said:


> The whole identify a molecule and block it big pharma extravaganza could be coming to an end!


For acute inflammation single treatment infliximab make sense, it manages to stop the inflammatory cascade very quickly. (that's how it was used initially)

(newer immunosuppressant biologics have very low and questionable success rates in inducing acute remission compared to infliximab)

But if you chronically start using it, and you have studies that show that the end result is that patients are not in a better situation than before the therapy. Then some serious questions should be asked if it is truthfully helping patients or if you are simply stimulating long term chronic disease.


----------



## Crohn2357

> The three most common NOD2 variations are found in about 40 percent of all people with Crohn disease.











						NOD2 gene: MedlinePlus Genetics
					

The NOD2 gene (previously known as CARD15 ) provides instructions for making a protein that plays an important role in immune system function. Learn about this gene and related health conditions.




					ghr.nlm.nih.gov
				






> Between 30% and 50% of CD patients in the Western hemisphere carry Nod2 mutations of at least one allele of the disease-causing mutations (DCMs).


Yamamoto, S., & Ma, X. (2009). Role of Nod2 in the development of Crohn's disease. _Microbes and infection_, _11_(12), 912–918. doi:10.1016/j.micinf.2009.06.005


----------



## Jonny84

kiny said:


> For acute inflammation infliximab make sense, it manages to stop the inflammatory cascade very quickly. (that's how it was used initially)
> 
> (newer immunosuppressant biologics have very low and questionable success rates in inducing acute remission compared to infliximab)
> 
> But if you chronically start using it, and you have studies that show that the end result is that patients are not in a better situation than before the therapy. Then some serious questions should be asked if it is truthfully helping patients or if you are simply stimulating long term chronic disease.


So your argument is that Infliximab should be used as a one off treatment to rescue patients who's inflammation is out of control?  I was on Inflix but I am now on Vedo and I feel a lot better in general, and my Crohn's is well under control.


----------



## kiny

Jonny84 said:


> So your argument is that Infliximab should be used as a one off treatment to rescue patients who's inflammation is out of control?


Right, that's how it was initially being used. No one had any idea what infliximab would do, TNF-α is an incredibly potent and important cytokine. Blocking such a cytokine was deemed very risky.

Infliximab was only administered once, it induced remissions and then people went back onto maintenance therapy. If the person relapsed a year later, it was used again and again stopped.

It wasn't until some people said it should be used chronically to avoid antibodies that it was used chronically.

Using strong anti-inflammatory for a very short period of time is not new. It is sometimes used when there is an infection to avoid escalating nerf damage. But you don't administer it chronically, because if you do, the infection worsens and people get sicker.


----------



## Jonny84

What are your thoughts on Vedo?


----------



## kiny

All other biologic immunosuppressant medication is less effective than infliximab, takes longer before people are in remissions, and people relapse faster.

The reasons infliximab is so incredibly effective in inducing acute remissions, is because it acts on the main cytokine that macrophages secrete in the lamina propria of the intestine. The lamina propria is full of macrophages and dendritic cells. There are more immune cells concentrated in your intestine than in any other part of your body.

Macrophages also secrete several interleukin cytokine, but they aren't nearly as important to induce acute inflammation as TNF-α is, blocking other cytokine is not going to be neaerly as effective to induce remission, which is why all those other medications are far less effective, why remissions rates are far lower, to even questionable at times.


----------



## kiny

I will put it another way if you like. If inflammation is music, then TNF-α is the director of the orchestra in the intestine. The director can make the band play louder, it can make it play softer. Infliximab acts on the director, newer biologics are far less effective because they act on band members.

A big reason why newer biologics even exist, is due to patents of infliximab that ran out, etc. There is money involved of course. The producer of infliximab its patents have run out, so you now have generic versions of infliximab, which is why the producer of infliximab invented new biologics and tries to claim they are just as effective, but they're not of course, studies show newer biologics are far less effective, because they don't act on the main orchestrator of inflammation, which is TNF-α.


----------



## Jonny84

Vedo has been great for me.  I was not in an acute flare when I started but I did start to feel better from the first infusion and I have so  much more energy, sleep better, feel better than I did during my 3 years on inflix...

I agree on the effectiveness for Inflix - I was in hospital and bleeding badly with a flare that was not responding to steroids.  They gave me an infusion and with 48-72 hours I was pretty much back to normal. Amazing!  I just found it too difficult to live my life on it long term.


----------



## kiny

Jonny84 said:


> They gave me an infusion and with 48-72 hours I was pretty much back to normal. Amazing!  I just found it too difficult to live my life on it long term.


That's right, it can shut down inflammation on a dime because it acts on the main orchestrator of inflammation in the intestine, TNF-α. It is incredibly effective in inducing acute remissions.

But if you start chronically blocking this cytokine, you might stimulate chronic disease because you decrease how effective macrphages are in removing bacterial content.


----------



## kiny

> Is the immunodeficiency in Crohn’s caused solely by genetic predispositions for all Crohn’s patients?


Yes. There are probably factors influencing how severe that innate immunodeficiency is though, vitamin D acts on the innate immune system and we know people with vit D defficiency have worse crohn's disease relapses.



Crohn2357 said:


> Also, why do you exclude colonic Crohn’s from your conception of Crohn’s disease?


Because peyer's patches are found in the small intestine in the ileum, not the colon. And the first signs of active inflammation in crohn's disease is inflamed peyer's patches.

If you start throwing all inflammatory intestinal diseases into one pile, you get lost in the woods trying to make any sense of them.


----------



## Jonny84

kiny said:


> I will put it another way if you like. If inflammation is music, then TNF-α is the director of the orchestra in the intestine. The director can make the band play louder, it can make it play softer. Infliximab acts on the director, newer biologics are far less effective because they act on band members.
> 
> A big reason why newer biologics even exist, is due to patents of infliximab that ran out, etc. There is money involved of course. The producer of infliximab its patents have run out, so you now have generic versions of infliximab, which is why the producer of infliximab invented new biologics and tries to claim they are just as effective, but they're not of course, studies show newer biologics are far less effective, because they don't act on the main orchestrator of inflammation, which is TNF-α.


The thing I don't understand is - presumably these big pharma companies must look around the research landscape to understand what is coming in the future and to some extent this will inform their activities as they are commercial companies and exist to maximise profit.  If I worked for one of these corporations I would look at the coming treatment from Qu BIologics and think ok something is set to come onto the market in the next 5-7 years which could reduce very significantly the demand for our products as well as the drugs we have in pipeline (which are being developed under the same model as current drugs). 

Are they just stupid or arrogant or is there some reason I am missing as to why they would want to invest billions into drugs that could well have significantly reduced demand when they come to market? Surely the only answer is to up their game and really push to find a new level of research which is above and beyond the current identify a molecule and block it model. Its the old 'move with the times or get left in the dust' argument.

I think it's fair to say big steps forwards in thinking tend to come from the margins rather than from the centre and Qu are very much outside of the commercialised, share holder value dominated world of the big pharmaceutical corporations. .


----------



## kiny

(I also don't think little kids are coming down with crohn's disease as has been suggested. That's certainly not because I don't appreciate how much those kids and parents are suffering, it is simply because peyer's patches aren't very active during those years, they are active during puberty.

Puberty is still the age where most people come down with ileal crohn's disease. If you have 5-year-old kids who are mysteriously developing inflammation in the intestine, you have to consider the fact that it might be another undefined disease. It certainly doesn't help to categorize every disease that features intestinal granuloma as crohn's disease.)


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## Crohn2357

@kiny, for how long have you been in remission? What medications do you use, if any?


----------



## kiny

Antibiotics and elemental nutrition. But I am not a relevant statistic because the reason I am given antibiotics is because I had idiopathic lymphopenia, which is now improving. Maybe it helps with CD, I have no idea.


----------



## Crohn2357

Do you use antibiotics as needed or chronically? What EN product do you use, and do you use it everyday, or as needed? Do you also eat food?


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## kiny

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). I have used many different EN, now it's the stuff from nutricia. It doesn't matter at all what brand you use, EN work because they are highly bioavailable and therefore they limit the fecal stream. All real EN on the market are highly bioavailable, brands don't matter. No I don't eat (real) food.


----------



## kiny

The biggest issue with EN is not if it works or not, it has clearly been shown that it works in people with ''classical'' ileal disease, especially if there is stenosis or bowel narrowing (it works far less well in non-classical disease if there is colonic involvement). The biggest issue is patient compliance, the stigma of running with a tube, the stigma of never being able to eat with others, the fact you need to be monitored for calorie defficiency. That stigma and the care needed to avoid nutritional defficiency, probably limits the adoption, but that stigma doesn't need to be there, as Japan has shown, where EN is standard care for adults.


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## Crohn2357

Aren’t you worried about vegetable oils, and laboratory impurities (and heavy metals, allergens) of the substances in the products? You are ingesting them every day.

Which of these are you currently using: https://www.nutricia.com/en/advanced-medical-nutrition/products.html

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

Also, you mentioned tube, do you not take the EN orally?


----------



## Crohn2357

Would EN also work for Crohn’s in the colon?


----------



## kiny

Crohn2357 said:


> Would EN also work for Crohn’s in the colon?


I doubt it.

In classical ileal disease, immune responses to the fecal stream are most likely coming from peyer's patches. The colon doesn't have them, if there is patchy inflammation in the colon it's probably more related to simple bacterial load in the colon instead of bacterial load from the fecal stream.


----------



## kiny

Crohn2357 said:


> 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. I have to go now, nice talking to you.


----------



## Guerrero

Studies show efficacy for enteral nutrition, but unfortunately the relapse rate remains high compare to the effort it takes to follow it...









						Enteral nutrition for maintenance of remission in Crohn's disease - PubMed
					

The results for the outcomes assessed in this review are uncertain and no firm conclusions regarding the efficacy and safety of enteral nutrition in quiescent CD can be drawn. More research is needed to determine the efficacy and safety of using enteral nutrition as maintenance therapy in CD...




					www.ncbi.nlm.nih.gov


----------



## kiny

ncman said:


> Some really great info here, I just wanted to highlight the summary from AW Segal's 2016 work:


He has been writing about crohn's disease for decades. He did studies on EN in the 80s, and was one of the first people who realized it was effective.

If you want to read interesting paper, looking through his papers is a good start. He is also one of the first people who realized crohn,s disease was an innate immunodefficiency.









						Elemental diet as primary treatment of acute Crohn's disease: a controlled trial.
					

Acute exacerbations of Crohn's disease are usually treated with prednisolone or potentially more toxic immunosuppressive drugs or by surgery. In pilot studies replacing the normal diet by a protein free elemental diet also induced remission. A controlled trial was therefore conducted in which 21...




					www.bmj.com
				




The same work he did in London was supported by other studies in London about the EN in the 80s, they knew the antigen causing inflammation in crohn's disease was bacterial, and they knew it was in large part from high bacterial load of the fecal stream. 

They were one of the few researches who correctly identified that it was bacteria entering the epithelium and lamina propria, acitving the peyer's patches and immune system in crohn's disease 35 years ago.



			https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1432937/pdf/gut00383-0014.pdf
		


1985


----------



## kiny

In 1986 these same people from London realised that the immune response in Crohn's disease is very different from that seen in UC.









						Differing acute phase responses in Crohn's disease and ulcerative colitis - PubMed
					

Thirty eight patients with Crohn's disease and 30 patients with ulcerative colitis have been assessed using the technique of faecal excretion of 111Indium granulocytes to quantify precisely acute inflammatory activity. At the time of each faecal granulocyte measurement the serum concentration of...




					www.ncbi.nlm.nih.gov
				




The present findings show that the *acute phase response differs significantly between Crohn's disease and ulcerative colitis*.


These same people in London then realised that macrophages in crohn's disease have issues clearning crohn's associated invasive E Coli.









						Defective macrophage handling of Escherichia coli in Crohn's disease - PubMed
					

CD macrophage responses to infection with E. coli are deficient, regardless of clinical phenotype, CD genotype or E. coli pathogenicity. This suggests host immunodeficiency is an important contributor to intramacrophage E. coli persistence in CD.




					www.ncbi.nlm.nih.gov
				





If crohn's disease is one day cured, these people should get a nobel price. The have written some of the most important papers on crohn's disease.


----------



## kiny

Segal is also responsible for the study where they first started checking innate immunocompetence in crohn's disease.

The irony is that the most interesting studies about crohn's disease are also the easiest to understand.

How do you test if someone is immunocompetent? Well, you check how they deal with infections.

What they did was inject heat killed E Coli into the forearm of healthy people, people with UC, and people with crohn's disease.

What you find is that people with crohn's disease do not have a competent acute inflammatory reaction, magrophage reaction and neutrophil recruitment is stunted.

The study is on the forum somewhere in full, I posted it in 2013, it's copyrighted but it's still there in full if you care to look for it, it was featured in The Lancet.


----------



## kiny

I don't know how QUbiologics, the company some people keep mentioning, got around the idea of injecting E coli into the skin to treat crohn's disease, but they of course read that study.


----------



## Jonny84

kiny said:


> I don't know how QUbiologics, the company some people keep mentioning, got around the idea of injecting E coli into the skin to treat crohn's disease, but they of course read that study.


I've followed their work since the first patients were treated - it gives me hope.


----------



## Jonny84

Ths could wel be the watershed moment we have been waiting for - a move from a immune suppressing to immune restoring treatments.  The implications go far beyond the treatment of only IBD.


----------



## kiny

GM-CSF, granulocyte-macrophage colony-stimulating factor, was the only real trial so far to boost the innate immune system in crohn's disease. With 15 patients, 12 improved significantly, 8 went into remission.

I don't know what happened after that, Segal (he wasn't involved in the study but he mentions the study in his papers) said it wasn't FDA approved, I don't know what happend with the treatment, I would have to ask people involved in the study.


----------



## kiny

Ah, they did keep trying GM-CSF after that first trial. It was developed as Leukine with brand name Sargramostim. Two trials I can find,  it failed in adults, one was successful in kids. The adult trials were done in Japan and Canada. The low success rate in adults was probably why it was never FDA approved.


----------



## kiny

It's also interesting that if you read Segal his studies, he shows that crohn's disease patients not only have a competent adaptive response, they also have competent neutrophils. The reason there isn't a competent neutrophil reaction is just because of lack of macrophage  cytokine release. There are not nearly  enough neutrophils recruited to have a competent reaction in the intestine. But neutrophils themselves are completely competent in CD.


----------



## Crohn2357

If I remember right, this was the first study which pointed out to immunodeficiency in Crohn’s patients: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(76)91024-2/fulltext


----------



## D Bergy

David said:


> Source
> 
> Quite an interesting study.  Anyone have any opinions on it?



Well, these type of treatments basically accomplish what I would expect given the nature of the disease.  Temporary relief.  

What is interesting to me is that the authors go out on a speculative limb, without any evidence at all, and indicate that improper use or compliance using the drug may be the underlying reason.  I will also speculate that not angering the large drug companies for the failure is the actual reason for that statement. 

Since that would require virtually all the study participants to be misusing or underutilizing the treatment that would seem very unlikely. 

I think Kiny’s thoughts on this far more likely although I have different  thoughts on the nature of the disease cause in some respects.  

I am more interested on Kiny’s treatment if it has improved her condition as it is real life and not subject to a financial interest.  Possibly she could start a thread on it.  

Best regards.  

Dan


----------



## Crohn2357

D Bergy said:


> I am more interested on Kiny’s treatment if it has improved her condition as it is real life and not subject to a financial interest. Possibly she could start a thread on it.


Judging by kiny’s way of thinking, interacting, arguing, writing and interests, I would be surprised if kiny turned out to be a woman.


----------



## D Bergy

Crohn2357 said:


> Judging by kiny’s way of thinking, interacting, arguing, writing and interests, I would be surprised if kiny turned out to be a woman.


Man or woman, he or she (I think she is a woman) has an unusually logical thought process.   That is why I am always interested in what she has to say.  

Her treatment would reflect this and that piques my interest.  

I am always interested in another angle of attack on this disease. 

Although I am in my seventh year from experiencing the disease, I never want to struggle with it again and I will spend time making sure that it does not occur again.  

Dan


----------



## Crohn2357

D Bergy said:


> I am always interested in another angle of attack on this disease.
> 
> Although I am in my seventh year from experiencing the disease, I never want to struggle with it again and I will spend time making sure that it does not occur again.


I agree. That’s also why I am asking him questions. I am sick of living with Crohn’s.


----------



## luxflow

@kiny thanks for sharing your knowledge first of all 
I have 2 questions
1. I'm also curious about reumatism and type 1 diabetes, I heard somehow they're related to crohn's disease, are they also immunodefeciency state?
2. if crohn's disease is immunodeficiency state, why some others organ other than intestine aren't infected?


----------



## kiny

luxflow said:


> 2. if crohn's disease is immunodeficiency state, why some others organ other than intestine aren't infected?


Hi, people with Crohn's disease have aphthous ulcers in their mouths, just like other diseases with impaired innate immunity like Chronic granulomatous disease.

Aphthous ulcers in UC are extremely rare compared to crohn's disease, most people don't have them. UC doesn't have impaired innate immunity.

Why the intestine in crohn's disease and not some other organ...because crohn's disease is impaired immunity of macropahages...the large large majority of macrophages are in the intestine. The ileum is rich in peyer's patches.


----------



## Scipio

luxflow said:


> @kiny thanks for sharing your knowledge first of all
> I have 2 questions
> 1. I'm also curious about reumatism and type 1 diabetes, I heard somehow they're related to crohn's disease, are they also immunodefeciency state?
> 2. if crohn's disease is immunodeficiency state, why some others organ other than intestine aren't infected?


Other organs besides the intestine ARE affected by Crohn's, sometimes seriously so.  It's the whole "extra-intestinal manifestations" thing.  Usually it is the joints that are also affected.  In my case it was pericarditis.  Several years after diagnosis my Crohn's inflammation also popped up in my pericardium - the membrane surrounding the heart.  I ended up getting open-chest surgery to remove the inflamed pericardium.  That's why I gave in and went on biologics.  I didn't want to go through another episode like that.  And so far, one and half years later, the Stelara is working pretty well.  There have been no further extra-intestinal episodes and the intestinal Crohn's is in complete remission.


----------



## kiny

Macrophages their life generally consists of waiting within tissue. They hide in the most strategic places where a bacteria might enter.

When a doctor does a white blood cell count, they are not measuring macrophages, they are measuring monocytes from the blood, they will eventually evolve into tissue macrophages.

Macrophes in the intestine are strategically hiding in the lamina propria, it is the tissue right behind the epithelium of the intestine, they hide behind M cells, they hide near peyer's patches, they hide in places where bacteria keep causing trouble. They are  are your first line of defense when a bacteria enters your intestine. Once they encountered a bacteria, they sound the alarm, they do this by releasing cytokine, one of them is TNF-α, which is the main orchestrator of fever and inflammation.

Macrophages in crohn's disease have issues in that specific acute response, the macrophages are impaired, they don't react appropriately, the acute phase is stunted because of it. As a result the adaptive immune system is chronically activated to compensate.


----------



## Crohn2357

kiny, when you think about the effects of thiopurines on immune cells, what do you think about their long term use in the acute and preventive treatment of Crohn’s disease? Could you put that into your perspective?


----------



## Guerrero

Revisiting Crohn's disease as a primary immunodeficiency of macrophages | Journal of Experimental Medicine | Rockefeller University Press
					

Despite two decades of mouse immunology and human genetics studies, the pathogenesis of Crohn's disease (CD) remains elusive. New clinical investigations sugges




					jem.rupress.org
				




this macrophage theory seems to have been already discussed in some studies. 
Now, could they find a cure easier if this is right?


----------



## Crohn2357

Guerrero said:


> Revisiting Crohn's disease as a primary immunodeficiency of macrophages | Journal of Experimental Medicine | Rockefeller University Press
> 
> 
> Despite two decades of mouse immunology and human genetics studies, the pathogenesis of Crohn's disease (CD) remains elusive. New clinical investigations sugges
> 
> 
> 
> 
> jem.rupress.org
> 
> 
> 
> 
> 
> this macrophage theory seems to have been already discussed in some studies.
> Now, could they find a cure easier if this is right?


I posted some of the relevant papers on immunodeficiency in *the anti-map therapy support group*, if anyone is interested.


----------



## kiny

Crohn2357 said:


> kiny, when you think about the effects of thiopurines on immune cells, what do you think about their long term use in the acute and preventive treatment of Crohn’s disease? Could you put that into your perspective?


All the serious side effects they saw in patients was on combination therapy, once they removed the azathioprine and realized that combo therapy wasn't needed to make infliximab effective, but they instead could regulate the dosage of infliximab, there were considerably less serious side effects. The serious side effects were clearly being caused by the addition of azathioprine, it is good that they stopped combo therapy, it is never needed when infliximab dosage can be modified.


----------



## Crohn2357

My question was more in regards to its use as a monotherapy, on its own.  I am also wondering your opinion on using rapamycin for Crohn’s.

Gut. 2008 Sep;57(9):1294-6. doi: 10.1136/gut.2008.157297.
*Use of sirolimus (rapamycin) to treat refractory Crohn's disease.*
Massey DC1, Bredin F, Parkes M.
*Author information
Abstract*
We present the case of a 37-year-old woman with severe refractory colonic and perianal Crohn's disease who had lost response to second-line, steroid-sparing treatments azathioprine, methotrexate and infliximab. For many such patients extensive surgery has often been considered the only option. *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.* Our patient was treated with sirolimus for 6 months at a dose that maintained serum trough levels of 5 ng/ml. There was marked and sustained improvement in Crohn's disease symptoms with the Harvey-Bradshaw index falling from 13 to 3, in serum markers of inflammation (C-reactive protein fell from 79 to 2) and endoscopic appearance. This is the first reported case of the use of sirolimus to treat Crohn's disease.
PMID: 18719139 DOI: 10.1136/gut.2008.157297








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

We present the case of a 37-year-old woman with severe refractory colonic and perianal Crohn's disease who had lost response to second-line, steroid-sparing treatments azathioprine, methotrexate and infliximab. For many such patients extensive surgery has often been considered the only option...




					www.ncbi.nlm.nih.gov
				





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










						To Evaluate the Efficacy and Safety of Rapamycin for Crohn's Disease-related Stricture - Full Text View - ClinicalTrials.gov
					

To Evaluate the Efficacy and Safety of Rapamycin for Crohn's Disease-related Stricture - Full Text View.




					clinicaltrials.gov


----------



## kiny

I don't know what rapamycin is. Regarding azathioprine, I don't think there is much of a future for it when you now have biologics.  If you're going to use immunosuppressant, you might as well use one that is highly effective like infliximab and is at least as safe, if not safer than the less effective treatment.

I don't agree with how infliximab is used chronically, I think we should go back to using it only during acute phases of inflammation (even with the risk of antibody development). Giving it chronically is clearly not the way forward if you look at that depressing study.

But infliximab will always remain the most effective of all the biologics to treat acute inflammation, since TNF-α is the cytokine behind the inflammatory escalation.


----------



## 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.


----------



## wildbill_52280

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

wildbill_52280 said:


> 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.


----------



## wildbill_52280

kiny said:


> 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

Crohn2357 said:


> 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

kiny said:


> 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

Crohn2357 said:


> 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

D Bergy said:


> 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

D Bergy said:


> 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

Crohn2357 said:


> 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

Crohn2357 said:


> 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

Scipio said:


> 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

Scipio said:


> 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

D Bergy said:


> 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

D Bergy said:


> 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:









						Search of: Recruiting Studies | Crohn’s - List Results - ClinicalTrials.gov
					






					www.clinicaltrials.gov
				




Here’s another list:






						Clinical Trial Finder - Crohns & Colitis Foundation
					

We are a non-profit, volunteer-fueled organization dedicated to finding cures for Crohn's disease and ulcerative colitis, and improving the quality of life of children and adults affected by these diseases.




					trials.crohnscolitisfoundation.org
				




——————









						Clinical Trials for Crohn’s Disease | NIDDK
					

Read about clinical trials for Crohn’s disease. Clinical trials are at the heart of all medical advances. Find out if clinical trials are right for you.




					www.niddk.nih.gov
				




This is the main webpage:









						Home - ClinicalTrials.gov
					






					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: 






						IBD News Today
					

Your Online Resource for the Latest IBD News




					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

Delta_hippo said:


> 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

Crohn2357 said:


> 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.











						A severe autoimmune condition may be triggered by 'good' gut bacteria
					

Antiphospholipid syndrome is an autoimmune condition that can lead to miscarriages or even death – and in some cases it might be brought on by a gut bacterium




					www.newscientist.com


----------



## Crohn2357

kiny said:


> 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

Crohn2357 said:


> 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

Guerrero said:


> 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 diseaseUlcerative colitisSmokingHigher risk for smokersLower risk for smokers[44]AgeUsual 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]











						Crohn's disease - Wikipedia
					






					en.m.wikipedia.org
				






Guerrero said:


> 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

The role of macrophages in the treatment of Crohn’s disease
					

Scientists at the University of Plymouth explored a novel mechanism for the treatment of Crohn’s disease using macrophages.




					www.medicalnewsbulletin.com


----------



## Crohn2357

Pangolin said:


> 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

kiny said:


> 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:



kiny said:


> 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.









						Why does Crohn's disease usually occur in terminal ileum?
					

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 diseas




					academic.oup.com
				






> 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.











						Endoscopic identification of Peyer’s patches of the terminal ileum in a patient with Crohn’s disease
					

We presented a 20-year-old patient with Crohn’s disease (CD). Colonoscopy revealed longitudinal ulceration in the terminal ileum and rectal aphtoid ulcers. After treatment with mesalamine and total parenteral nutrition, repeat colonoscopy revealed ...




					www.ncbi.nlm.nih.gov
				




Histopathology of Crohn’s disease and ulcerative colitis


			http://www.forpath.org/workshops/minutes/0411/Crohn_s_disease_and_ulcerative_colitis.pdf
		










						Peyer's patch - Wikipedia
					






					en.m.wikipedia.org
				









						Microfold cell - Wikipedia
					






					en.m.wikipedia.org
				









						Gut-associated lymphoid tissue - Wikipedia
					






					en.m.wikipedia.org
				












						Lamina propria - Wikipedia
					






					en.m.wikipedia.org


----------



## kiny

Crohn2357 said:


> 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

Crohn2357 said:


> 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

kiny said:


> 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

Guerrero said:


> 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

kiny said:


> ''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.



Crohn2357 said:


> _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
> 
> 
> 
> 
> 
> 
> 
> 
> 
> To Evaluate the Efficacy and Safety of Rapamycin for Crohn's Disease-related Stricture - Full Text View - ClinicalTrials.gov
> 
> 
> To Evaluate the Efficacy and Safety of Rapamycin for Crohn's Disease-related Stricture - Full Text View.
> 
> 
> 
> 
> clinicaltrials.gov






Guerrero said:


> 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.









						Why does the Vitamin D Council recommend 5,000 IU/day?
					

Organizations and institutions each recommend widely varied daily intake of vitamin D. How did the Vitamin D Council settle on 5,000 IU/day?




					www.vitamindcouncil.org
				






			https://www.tandfonline.com/doi/full/10.1586/eci.10.31
		










						Vitamin D, Vitamin D Receptor, and Macroautophagy in Inflammation and Infection
					

Vitamin D is involved in mineral and bone homeostasis, immune responses, anti-inflammation, anti-infection, and cancer prevention. Vitamin D receptor (VDR) is a nuclear receptor that mediates most biological functions of 1,25(OH)[2] D[3]  or vitamin D[3] ...




					www.ncbi.nlm.nih.gov
				












						Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility
					

BACKGROUND—The vitamin D receptor (VDR) gene represents a strong positional candidate susceptibility gene for inflammatory bowel disease (IBD). The VDR gene maps to a region on chromosome 12 that has been shown to be linked to IBD by genome ...




					www.ncbi.nlm.nih.gov
				






			https://www.hindawi.com/journals/bmri/2015/470805/
		










						Role of autophagy in the pathogenesis of inflammatory bowel disease
					

Inflammatory bowel disease (IBD) results from a complex series of interactions between susceptibility genes, the environment, and the immune system. Recently, some studies provided strong evidence that the process of autophagy affects several aspects ...




					www.ncbi.nlm.nih.gov
				




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:



Crohn2357 said:


> These are currently recruiting phase 3 and phase 4 studies for Crohn’s, all around the world:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Search of: Recruiting Studies | Crohn’s | Phase 3, 4 - List Results - ClinicalTrials.gov
> 
> 
> 
> 
> 
> 
> 
> www.clinicaltrials.gov


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## Crohn2357

kiny said:


> 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.





kiny said:


> 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.


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## 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)


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## 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.


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## Crohn2357

kiny said:


> 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.


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## 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.


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## 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)


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## 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.


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## 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_






						Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease | Journal of Experimental Medicine | Rockefeller University Press
					

The cause of Crohn's disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could res




					jem.rupress.org


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## 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.


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## 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.


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## Guerrero

What about Rifaximin? Seems a good treatment option too.


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## kiny

Guerrero said:


> 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.)


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## 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.


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## 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

kiny said:


> 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.


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## 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

Hopeful girl said:


> 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.



Hopeful girl said:


> 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.




Hopeful girl said:


> 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




Hopeful girl said:


> 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



Hopeful girl said:


> 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).




Hopeful girl said:


> 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.




Hopeful girl said:


> 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.



Hopeful girl said:


> 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).


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## 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

kiny said:


> 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

Crohn2357 said:


> Do you use antibiotics as needed or chronically?





kiny said:


> 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).





Crohn2357 said:


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





kiny said:


> 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.



—————




kiny said:


> 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

Hopeful girl said:


> 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): 









						What Is A Leaky Gut? (And How Can It Cause So Many Health Issues?)
					

However, the body of scientific literature showing that increased intestinal permeability is inextricably linked to diverse diseases is convincing.




					www.thepaleomom.com
				




Here’s another simple explanation: 



			Page Not Found - Cleveland Clinic Center for Continuing Education
		


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: 






						(Podcast) Pioneering Researcher Alessio Fasano on Gluten, Autoimmunity & Leaky Gut
					

It's an honor to welcome Dr. Alessio Fasano as a guest on the show. Dr. Fasano is globally recognized for his pioneering research in the fields of Celiac disease and gluten intolerance. In 2003, he published the groundbreaking study in the Annals of Medicine that established the prevalence rate...



					www.crohnsforum.com
				




(2): 



			https://www.physiology.org/doi/full/10.1152/ajpgi.2001.280.1.G7
		










						Effects of acute stress provocation on cortisol levels, zonulin and inflammatory markers in low- and high-stressed men
					

The virtual version of the Trier Social Stress Test (V-TSST) is an effective and standardized tool for social stress induction. This study aimed to ex…




					www.sciencedirect.com
				












						Stress Induces Endotoxemia and Low-Grade Inflammation by Increasing Barrier Permeability
					

Chronic non-communicable diseases (NCDs) are the leading causes of work absence, disability, and mortality worldwide. Most of these diseases are associated with low-grade inflammation. Here, we hypothesize that stresses (defined as homeostatic disturbances) ...




					www.ncbi.nlm.nih.gov


----------



## Crohn2357

Leaky Gut, Demystified
					

Learn what leaky gut is, why it's a big deal, what it has to do with diet, and what you can do about it.




					paleoleap.com


----------



## 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

kiny said:


> bacteriophages


----------



## Hopeful girl

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


----------



## kiny

Crohn2357 said:


> 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

kiny said:


> 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

Crohn2357 said:


> 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:






—






—
















—









						Your Immune System: Natural Born Killer - Crash Course Biology #32
					

Hank tells us about the team of deadly ninja assassins that is tasked with protecting our bodies from all the bad guys that want to kill us - also known as o...




					m.youtube.com
				












						Immune system - Wikipedia
					






					en.m.wikipedia.org


----------



## kiny

Macrophages respond to bacteria and fungi, but they also interact with *in*organic (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

kiny said:


> How do these metallic particles enter the body





kiny said:


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












			THE PHENOMENON OF PERSORPTION: PERSORPTION,  DISSEMINATION, AND ELIMINATION OF MICROPARTICLES  – Functional Performance Systems (FPS)
		







						Prof. Dr. Gerhard Volkheimer – Gastroenterologist (Persorption)
					

Prof. Gerhard Volkheimer researched in the field of gastroenterology at the medical faculty of the Charité at Berlin from 1948 to 1967



					christiane-volkheimer.com
				




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.









						[Persorption of microparticles] - PubMed
					

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...




					www.ncbi.nlm.nih.gov
				









						Persorption - Drug Delivery - European Medical
					

There is a special mode of permeation across the intestinal wall in which the cell membranes are not involved. Intestinal cells are continuously produced in




					www.europeanmedical.info
				




*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

kiny said:


> 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.



Crohn2357 said:


> 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.





kiny said:


> 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

kiny said:


> 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

Crohn2357 said:


> The immune system:
> 
> 
> 
> 
> 
> 
> —
> 
> 
> 
> 
> 
> 
> —
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> —
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Your Immune System: Natural Born Killer - Crash Course Biology #32
> 
> 
> Hank tells us about the team of deadly ninja assassins that is tasked with protecting our bodies from all the bad guys that want to kill us - also known as o...
> 
> 
> 
> 
> m.youtube.com
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Immune system - Wikipedia
> 
> 
> 
> 
> 
> 
> 
> en.m.wikipedia.org


Brilliant!  Thanks again!


----------



## Crohn2357

Jonny84 said:


> 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.






						QBECO-SSI Clinical Trial
					

This clinical trial is about to change the Crohn's community as we know it. Learn what it is, how it works, and if you qualify to be apart of it.  ......



					www.healingwell.com
				









						QBECO-SSI Clinical Trial
					

This clinical trial is about to change the Crohn's community as we know it. Learn what it is, how it works, and if you qualify to be apart of it.  ......



					www.healingwell.com
				




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.


----------



## Jonny84

Crohn2357 said:


> 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.
> 
> 
> 
> 
> 
> 
> QBECO-SSI Clinical Trial
> 
> 
> This clinical trial is about to change the Crohn's community as we know it. Learn what it is, how it works, and if you qualify to be apart of it.  ......
> 
> 
> 
> www.healingwell.com
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> QBECO-SSI Clinical Trial
> 
> 
> This clinical trial is about to change the Crohn's community as we know it. Learn what it is, how it works, and if you qualify to be apart of it.  ......
> 
> 
> 
> www.healingwell.com
> 
> 
> 
> 
> 
> 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.


Thanks for this - absolutely, there is hope in the future. The main future treatment I was aware of was QBECO. I'm also aware of map vaccine but that's not one I see a great deal of hope in.  Will check out the others!


----------



## kiny

IBD susceptibility loci

Note the strong relationship with autophagy related genes NOD2, ATG16L1 and IRGM   in crohn's disease and non-existing relationship in UC.

Crohn's disease has all the hallmarks of a primary immunodeficiency disease of macrophages. Autophagy is crucial for acute host defense against pathogens like salmonella.


----------



## Crohn2357

kiny said:


> IBD susceptibility loci
> 
> Note the strong relationship with autophagy related genes NOD2, ATG16L1 and IRGM   in crohn's disease and non-existing relationship in UC.
> 
> Crohn's disease has all the hallmarks of a primary immunodeficiency disease of macrophages. Autophagy is crucial for acute host defense against pathogens like salmonella.
> 
> 
> View attachment 3745


Source (if anyone wants to read): Jostins, Luke et al. “Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.” _Nature_ vol. 491,7422 (2012): 119-24. doi:10.1038/nature11582


----------



## Pangolin

@kiny I love all of your posts here, but I suspect there's a piece missing.

The general model of initial insult -> overloaded immune system -> continuing inflammation sounds completely correct. The body is trying to eliminate some antigens (bacterial or otherwise foreign) via inflammation, and the immune response just can't keep up with the antigens.

In general, if the body is unable to clear antigens as fast as they come in at a low enough level of inflammation, you have a problem. If you're not balancing antigens in with antigens out at minimal level of inflammation (clearance is partly a function of inflammation level), that becomes Crohn's disease. I think there may be a number of components at play here, and not all of these may be applicable to every patient:

1. Deficiency of innate immune response, ie your natural clearance rate is low compared to normal people
2. Damaged intestines may allow more antigens in, resulting in overloading of the antigens in = antigens out equation
3. Infection, eg MAP, producing antigens too fast and not resulting in the right kind of immune response
4. Specific antigens in the food causing direct immune response (comparable to Celiac), possibly including certain proteins, microparticles, or inorganic components.
5. Too much of the wrong kinds of bacteria in the food causing overloading of the clearance rate
6. Chemical damage to intestines caused by food, eg excessive oxidative stress, resulting in #2.

My suspicion is that #1 is not the only reason for the continuing inflammation and that #4 and/or #6 also play a role in many people. All of these possibilities should be investigated, and it's notable that EEN helps with essentially all of these possibilities (obviously it won't correct innate immune deficiency, but it will allow the immune system to catch up).


----------



## kiny

The inflammation in Crohn's disease is deep and transmural, it features patchy skip lesions, granuloma full of macrophages. (UC doesn't look like this at all, it's superficial inflammation of the colon)

So what diseases does Crohn's disease look like if it doesn't look like UC.

1)* Intestinal tuberculosis*. A chronic granulomatous disorder caused by a mycobacteria. Usually located in the ileum just like crohn's disease. Skip lesions and granuloma just like crohn's disease.

Intestinal tuberculosis is rare in the West (but common among people with immunodeficiencies like HIV patients).

But in countries where intestinal TB is common, and you have increasing incidence of crohn's disease cases, misdiagnosis between intestinal TB and crohn's disease is increasingly common. India for example.

2) *Chronic granulomatous disease*. Primary immunodeficiency of phagocytes like crohn's disease, chronic granulomatous inflammation in the intestine is increasingly seen in these patients now that they live longer with treatment.

When these patients develop deep transmural and granulomatous inflammation of the intestine, it is called a CGD-IBD, subset crohn's disease, or simply...crohn's disease. They simply develop crohn's disease.


The diseases that feature the deep transmural inflammation and granuloma in the intestine seen in crohn's disease, feature an intracellular bacteria and a primary immunodeficiency.

Crohn's disease is common in the West. What bacteria would exploit xenophagy and immunodeficiency of macrophages, what bacteria is widespread in the West, what bacteria would invade peyer's patches.

The best candidate I can think of is salmonella. Are the flares in crohn's disease related to reinfection? Maybe.


All the chronic superficial inflammation would be caused by antigen entering the breached epithelial barrier. Fecal stream, bacteria (like AIEC) and fungi residing and attaching to the epithelial wall, etc. Maybe food intolerances like you said.

But to create such deep inflammation, you need a serious initial infection to make sense of crohn's disease. And the ''flares'' no one seems to be able to explain in crohn's disease, might simply be reinfections with that same bacteria.


----------



## kiny

Crohn's disease is also being used as a sort of umbrella terms nowadays. Which isn't a good thing because it doesn't allow for personalized treatment.

Classic crohn's disease is ileal crohn's disease that Dalziel described, chronic granulomatous inflammation of the ileum, onset around puberty which correlates with activity of peyer's patches.

If children aged 6 in Singapore suddenly start developing chronic granulomatous inflammation of the intestine, don't have any susceptible gene, no NOD2 or ATG16L1 involvement that you see in caucasians...do they actually have crohn's disease or something else.

How helpful is it to label all these early onset cases of intestinal inflammation as crohn's disease.

It doesn't help to use IBD to describe crohn's disease and UC, because they are vastly different diseases, crohn's disease is much more closely related to CGD than it is to UC. It also doesn't help to label every unexplained form of chronic granulomatous inflammation as crohn's disease.


----------



## Crohn2357

kiny, what is your opinion of Crohn’s disease that mostly or only manifests itself in the colon and anus, with minimal or no small intestinal involvement?


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## kiny

If there is no ileal involvement at all, it makes it less likely that salmonella or mycobacteria are involved, it also complicates what is keeping the inflammation going.

Salmonella, suggested mycobacteria, AIEC, they specifically invade peyer's patches. There are no peyer's patches in the colon, they're only found in the ileum.

It's not a loss of tolerance against the microbiome, or specific reaction against the micriobiome, because you'd have inflammation all over the intestine if that was the case. Crohn's disease are skip lesions instead.


----------



## Pangolin

I've been thinking about clearance rate, which could be the best concept in this thread. The intestine is constantly in contact with foreign material--bacterial and food--and the body has to carefully balance between letting components in and having them pass through.

At equilibrium, antigens in = antigens out (or deactivated)

Inflammation is one way the body can attempt to increase the antigens out side of the equation. If the antigens in side of the equation is increased for any of a variety of reasons (including, potentially, low motility--the longer you have antigens in contact with the gut walls, the more they get in--which I forgot to include in the post above), the antigens out side has to increase as well in order to return to equilibrium.

Let's say you have patches of AIEC or salmonella sticking to the intestinal walls. Those patches are producing antigens locally and increasing the antigens in side of the equation. The body might try to clear this with inflammation and motility increase, but if those are ineffective at clearing then you may get a constant state of activation.

We can look at each side of this equation and try to lower the "antigens in" side and raise the "antigens out" side, in order to help achieve an equilibrium at a lower level. QBECO targets the "antigens out" side and hopefully increases the response to AIEC, allowing better clearance and then a reset to a lower equilibrium with no gross inflammation.


----------



## kiny

We don't know how much AIEC is contributing to crohn's disease. It certainly isn't a good sign that it keeps getting isolated from crohn's disease patients where they have active inlammation, AIEC is not an innocent bystander.

The new bacteriophage trial will use people in remissions and check their stool for the presence of AIEC. If the bacteraiphage group relapses slower than the people who don't get the therapy, they can show that their bacteriophage therapy works.




That the fecal stream sets off inflammation in crohn's disease is based on multiple studies with solid evidence behind it going back decades.

If you remove the fecal stream and the intestine heals, and if you introduce a fecal stream in previously unaffected tissue, and you get inflammation with neutrophil activity, you have solid evidence the fecal stream is directly involved in the inflammation.

(which is why it is shocking to me that they are still experimenting with fecal stream transplantation in crohn's disease, doctors who do that need to start losing their license)

*Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum.*

D'Haens GR1, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P.

1998

*BACKGROUND & AIMS: *
Postoperative recurrence of Crohn's disease may be triggered by agents in the fecal stream. The aim of this study was to examine intestinal mucosal inflammation induced by contact with intestinal fluids in surgically excluded ileum.

*METHODS: *
The effects of infusion of intestinal luminal contents into excluded ileum in 3 patients with Crohn's disease who had undergone a curative ileocolonic resection with ileocolonic anastomosis and temporary protective proximal loop ileostomy were studied by histopathology and electron microscopy.

*RESULTS: *
Contact with intestinal fluids for 8 days induced focal infiltration of mononuclear cells, eosinophils, and polymorphonuclear cells in the lamina propria, small vessels, and epithelium in the excluded neoterminal ileum that was previously normal. Epithelial HLA-DR expression increased, and mononuclear cells expressed the KP-1 antigen associated with activation. Marked up-regulation of RFD-7, RFD-9, intercellular adhesion molecule 1, and lymphocyte function-associated antigen 1 was observed after infusion, reflecting epithelioid transformation and transendothelial lymphocyte recruitment. At the ultrastructural level, dilatation of the endoplasmic reticulum and Golgi apparatus occurred in epithelial cells, where also basally located transport vesicles were identified.

*CONCLUSIONS: *
Intestinal contents trigger postoperative recurrence of Crohn's disease in the terminal ileum proximal to the ileocolonic anastomosis in the first days after surgery.


----------



## Pangolin

In defense of the fecal transplant idea, not all fecal streams are equal. The idea that possibly adding different bacteria with the hope that they can outcompete other more problematic bacteria is sound. Obviously the results have not been good for Crohn's, but at least initially it was worth a try. I do agree that at this point it's time to stop.


----------



## kiny

https://www.gastrojournal.org/article/S0016-5085(04)00771-1/fulltext?referrer=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2F
		


63 with ileal CD and 16 ileal controls
27 with colonic CD and 102 colonic controls
8 with UC

_''_In ileal specimens, AIEC strains were found in 21.7% of CD chronic lesions vs. in 6.2% of controls. In neoterminal ileal specimens, AIEC strains were found in 36.4% of CD early lesions (P = 0.034 vs. controls) and 22.2% of healthy mucosa of CD patients. In colonic specimens, AIEC strains were found in 3.7% of CD patients, 0% of UC patients, and 1.9% of controls._''_


----------



## Cucurbita

In the following replies in this thread, I will be sharing some speculative ideas that may be relevant to the conversation.

Must say that I lack academic training in the subject, and only recently did I begin to read papers. But perhaps some idea could give rise to discussion among those of you who know best.


----------



## Jonny84

Cucurbita said:


> In the following replies in this thread, I will be sharing some speculative ideas that may be relevant to the conversation.
> 
> Must say that I lack academic training in the subject, and only recently did I begin to read papers. But perhaps some idea could give rise to discussion among those of you who know best.


Go for it - I have no academic training either but everyone is entitled to get involved in the discussion!


----------



## Cucurbita

First idea.

As a context, first I'll quote Kiny from this same thread:

_"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."

"What you find is that people with crohn's disease do not have a competent acute inflammatory reaction, magrophage reaction and neutrophil recruitment is stunted [...] But neutrophils themselves are completely competent in CD."_

A study found that fibre might enhance the impaired neutrophil recruitment in the colon through an increase in G-protein coupled receptor 43 (GPR43+) neutrophil infiltration [1].

GPR43 is a receptor of short-chain fatty acids (SCFA), which acts as a link between dietary fiber and its influence on inflammation.

Which is to say: Fibre is fermented by bacteria, which produces SCFA, which stimulate this receptor. By some mechanism, it may lead to an increase of infiltration of neutrophil.

However, as discussed in this thread, stimulating the growth of bacteria may not be good. What we want is to stimulate the GPR43 with SCFA, but without feeding the bacteria.

*Perhaps the best strategy to do so might be to use Exclusive Enteral Nutrition (EEN), without fibre added, and add enemas of SCFA as a treatment. This may stimulate the infiltration of neutrophils without the need for fibre nor feeding bacteria.*

Of course it is tremendously speculative because things are not so simple and both the SCFA and the GPR43 fulfills other functions that interfere with inflammation in other ways [2]. But well... it's an idea. (And in that case we should also discuss which SCFA to use. For example, acetate is pro-inflammatory, while propionate and butyrate are not).

Finally, the authors of the study conclude that dietary fiber might increase neutrophil recruitment, but they wonder if this is favorable for Crohn's patients or not [1]. Logic says yes, since it would be helping to lessen this innate immune deficiency. But there are contradictory studies in rats. I'm going to review them and post back.

[EDIT: I found another study to read, called "Short-chain fatty acids stimulate the migration of neutrophils to inflammatory sites.": https://www.ncbi.nlm.nih.gov/pubmed/19335337/]

-----
References:
[1] Zhao M, Zhu W, Gong J, et al. Dietary Fiber Intake is Associated with Increased Colonic Mucosal GPR43+ Polymorphonuclear Infiltration in Active Crohn's Disease. _Nutrients_. 2015;7(7):5327–5346. Published 2015 Jul 1. doi:10.3390/nu7075223








						Dietary Fiber Intake is Associated with Increased Colonic Mucosal GPR43+ Polymorphonuclear Infiltration in Active Crohn’s Disease
					

G protein-coupled receptor 43/free fatty acid receptor 2 (GPR43/FFAR2) is essential for polymorphonuclear (PMN) recruitment. We investigated the expression of GPR43/FFAR2 in the colon from Crohn’s disease patients and whether dietary fiber in ...




					www.ncbi.nlm.nih.gov
				



[2] Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. _Nutrients_. ;3(10):858–876. doi:10.3390/nu3100858








						Regulation of Inflammation by Short Chain Fatty Acids
					

The short chain fatty acids (SCFAs) acetate (C[2] ), propionate (C[3] ) and butyrate (C[4] ) are the main metabolic products of anaerobic bacteria fermentation in the intestine. In addition to their important role as fuel for intestinal epithelial cells, ...




					www.ncbi.nlm.nih.gov
				




-----

Edit: Interesting fact. According to a review published in Gut 2018, Crohn's disease patients suffer a loss of GPR43 receptors [4].

[4] Levine A, Sigall-Boneh R, Wine E. Evolving role of diet in the pathogenesis and treatment of inflammatory bowel diseases _Gut._ 2018;66:1–13.


----------



## Pangolin

I just want to point out that direct inflammation suppression, eg anti-TNF, would be expected to reduce clearance rates, which is essentially what the paper on the causes of Crohn's referenced previously in this thread said. Inflammation may need to be suppressed to prevent damage (damage which may cause an increase in the "antigens in" side), but inflammation suppression alone does not balance out the long-term antigens in = antigens out equation.

The goal is some combination of raising clearance rates (immune stimulation, etc.) and/or lowering the "antigens in" side (dietary changes, avoiding reinfection, healing from damage, etc.)


----------



## Crohn2357

Crohn2357 said:


> Qu Biologics’ vaccine trial











						Qu Biologics
					

Qu Biologics is a private, clinical-stage biopharmaceutical company located in Vancouver, BC, that develops Site Specific Immunomodulators (SSIs) which are d...




					m.youtube.com


----------



## Crohn2357

kiny said:


> 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)





kiny said:


> The best candidate I can think of is salmonella. Are the flares in crohn's disease related to reinfection? Maybe.


----------



## Cucurbita

I also suffered a salmonella infection before I was diagnosed with ileocolonic Crohn's. My initial flare started with vomiting, night sweats and fever.

As if that wasn't enough, months after my diagnosis I was again diagnosed with a salmonella infection.

I was a child and I don't remember much. That was 13 years ago.


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## kiny

Crohn's clustering is very common (and underreported). You can't explain this clustering without a localised infectious agent in the food or water supply.

Foodborne infections are often clustered of course. People in the same family or same town, go to the same restaurants, same grocery stores, etc. This results in infection clusters.

It needs to be an infectious agent that is very common in the West...that causes clustered infections...it needs to result in diffuse lesions you see in crohn's disease....salmonella is a great candidate, so is campylobacter and Yersinia. The list is pretty short, only a handful of foodborne bacteria are common enough to explain this.


----------



## Gabriel89

QBECO, MAP vaccine etc. have a very small chance to reach market ever. I am optimistic about them but so far the evidence is not close to satisfactory.
Bigger Pharma companies are just choosing low risk research directions with biologics.
The idea of using biologics other than TNF-alpha is adapted from trials for psoriasis and other conditions. They dont need to redo a lot of paperwork just to copy it to crohn aswell. Not to mention psoriasis affects much more people than crohn's, so its like a market *extension* for them. Personally i don't think its a bad thing since for me I have psoriasis and crohn's at the same time, also my mom has psoriasis, there should be some connection between the two conditions.


----------



## Crohn2357

kiny said:


> Are the flares in crohn's disease related to reinfection? Maybe.
> 
> ...
> 
> And the ''flares'' no one seems to be able to explain in crohn's disease, might simply be reinfections with that same bacteria.


kiny, I have been thinking about your proposal that flare-ups might be caused by re-infections with the suspected bacteria; if that was the case, wouldn’t people who use immunosuppressants (especially the combination therapies) flare-up more frequently than those who don’t, since they would be more likely to get infected? Or, would you say that the additional immunosuppressants wouldn’t be really important in this case as Crohn’s patients have already a specific immunodeficiency that predisposes them to be exploited by these bacteria? If the latter is the case, then I guess what matters is being very careful to reduce the risk of exposure to these bacteria (look at the above salmonella video for example)?


----------



## kiny

Crohn2357 said:


> Or, would you say that the additional immunosuppressants wouldn’t be really important in this case as Crohn’s patients have already a specific immunodeficiency that predisposes them to be exploited by these bacteria?


People on immunosuppressants are far more vulnerable to foodborne infections, including salmonella and listeria.

Considering the very high prevalence of these foodborne infections in the West, it is inevitable that a subset of people with crohn's disease who are on immunosuppressants are getting reinfected with foodborne infections, and it might be an explanation for flaring.

The acute flaring you see in some crohn's disease patients is a phenomenon that no one has been able to explain so far.









						The Occurrence and Prevention of Foodborne Disease in Vulnerable People
					

In developed countries, such as the United Kingdom and the United States, between 15% and 20% of the population show greater susceptibility than the general population to foodborne disease. This proportion includes people with primary immunodeficiency, ...




					www.ncbi.nlm.nih.gov
				




_''Inflammatory bowel disease: Immunosuppressants, including MTX, azathioprine/6-mecaptopurine, cyclosporine, steroids, and biological therapies such as infliximab, used to treat inflammatory bowel disease (IBD), increase susceptibility to infection, particularly when two or more drugs are used (Viget et al., 2008). 

Foodborne infections associated with immunosuppressant therapy in IBD patients include Salmonella, L. monocytogenes, and T. gondii (Williams et al., 2005; Viget et al., 2008; Epple, 2009; Rim and Tenorio, 2010). 

For example, a man with Crohn's disease receiving infliximab treatment died from listeriosis after eating a contaminated chicken salad from a retail store (Marcus et al., 2009).''_


----------



## Crohn2357

What I am saying is, if “getting reinfected with foodborne infections” might be an explanation for flaring, and being on immunosuppressants increase the likelihood of getting reinfected with foodborne infections, then wouldn’t people who use immunosuppressants be more likely to relapse than people who don’t use immunosuppressants (like people who don’t use any maintenance medicine or only use 5-ASA)?

Doesn’t your proposal contradict with the fact that people who are on immunosuppressants as maintenance therapies are much less likely to experience flare-ups than people who are not using immunosuppressants, statistically?


----------



## kiny

Crohn2357 said:


> Doesn’t your proposal contradict with the fact that people who are on immunosuppressants as maintenance therapies are much less likely to experience flare-ups than people who are not using immunosuppressants, statistically?


Well, crohn's disease patients relapse on immunosuppressants. That's why there is a constant escalation of stronger and stronger immunosuppressive drugs in those patients.

Why are these patients relapsing on immunosuppressants. Why is there a constant escalation of drugs in those patients to try to keep them in remission.

What is causing the chronic relapses in those patients that results in immunosuppressant escalation. The rates of relapse are all over the place, some relapse after a few weeks, others after months, others after years. Why.


----------



## kiny

Lumen content and fecal content entering a permeable bowel after an acute infection explains chronic inflammation you see in crohn's disease patients, but it doesn't explain acute relapses after mucosal healing.

Why do some patients who show complete mucosal healing and no inflammation, relapse after 1 year, 2 years or 6 years. Why do they relapse at all? Why isn't everything reset to a pre-disease state.

They just relapse for no reason after 6 years of remission? Why?

Reinfection could explain why.

If the initial trigger of crohn's disease is a common foodborne infection like Salmonella or campylobacter, which is supported by studies and by the sheer prevalence of those infectious agents in the Western food chain...then it's only normal to suspect that relapses might be tied to reinfections.


----------



## kiny

Due to the sheer numbers of Salmonella and Campylobacter outbreaks in the Western world (many of which go unreported), it is a certainty that a large number of patients with crohn's disease, are going to come into contact with these bacteria, if not multiple times.

https://www.efsa.europa.eu/en/press/news/190218

*Salmonella in the EU*

Salmonellosis is the second most common foodborne disease after campylobacteriosis in the EU and _Salmonella_ is an important cause of foodborne outbreaks. In 2017, Member States reported *91,662* cases in humans.

*Campylobacter in the EU*

Cases of campylobacteriosis decreased slightly in 2017 compared to 2016 (*246,158 *vs 246,917), but it is still the most commonly reported zoonotic disease in the EU.


----------



## Crohn2357

kiny said:


> it is a certainty that a large number of patients with crohn's disease, are going to come into contact with these bacteria


That’s why I am saying that the conclusion inferred from your propositions lead to a contradiction (with the statistical fact).

If reinfection with the foodborne infections might explain the flare ups, and the CD patients who are on immunosuppressants are more likely to get a reinfection with the foodborne infections (both of these are your propositions), then the logical conclusion is that the patients who use immunosuppressants should be more likely to get flare ups than the patients who don’t use immunosuppressants, which is statistically incorrect.



kiny said:


> They just relapse for no reason after 6 years of remission? Why?



I think maybe a more likely scenario is something (be it getting reinfected with foodborne infections, stress, ingestion of problematic foods/substances, nutritional deficiencies, alcohol consumption, NSAIDs, chronic constipation, bacterial-fungal overgrowth, a more general systemic infection, a combination of these etc.) causes a breach in the intestinal epithelial barrier, which leads to immune reaction to the luminal content that gets into the deeper layers of the intestine. I think you might be wrong in ascribing “getting reinfected with foodborne infections” this almost exclusive importance (correct me if I am wrong) as an explanation for why flare-ups happen.


----------



## Crohn2357

I think getting more and better research on the histological changes in Crohn’s patients could provide great insights on the questions surrounding why flares occur, also make people question the current conceptions of remission, flare-ups, aetiology, pathogenesis, disease activity, prognosis, risk evaluation, medications’ effectiveness and safety etc.



> Therefore, adding histological healing as an endpoint, at least in clinical trials, would substantially improve the evaluation of the actual effectiveness of a given treatment. Histological assessment is cheap and widely available. The features of disease activity are known. They include the presence of neutrophils in the lamina propria and the epithelium, epithelial cell damage (loss of cells, mucin depletion, cryptitis, crypt abscesses, erosion), and an increase in lymphocytes and plasma cells. Some of these features such as the presence of neutrophils can reliably be evaluated with good interobserver agreement. In addition, histology could help the management of the patient. Some histological variables are indeed associated with relapse. They include persistence of neutrophils, basal plasmacytosis and persistence of eosinophils in the lamina propria[29,88,89]. Furthermore, microscopic activity may be related to the development of dysplasia[90].











						Histological healing in inflammatory bowel disease: A still unfulfilled promise
					

Treatment of inflammatory bowel disease (IBD) is traditionally based on several drugs, including salicylates, corticosteroids, and antibiotics; in addition, the therapeutic armamentarium has considerably evolved with the advent of newer, effective therapeutic ...




					www.ncbi.nlm.nih.gov
				












						Systematic review: Histological remission in inflammatory bowel disease. Is ‘complete’ remission the new treatment paradigm? An IOIBD initiative
					

Abstract. Background and aims: Advances in the medical management of inflammatory bowel disease (IBD) have altered treatment targets. Endoscopic mucosal healing




					academic.oup.com
				












						Histologic measurement tools for evaluation of disease activity in Crohn’s disease
					






					www.cochrane.org


----------



## kiny

Crohn2357 said:


> CD patients who are on immunosuppressants are more likely to get a reinfection with the foodborne infections (both of these are your propositions)


Why would they be more likely to be infected, they have the same statistical chance of anyone else to be infected with foodborne infections.

Immunocompromised people or people on immunosupressants do have more severe presentation, they also have higher mortality rates.


----------



## kiny

To be clear, everyone who comes into contact with salmonella is going to get sick from it. 

Salmonella enters through M cells and becomes intracellular, M cells have no mucus layer on them, they have no microvilli, they are completely exposed to pathogens. All foodborne bacteria exploit M cells.

But, not everyone has the same disease presentation, not everyone is as vulnerable. People with primary immunodeficiency, people with HIV, people on immunosuppressants, get a lot sicker from salmonella and campylobacter and have much higher mortality rates, than people with a competent immune system.


----------



## Crohn2357

kiny said:


> Why would they be more likely to be infected, they have the same statistical chance of anyone else to be infected with foodborne infections.


That’s what I asked you in the first place:



Crohn2357 said:


> Or, would you say that the additional immunosuppressants wouldn’t be really important in this case as Crohn’s patients have already a specific immunodeficiency that predisposes them to be exploited by these bacteria? If the latter is the case, then I guess what matters is being very careful to reduce the risk of exposure to these bacteria (look at the above salmonella video for example)?



I think we might had a misunderstanding then.

But, regarding your question (“Why would they be more likely to be infected”), the rate of exposure would probably be same or very similar for both groups, but the patients on the immunosuppressants would experience more catastrophic results in their intestines, resulting in more severe and maybe more frequent clinical outcomes for them, I would think.

Nonetheless, being really careful with foods is very important, obviously. My last flare happened after I had eaten ground beef almost every meal for about a month. I think maybe I have undercooked them some of the times. This thought came to me after I watched the salmonella video I posted a few days ago.


----------



## kiny

''Food, stress, nutritional deficiencies, alcohol consumption, NSAID, gut flora'' etc etc etc.

There have been a lot of explanations. But none of these explain patchy skip lesions and the deep transmural inflammation you see in crohn's disease.

They don't explain inflamed lymphoid follicles, they don't explain activated M cells, they don't explain fevers. They don't explain the clustering in crohn's disease. They don't explain the genetic links with autophagy and xenophagy.

They don't explain why the average age of onset is around 15-24.


The theory that Anthony Segal proposed, initial foodborne infection leaving a permerable bowel behind leading to chronic inflammation explains all the above.

I have long stopped believing in theories about stress, alcohol, diet, autoimmune or western lifestyles.


----------



## Crohn2357

I don’t take those that I have mentioned as the cause of Crohn’s; but I take them as solid risk factors for flare-ups, at the very least. There’s no sure way to get into remission with Crohn’s, but there are sure ways a Crohn’s patient can fall out of remission, and all of those ways share at least one common mechanism: disruption of intestinal epithelial barrier. Those that I have mentioned probably have roles in the pathogenesis of Crohn’s in some instances, even if they may not have a role in the aetiology.

As a Crohn’s patient, what matter to me most are things that I can control, in order to reduce the risk of my Crohn’s getting more severe and increase my chances of staying as healthy as possible.


----------



## Crohn2357

kiny, could you comment on *this *article?

Here's a summary of it, written by one of its authors:









						A possible peptide-based vaccine for MAP | Human Para Foundation
					

Dr. William C. Davis summarizes the discovery of a MAP mutation that may lead to the development of a MAP vaccine for both animals and humans




					humanpara.org
				




Another summary:



> *Research Summary*
> 
> The long term objectives of our research program are to elucidate the mechanisms regulating the immune response to infectious agents and develop protective vaccines. To achieve these objectives, we continue to develop and use monoclonal antibodies and assays to study the immune response in domestic animals with a primary focus on ruminants. M. avium subsp. Paratuberculosis (Map) has been selected as the model pathogen for our investigations because of its economic importance and its potential for providing insight into the mechanisms regulating the immune response to Map and other intracellular pathogens. Map is the causative agent of Johne’s disease (JD) in cattle, a chronic wasting disease of the intestine. It causes significant economic loss to producers, especially the dairy industry, due to increase in forage consumption, decreased milk production and early culling due to poor health of affected animals. There is also a concern that Map is a zoonotic pathogen. Map has been isolated from human patients with Crohn’s disease (CD), a chronic inflammatory disease of the intestine. It is not clear whether Map is the etiologic agent causing Crohn’s disease. However, recent studies on CD and mycobacterial pathogens M. tuberculosis (Mtb) and Map have shown a similarity in the mechanisms of pathogenesis at the cellular and molecular level. The studies have revealed the cross regulation of the immune system by regulatory T cells and effector T cells mediating protective immune responses is dysregulated, giving rise to an imbalance that results in chronic inflammation of target tissues, and in the case of Mtb and Map dysregulation of protective immunity. To extend these observation we developed a bovine cannulated ileum model to conduct studies on the mechanisms of pathogenesis mediated by Map in the natural host, studies that cannot be conducted in humans. The model has offered an opportunity to study the interaction of Map during the early and late stages of infection. We have also developed and used a flow cytometric assay to analyze the immune response to Map and methods to elucidate the functional changes associated with dysregulation of the immune system. Use of these methods in conjunction with development of methods to monitor the intracellular killing of bacteria by cytotoxic T cells have facilitated analysis of the functional activity of cytotoxic T cells responding to Map and derived candidate antigens. Ongoing studies with a mutant of Map, with a deletion in relA, has shown deletion abrogates the capacity of the mutant to establish a persistent infection. Further studies have shown the target of the immune response is directed towards a membrane protein (MMP). Ex vivo studies have shown stimulation with the MMP leads to the development of cytotoxic T cells with the capacity to kill intracellular bacteria. This major finding indicates a peptide based vaccine is possible against a major pathogen. These findings will now be used to advance our studies to the next phase, development and validation of a virus vector containing the gene encoding the MMP as a vaccine for JD.





			https://vmp.vetmed.wsu.edu/people/faculty/profile/william-c-davis
		



Another one:









						MAP protein may aid battle against Johne's disease
					

Vaccine investigators use Johne's disease-causing bacterium's own protein against it.




					www.feedstuffs.com


----------



## Crohn2357

kiny said:


> I haven't read anything about site specific stimulation of macrophages. Granulocyte-macrophage colony-stimulating factor has been used, but it's not site specific, but it does seem to correct innate immunodeficiencies.
> 
> The underlying premise to correct the innate immune deficiencies and clear the infection is an attractive way to treat crohn's disease because it would lead to sustained improvement and should have far less side effect than stopping inflammation by blocking the adaptive response.
> 
> All you really need is a competent macrophage reaction, our immune system is completely capable of shutting down inflammation after an infection subsides, effector cells of the adaptive immune system don't live very long, they die by apoptosis and all that's left is memory cells.
> 
> If you correct the innate immune response, a secondary infection would also be cleared more competently since you would have more competent adaptive immune system and more competent memory cells. It should in theory lead to sustained improvement.





kiny said:


> I don't know how QUbiologics, the company some people keep mentioning, got around the idea of injecting E coli into the skin to treat crohn's disease, but they of course read that study.



*Discussion*
While CD is an immune-mediated disease, it is not an autoimmune disease [7, 13]. The CD_ immunodeficiency hypothesis _(IDH), dating in part to the late 1970s [14], asserts that (1) infectious agents breach the bowel mucosal lining, (2) a predisposing innate immune deficiency prompts an ineffective acute physiological inflammation and impaired recruitment of phagocytes, (3) the neutrophil-based phagocytes become overwhelmed, (4) macrophages therefore attempt to contain the pathogens but are less capable at this function, and (5) these macrophages drive a chronic but inefficient immune response [5] (Figure 3(a)). This hypothesis was perceived to be in conflict with the apparent clinical efficacy of immunosuppressive medications used to treat CD symptoms and its popularity waned. However, new supporting IDH evidence [5, 6, 9, 15, 16] suggests that there are, in fact, several discreet phases of immunodeficient responses in CD: the first involving poor cytokine production by resident tissue macrophages followed by diminished neutrophil recruitment and subsequent chronic inflammation [16]. Indeed, it is this compensatory chronic inflammation response that is suppressed by medications such as azathioprine, infliximab, and adalimumab (which have been the focus of current CD treatment).




By extension, treatment of the deficient first acute innate immune response could also address the subsequent inefficient inflammation phase that results in clinical manifestation of CD and thereby potentially reduce or eliminate the need for the long-term use of immunosuppressive medications in CD patients. SSIs initiate such a response, one that is innate, acute, functional, organ-specific, and nontoxic to the tissue in which the respective bacterial species commonly causes infection (Figure 3(b)). In preclinical models, the SSI QBECO specifically targets the gut and we have demonstrated that it stimulates innate immune responses in the colon and gastrointestinal tract (unpublished observation). Since macrophage defect or deficiency, in particular, may be the underlying trigger for CD, the SSI QBECO was designed to induce organ-specific macrophage recruitment and activation, resulting in the clearance of bacterial infection and necrotic debris.

The deficiency observed in the first innate mucosal immune response in CD patients may be that of defective M1 macrophages, and the resultant inflammation phase of clinical symptoms may be caused by the accumulation of other dysfunctional (potentially M2) macrophages concurrently with the unresolved infection. While M2 macrophages lead to tissue regeneration and repair [17], they are incapable of either killing/removing bacteria or instigating an effective innate immune response, which is the hallmark of M1 macrophages. This ultimately Sisyphean effort leads to cyclic, but futile, attempts at repair with the simultaneous ineffective clearance of the initial infection. Thus, we hypothesized that the SSI QBECO, which drives M1 macrophage polarization_ in vitro_, may also drive M1 expansion in patients and thereby lead to more effective treatment of the underlying cause of CD, and not just its symptoms. By extension, once the underlying source of inflammation was cleared, the symptoms characteristic of CD would resolve in patients who received the SSI QBECO medication. We observed clinical remission during administration of the SSI QBECO in a compassionate-use context in seven of 10 patients who had moderate to severe clinical symptoms of active CD at baseline, with the remaining three of 10 noting improvement of their symptoms during treatment. Three of the 10 patients have experienced ongoing long-term remission. Based on these initial findings, and the recognized limitations of compassionate-use studies regarding causal attribution and mechanism of action, induction of clinical response and remission by SSI QBECO therapy is now being evaluated through a Phase 1/2 randomized, placebo-controlled, double-blind clinical trial. QB is currently characterizing the unique qualities of SSI-stimulated M1 macrophage populations, and, in future studies, QB will explore the potentially unique genetic differences of the long-term responder cohort in order to develop assays that would identify,_ a priori_, likely future candidates for which treatment would be efficacious and warranted.

Source: *Site-Specific Immunomodulator: A Novel Treatment for Crohn's ...*

Bressler, Brian et al. “Site-Specific Immunomodulator: A Novel Treatment for Crohn's Disease.” _Gastroenterology research and practice_ vol. 2015 (2015): 231243. doi:10.1155/2015/231243


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## Crohn2357

Crohn2357 said:


> rapamycin for Crohn’s





Crohn2357 said:


> *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.*



Another mechanism for rapamycin, proposed by Greenstein et al.: Antimycobacterial effect.

PLoS One. 2008 Jun 25;3(6):e2496. doi: 10.1371/journal.pone.0002496.
*On the action of cyclosporine A, rapamycin and tacrolimus on M. avium including subspecies paratuberculosis.*
Greenstein RJ1, Su L, Juste RA, Brown ST.
*Author information

Abstract*
*BACKGROUND: *
Mycobacterium avium subspecies paratuberculosis (MAP) may be zoonotic. Recently the "immuno-modulators" methotrexate, azathioprine and 6-MP and the "anti-inflammatory" 5-ASA have been shown to inhibit MAP growth in vitro. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. The "immunosuppressants" Cyclosporine A, Rapamycin and Tacrolimus (FK 506) treat a variety of "autoimmune" and "inflammatory" diseases. Rapamycin and Tacrolimus are macrolides. We hypothesized that their mode of action may simply be to inhibit MAP growth.
*METHODOLOGY: *
The effect on radiometric MAP (14)CO(2) growth kinetics of Cyclosporine A, Rapamycin and Tacrolimus on MAP cultured from humans (Dominic & UCF 4) or ruminants (ATCC 19698 & 303) and M. avium subspecies avium (ATCC 25291 & 101) are presented as "percent decrease in cumulative GI" (%-DeltacGI.)
*PRINCIPAL FINDINGS: *
The positive control clofazimine has 99%-DeltacGI at 0.5 microg/ml (Dominic). Phthalimide, a negative control has no dose dependent inhibition on any strain. Against MAP there is dose dependent inhibition by the immunosuppressants. Cyclosporine has 97%-DeltacGI by 32 microg/ml (Dominic), Rapamycin has 74%-DeltacGI by 64 microg/ml (UCF 4) and Tacrolimus 43%-DeltacGI by 64 microg/ml (UCF 4)
*CONCLUSIONS: *
We show heretofore-undescribed inhibition of MAP growth in vitro by "immunosuppressants;" the cyclic undecapeptide Cyclosporine A, and the macrolides Rapamycin and Tacrolimus. These data are compatible with our thesis that, unknowingly, the medical profession has been treating MAP infections since 1942 when 5-ASA and subsequently azathioprine, 6-MP and methotrexate were introduced in the therapy of some "autoimmune" and "inflammatory" diseases.


---- ----

*Discussion*
Rapamycin was initially evaluated as an anti-fungal agent. [54] To our knowledge however, this is the first time that antiMAP activity has been demonstrated for the “immunosuppressant” agents Cyclosporine, Rapamycin and Tacrolimus. These observations are therefore compatible with our thesis that MAP may be responsible for multiple “autoimmune” and “inflammatory” diseases, and that the action of these three “immunosuppressant” agents may simply be to inhibit MAP growth.

We have observed that methotrexate and 6-MP are used in “high” doses to treat human malignancies and at “low” doses in “autoimmune” and “inflammatory” conditions. [34] Similarly, there are “high” and “low” doses of the three “immunosuppressants” we now study (See Table 7.) The “high” doses are used to prevent or treat transplanted organ rejection. The “low” doses are used to treat “autoimmune” and “inflammatory” diseases. These data are compatible with our hypothesis that Cyclosporine, a cyclic undecapeptide, as well as Rapamycin and Tacrolimus, from the macrolide family of antibiotics, may have “low” dose prokaryotic antibiotic action in addition to “high” dose eukaryotic immunosuppressant activity.









						On the Action of Cyclosporine A, Rapamycin and Tacrolimus on M. avium Including Subspecies paratuberculosis
					

Mycobacterium avium subspecies paratuberculosis (MAP) may be zoonotic. Recently the “immuno-modulators” methotrexate, azathioprine and 6-MP and the “anti-inflammatory” 5-ASA have been shown to inhibit MAP growth in vitro. ...




					www.ncbi.nlm.nih.gov
				





From another article by Greenstein:

_Both methotrexate and 6-MP interfere with DNA replication. Methotrexate acts by inhibiting dihydrofolate reductase, folate generation and the consequent production of adenine.[12] The mechanism of action of 6-MP is to substitute for guanine in DNA replication.[12] Because prokaryotes must synthesize their own folic acid, they should be more susceptible to folate inhibition than eukaryotes. It is noteworthy that there are two distinct doses in human clinical use for both methotrexate and 6-MP. Each agent has a “high” dose, (used in to treat reticuloendothelial malignancies [13], [14]) and a “low” dose (used to treat “inflammatory” diseases. [15] [16])

We hypothesized that the clinically relevant mechanism of action of “low” dose methotrexate and 6-MP in the therapy of IBD, may, in whole or part, be due to the inhibition of MAP growth. If this hypothesis is correct, the decrease in the pro-inflammatory cytokines, heretofore considered the primary mechanism of action of these two agents, could simply represent a secondary phenomenon. The observed decrease in pro-inflammatory cytokines could be ascribed to the treatment of the instigating MAP infection. To evaluate this hypothesis we have studied the effect of methotrexate and 6-MP on MAP and other M. avium isolates in culture. The effect of methotrexate has been evaluated on E. coli [17], 6-MP on Salmonella typhimurium [18] and both agents on M. tb. [19] To our knowledge, however, this is the first time that these two agents have been evaluated for their effect on MAP._









						On the Action of Methotrexate and 6-Mercaptopurine on M. avium Subspecies paratuberculosis
					

Clinical improvement in inflammatory bowel disease (IBD) treated with methotrexate and 6-mercaptopurine (6-MP) is associated with a decrease in pro-inflammatory cytokines. This has been presumed to indicate the mechanism of action of methotrexate and ...




					www.ncbi.nlm.nih.gov


----------



## Crohn2357

kiny said:


> 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 said:


> What we will see is specifically designed bacteriophages that target specific bacteria found in crohn's disease. It will hopefully lead to more personalised therapy, where a stool sample or biopsy serves as a guideline to determine which bacteriophage might be useful.
> 
> Bacteriophages Targeting Adherent Invasive Escherichia coli Strains as a Promising New Treatment for Crohn's Disease. - PubMed - NCBI
> There are currently ongoing trial underway with bacteriophages to treat crohn's disease. It might be helpful in people who harbour invasive E coli.
> 
> What the benefit of bacteriophages is over antibiotics is of course their specificity, the fact they don't have any known side effects, and unlike antibiotics they don't suffer from resistance.
> 
> Broad spectrum antibiotics that are used currently, have no such specificity, and they create resistance.



Some explanatory videos on these topics:


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## Crohn2357




----------



## kiny

I read studies about MAP and mycobacteria in general, but I became more interested in common foodborne infections because they don't require zoonosis, MAP is purely zoonotic.

An example is campylobacter, it is a zoonotic infection, but it doesn't have to be, you have human campylobacter that lives in people's mouths for example.  Oral reinfection of the gastrointestinal tract has been proposed before. You can't do that with MAP because the vector is purely zoonotic.

You need elegant explanations that explain the aphthous ulcers in crohn's disease for example. Yes the ulcers are caused by innate immunodeficiencies but you still need the trigger. It would be nice if you could find a strong bacterial link between the aphthous ulcers and the intestinal ulcers.


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## Pangolin

Anti-TNF agents linked to increased risk of IBD. https://www.medscape.com/viewarticle/915613


----------



## my little penguin

This has been known for years in jia 
Kids treated with enbrel as monotherapy were more likely to develop crohns 
But not kids with enbrel plus mtx 



> *Inflammatory Bowel Disease in Juvenile Idiopathic Arthritis Patients Treated with Biologics.*
> Barthel D, et al. J Rheumatol. 2015.
> Show full citation
> *Abstract*
> OBJECTIVE: Evolving inflammatory bowel disease (IBD) is a matter of interest in patients with juvenile idiopathic arthritis (JIA) and might be associated with JIA therapy.
> METHODS: Data from the German biologics registry (Biologika in der Kinderrheumatologie; BiKeR) from 2001 to 2013 were analyzed.
> RESULTS: There were 3071 patients with 8389 patient-years (PY) of observation followed. IBD was diagnosed in 11 patients, 8 with Crohn disease and 3 with ulcerative colitis. IBD incidence in patients with JIA was 1.31/1000 PY and higher than published IBD incidences in pediatric populations. Compared with the total BiKeR cohort, patients with IBD more commonly had enthesitis-related arthritis, extended oligoarthritis, psoriatic arthritis, and also rheumatoid factor (RF)-negative polyarthritis. No IBD occurred in patients with systemic JIA or RF-positive polyarthritis. In patients treated with methotrexate (MTX), the IBD incidence was significantly lower compared with patients not treated with MTX. Etanercept (ETN) monotherapy, but not the combination of ETN and MTX, was associated with an increased incidence of IBD.
> CONCLUSION: Incidence of IBD in patients with JIA is higher than in the population. MTX turned out to be protective, even in combination with ETN.











						Inflammatory Bowel Disease in Juvenile Idiopathic Arthritis Patients Treated with Biologics - PubMed
					

Incidence of IBD in patients with JIA is higher than in the population. MTX turned out to be protective, even in combination with ETN.




					www.ncbi.nlm.nih.gov
				





Of note remember the genes for juvenile spondyloarthritis arthritis overlap a lot with genes for crohns


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## Crohn2357

Pangolin said:


> Anti-TNF agents linked to increased risk of IBD. https://www.medscape.com/viewarticle/915613



A comment on that report:



> Dr. Aleksander Feoktistov 28 minutes ago
> 
> Complete misrepresentation of findings. The conclusion of the article per side effect refers to etanercept rather than "Anti-TNF agents as the title of the article says and misleading. Etanercept is known for possibility of exacerbation of granulomatous disease i.e. Uveitis in Ankylosing spondylitis. The title of the article should be  changed appropriately.



Still interesting though.


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## Pangolin

Enbrel had a much stronger relationship with developing Crohn's, but the others might also have some increased risk (1.3 and 1.2 odds ratio). We might say that there's strong evidence that the anti-TNFs aren't preventing Crohn's disease, at least:

"Korzenik and colleagues found that patients treated with etanercept were twice as likely to be diagnosed with de novo CD (adjusted hazard ratio [aHR] 2.0; 95% confidence interval [CI], 1.4 ‐ 2.8), whereas the aHR for infliximab and adalimumab were 1.3 (95% CI, 0.8 ‐ 2.2) and 1.2 (95% CI, 0.8 ‐ 1.8), respectively."

Study: https://onlinelibrary.wiley.com/doi/10.1111/apt.15370


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## Jonny84

Based on what I've read in this thread, it sounds like in a few decades, they'll look back at giving anti-TNFs chronically as a bit of a crazy idea.

Its interesting that those who have been treated with QBECO and have previously been on the anti-TNFs take significantly longer to respond than those who are anti-TNF naive.  I guess that would also count as evidence that Inflixmab actually contributes to the innate immune suppression and dysregulation that underlines Crohn's disease?


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## Crohn2357

"In this work, we present the results from a Phase 1/2 randomized, double-blind, placebo-controlled trial of a novel immunotherapy approach to optimize innate immune function in CD. QBECO, an investigational immunotherapy derived from an inactivated GI pathogen, aims to elicit an acute innate immune response targeting the GI tract to re-establish competent barrier function and immune competency (14)."

QBECO SSI, published two days ago:



*Original Research ARTICLE                         *

                        Front. Med., 19 July 2019                                 | https://doi.org/10.3389/fmed.2019.00170

*Novel Microbial-Based Immunotherapy Approach for Crohn's Disease*
Simon Sutcliffe1, Shirin Kalyan1,2, Jim Pankovich1, Jenny M. H. Chen1, Rashieda Gluck1, Darby Thompson3,4, Momir Bosiljcic1, Mark Bazett1, Richard N. Fedorak5†, Remo Panaccione6, Jeffrey Axler7, John K. Marshall8, David W. Mullins9, Boyko Kabakchiev10, Dermot P. B. McGovern11, Julie Jang1, Andrew Coldman12, Gillian Vandermeirsch1, Brian Bressler13 and Hal Gunn1*

1Qu Biologics Inc., Vancouver, BC, Canada
2Department of Medicine, University of British Columbia, Vancouver, BC, Canada
3Emmes Canada, Burnaby, BC, Canada
4Department of Statistics and Actuarial Sciences, Simon Fraser University, Burnaby, BC, Canada
5Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
6Inflammatory Bowel Disease Unit, University of Calgary, Calgary, AB, Canada
7Toronto Digestive Disease Associates Inc., Vaughan, ON, Canada
8Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
9Department of Microbiology, Immunology and Medical Education, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
10Zane Cohen Centre for Digestive Diseases, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
11Cedars-Sinai Medical Center, Los Angeles, CA, United States
12Cancer Control Research, British Columbia Cancer Agency, Vancouver, BC, Canada
13Gastrointestinal Research Institute, Vancouver, BC, Canada
*Background:* Current Crohn's disease (CD) therapies focus on suppressing immune function and come with consequent risk, such as infection and cancer. Notwithstanding, most CD patients still experience disease progression. There is a need for new CD treatment strategies that offer better health outcomes for patients.
*Aims:* To assess safety, efficacy, and tolerability of a novel microbial-derived immunotherapy, QBECO, that aims to restore rather than suppress immune function in CD.
*Methods:* A randomized, double-blind, placebo-controlled trial was conducted in 68 patients with moderate-to-severe CD. Primary endpoints: safety and Week 8 clinical improvement. Secondary endpoints: Week 8 clinical response and remission. Week 8 responders continued blinded treatment through Week 16; non-responders received open-label QBECO from Weeks 9–16. Exploratory analyses included immune biomarker and genotype assessments.
*Results:* QBECO was well-tolerated. Mean reduction in Crohn's Disease Activity Index (CDAI) score was −68 for QBECO vs. −31 for placebo at Week 8. Improvement with QBECO continued through Week 16 (-130 CDAI reduction). Week 8 QBECO clinical response, improvement and remission rates were 41.2%, 32.4%, 29.4% vs. 26.5%, 23.5%, 23.5% for placebo. TNFα inhibitor-naïve subjects achieved higher response rates at Week 8 with QBECO (64%) vs. placebo (26%). Specific immune biomarkers were identified that linked to QBECO response.
*Conclusion:* This proof-of-concept study supports further investigation for the use of QBECO as a novel immunotherapy approach for CD. Biomarker analyses suggests it may be feasible to personalize CD treatment with QBECO. Larger trials are now needed to confirm clinical improvement and the unique biological findings.
*Clinical Trial Number:* NCT01809275 (https://clinicaltrials.gov/ct2/show/NCT01809275)


...


*Introduction*
Accumulating clinical and genetic evidence suggests that a defective innate immune response may be fundamental to the pathogenesis of CD (5–8) and precedes the consequent over-reactive adaptive immune response that is characteristic of the disease and the target of current treatments (9, 10). Segal and Lowei first demonstrated that patients with CD exhibited an impaired systemic acute inflammatory response (11). Subsequent genetic studies provided further support for the hypothesis that defective or inefficient innate immune function, particularly that of macrophages, is linked to CD (12, 13). In this work, we present the results from a Phase 1/2 randomized, double-blind, placebo-controlled trial of a novel immunotherapy approach to optimize innate immune function in CD. QBECO, an investigational immunotherapy derived from an inactivated GI pathogen, aims to elicit an acute innate immune response targeting the GI tract to re-establish competent barrier function and immune competency (14). Treatment is self-administered by subcutaneous injection. Promising early clinical experience with QBECO for the treatment of CD in a compassionate use program (15) and a translational study in ulcerative colitis showing improved GI barrier function with QBECO treatment (14) motivated this proof-of-concept clinical trial to explore safety, efficacy, and tolerability of this novel immunotherapy in subjects with moderate-to-severe CD.

...







*Table 2*. Clinical response, improvement, and remission rates at Week 8 by treatment.








*Figure 3*. Mean change in Crohn's Disease Activity Index (CDAI) score in study groups Week 8 and Week 16. Mean change in CDAI score for subjects randomized to QBECO (solid red line) and placebo (solid blue line) from baseline to Week 8 and Weeks 16 of study treatment. Those responding to allocated blinded treatment at week 8 continued blinded treatment for another 8 weeks [light blue solid line for responders originally blinded to placebo treatment (_n_ = 9); light red solid line for QBECO responders (_n_ = 13)]. All placebo (_n_ = 22) and QBECO (_n_ = 14) non-responders at week 8 received open-label QBECO (dashed red lines) for weeks 9–16. Dark solid red line represents the average of all subjects on QBECO for weeks 9–16.

Patients naïve to anti-TNFα agents achieved a 64% response rate at Week 8 with QBECO vs. 26% placebo (_p_ = 0.041; ITT analysis), and more than double the improvement and remission rates (Table 2). Anti-TNFα naïve Week 8 placebo non-responders (_n_ = 17) treated with 8 weeks open-label QBECO from weeks 9 to 16 achieved response, improvement and remission rates of 71, 47, and 47%, respectively. This was similar to the response, improvement and remission rates observed after 8 weeks of treatment in the anti-TNFα naïve group initially randomized to QBECO. A longitudinal analysis including previous TNFα inhibitor exposure interaction with treatment following week 8 shows that subjects previously treated with anti-TNFα agents may respond to QBECO treatment with longer course of treatment (Supplement Figure 1).

In subjects with baseline CDAI ≥ 250 (_n_ = 24 [70.6%] QBECO, _n_ = 19 [55.9%] placebo), the response, improvement and remission rates in subjects treated with QBECO vs. placebo were: 42%, 29%, 25% vs. 16%, 11%, 11%, respectively. To account for differences in baseline characteristics that may be important in the change in CDAI score by treatment, a regression analysis was performed taking into account baseline CDAI, disease severity at baseline (>250), use of concomitant immunosuppressive medication, disease duration and prior exposure to anti-TNFα agents (Supplement Figure 2). Following adjustment for imbalanced prognostic variables, the reduction in CDAI at Week 8 was 48 points greater in the QBECO than placebo treated cohort (_p_ = 0.024; ITT analysis).

...

*Immune Biomarker Analysis*

Forty-two serum immune factors were assessed at baseline, Week 8, 16, and 24. Interleukin-18 (IL-18) increased from baseline to Week 8 and 16 with QBECO treatment (median change 24 pg/mL, adjusted _p_ = 0.066 at Week 8 and 56 pg/mL, adjusted _p_ = 0.067 at Week 16), but not with placebo treatment. None of the serum cytokine biomarkers remained elevated at Week 24 (i.e., 8 weeks after stopping study treatment).

Among QBECO treated subjects, IFNγ, IL-12p70, IL-17A, and TGFα were significantly elevated in QBECO responders vs. QBECO non-responders (adjusted _p_ = 0.037 for all) (Figure 4).






*Figure 4*. Serum cytokines that differed in QBECO responders and non-responders. A 42-plex cytokine/chemokine analysis was performed on serum. Four cytokines- IFNγ, IL-12p70, IL-17A, and TGFα- differentiated QBECO responders from non-responders over the study period after adjusting for multiple comparisons. 

Week 8 clinical remission with QBECO treatment occurred more frequently in patients with lower baseline serum Eotaxin-1 levels (adjusted _p_ = 0.0062) and IL-10 and IL-12p40 (_p_ > 0.05 after correcting for multiple comparisons). This relationship between lower Eotaxin-1 levels and increased Week 8 remission was not found in placebo treated patients. These 3 cytokines tended to be higher in patients previously treated with TNFα inhibitors (Supplement Table 2), and in a longitudinal analysis, as performed with previous anti-TNFα agent use, patients with high baseline Eotaxin-1 levels responded equally well to QBECO treatment with a longer course of treatment (Supplement Figure 3).

CRP, an acute phase response protein upregulated in response to bacterial infections, and FCP, a cation-binding protein released by granulocytes in response to infection, were not anticipated to be reduced during active QBECO treatment given its mechanism of action. We assessed levels of these immune biomarkers leading up to Week 24 (when subjects were off study treatments). At Week 24, 44% of those who had been on QBECO from the beginning of the study, 42% of those who had switched to QBECO from placebo at Week 8, and 0% of those who were on placebo since the beginning had CRP levels < 5 mg/L (Supplement Table 3). Similarly, 35% of those who had been on QBECO from the beginning of the study, 18% of those who had switched to QBECO from placebo at Week 8, and 0% of those who were on placebo since the beginning had FCP levels of <250 ug/g (Supplement Table 4).


*Genetic Associations With Response to QBECO*

One hundred and thirteen SNPs reported to be linked to IBD were analyzed for response to QBECO treatment. A gene risk score, which is a weighted value based on variation in multiple genetic loci, was computed to assess the ability to stratify subjects' response to QBECO. Figure 5 shows that the gene risk score could differentiate QBECO responders from non-responders in this cohort, _p_ = 0.0000243. Supplement Table 5 lists the IBD-linked SNPs and their weighted contribution to the construction of the gene risk score.







*Figure 5*. Gene risk score separates QBECO responders from non-responders. One hundred and thirteen inflammatory bowel disease (IBD)-related SNPs were included in computing the gene risk score for response to QBECO to assess the potential contribution of subjects' genetics to treatment outcome. The derived gene risk score could successfully distinguish QBECO responders from non-responders, _p_ = 0.0000243.


Some of the Supplementary Material:



*****



*****



*****



*****




*Discussion*
In this proof-of-concept study assessing QBECO, a first-in-class microbial-based immunotherapy, for the treatment of CD, a greater reduction in disease was observed by Week 8 in subjects randomized to QBECO compared to placebo. For the pre-specified Week 8 primary analysis in this 68-patient study, the difference did not reach statistical significance, but secondary analyses suggest that the biological effect induced by QBECO may be of benefit to patients with moderate-to-severe CD and warrants further study.

Notably, patients with prior exposure to anti-TNFα agents, who are known to generally be more difficult to treat (22, 23), were less likely to respond to QBECO by Week 8. Due to unequal randomization, these patients were significantly more prevalent in the QBECO arm than in the placebo arm. However, subjects previously treated with TNFα inhibitors did experience symptom improvement with QBECO as treatment continued to Week 16, suggesting that a longer course of treatment may be required to achieve optimal results in these subjects. QBECO Week 8 clinical response, improvement and remission rates in anti-TNFα naïve patients compare favorably to those reported at similar time-points in recent Phase 3 trials with biologics such as vedolizumab and ustekinumab (22, 23).

The current treatment approach for CD largely targets the overzealous adaptive immune response to invading bacteria in the GI tract, but accumulating evidence suggests patients with CD have impaired or deficient innate immunity that predisposes to defective barrier function (3, 5, 7, 8). Identification of genetic variants linked to CD that associate with innate immune function lends support to the idea that innate immune insufficiency plays a role in disease pathophysiology, at least for a significant segment of those suffering from CD (5, 7). Serum cytokine analysis in this study demonstrated a QBECO-induced increase in IL-18, a cytokine known to promote phagocytosis and bacterial clearance (24). This corroborates our findings in experimental models of colitis in which colonic expression of IL-18 increased in response to QBECO treatment—resulting in marked improvements in gastrointestinal histopathology and barrier function (14). Other studies of colitis have shown a lack of IL-18 results in more severe disease (25), and the administration of IL-18 can reverse the phenotype (26). IL-18 with IL-12 acts on natural killer (NK) cells, γδ T cells and other “Th1” cells to stimulate the production of IFNγ (27, 28), which in turn acts on macrophages to further enhance phagocytosis, bacterial clearance and antigen presentation (24). CD patients who improved with QBECO treatment produced IL-18 and had increases in serum IFNγ, IL-12p70, and IL-17A levels, whereas, subjects deemed as QBECO non-responders did not show the same increases in these three cytokines. This may reflect an inability to launch a productive immune response to bacterial stimulation. The observed higher incidence of transient flu-like symptoms in QBECO treated subjects likely reflects this immune mobilization, and we believe it is part of QBECO's mechanism of action. Of note, CD patients who improved with QBECO treatment also had increases in their levels of TGFα, which has been reported to be reduced in diseased regions of the colon of patients with inflammatory bowel disease and increased in healthy regions (29).

Patients with lower baseline levels of Eotaxin-1, IL-10, and IL-12p40 were more likely to achieve response and remission with 8 weeks of QBECO treatment. Of note, these cytokines tended to be higher in those who had previously been treated with anti-TNFα therapy and may reflect greater immune dysregulation in patients (30–33). For such individuals, a longer course of QBECO treatment may be required to overcome the presence of greater immune dysfunction, as is suggested by the study's 16-week data showing that patients with higher baseline levels of these cytokines achieved more optimal responses with a longer duration of treatment.

A personalized approach to CD treatment has been elusive to date, possibly because current treatments focus on symptom management (3, 34, 35), rather than upstream biological processes predisposing CD symptoms. Subject genotype was found to differentiate QBECO responders from non-responders. Collectively, the genetic and cytokine findings of this study provide promise for personalized medicine in CD with QBECO, and they now need replication in larger cohorts.

This proof-of-concept study is limited by its small size, short treatment duration, lack of stratification for previous TNFα inhibitor use, and lack of endoscopic and histological assessment. The therapeutic paradigm has now moved from symptom-based assessment to objective measures of disease activity (36). QBECO treatment has shown endoscopic and histological improvement in moderate-to-severe ulcerative colitis (14) and now needs to be demonstrated in patients with CD.

In conclusion, QBECO warrants further study as a novel immunotherapy approach for the management of CD. This approach not only provides a new way of thinking about the treatment of the disease, but also sheds more light on the heterogeneity of CD pathogenesis. QBECO may be the optimal choice for those patients with disease characterized by innate immune dysfunction rather than other underlying etiologies. The data from this trial will inform the design of larger definitive Phase II trials, which will include evaluation of endoscopic and histological endpoints, assessment of the impact of prior TNFα inhibitor exposure on QBECO response, evaluation of patients over a longer treatment period, microbiome assessment, and confirmation of the genetic and immune biomarker findings.

*Funding*
This study was funded by Qu Biologics and Genome BC (SoFI Program).

*Conflict of Interest Statement*
SS, DT, RF, RP, DMu, BK, DMc, AC, and BB have served as consultants and/or advisors to Qu Biologics. SK, JP, JC, RG, MBo, MBa, JJ, and GV are (or were) employees of Qu Biologics. HG is the CEO and major shareholder of Qu Biologics. Qu Biologics owns patents across all the major markets (including U.S. Patent No. 8,980,279) relating to the use of Site Specific Immunomodulators derived from components of _E. coli_ (QBECO) to treat inflammatory bowel disease. Qu Biologics has also filed patents for the use of immune and genetic biomarkers for the use of QBECO in patients with inflammatory bowel disease. In addition to the above, the following author affiliations are non-academic incorporated for-profit entities: Emmes Canada (DT) and Toronto Digestive Disease Associates, Inc. (JA).

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.










						Novel Microbial-Based Immunotherapy Approach for Crohn's Disease
					

Background: Current Crohn's disease (CD) therapies focus on suppressing immune function and come with consequent risk, such as infection and cancer. Notwithstanding, most CD patients still experience disease progression. There is a need for new CD treatment strategies that offer better health...




					www.frontiersin.org


----------



## Crohn2357

Someone shared her conversation with Dr. Hal Gunn on Facebook:



> I will share what Hal Gunn told me a while back when I had questions. Hope this helps!
> 
> Hal Gunn:
> “There is growing evidence that there isn't a single bacterial pathogen that 'causes' Crohn's disease, but, instead, that the underlying problem is defect or suppression of the innate immune system, which thus, results in infection and dysbiosis with one or more different bacterial pathogens - in some patients pathogenic E. coli may predominate, in others it may be different bacterial pathogens - most patients with Crohn's disease have a increase in multiple different bacterial pathogens in their microbiome.
> 
> Qu's QBECO SSI is designed to restore innate immune function to clear all of these different pathogens.”
> 
> Me:
> Does the SSI treatment take into account T Cell function? In other words, if Crohn's patients have impaired T Cell function and simply can't respond to Site Specific stimulation because they are blind to it, would the treatment be expected to have any effect at all?
> 
> Hal:
> “In patients with Crohn’s disease (CD), innate immune function is suppressed/dysregulated, so innate immune cells, including macrophages, are unable to function optimally to clear bacterial infection, including MAP infection. When the innate immune system is dysregulated, this also dysregulates the adaptive immune system (including T cell function), and vice-versa, since the innate and adaptive immune systems are not two separate independent immune systems, they work together and one effects the other. The goal of SSIs treatment is to restore innate immune function and, in so doing, to restore adaptive immune function.
> By restoring innate immune function, SSIs help to restore adaptive immune function. The innate immune system is non-specific, so unlike the MAP vaccine which will only target MAP, SSIs are designed to restore innate immune function to clear any kind of bacteria or virus.
> 
> SSIs upregulate the NKG2D pathway, which, in CD, may help to clear dead and dying cells by putting ‘flags’ on immune cells and other cells marked for destruction.”
> 
> Me:
> How do you think people who actually responded well and continue to respond well to anti-TNFs would respond to SSI?
> 
> Hal:
> “We know from our study that patients who had not taken anti-TNFs had less suppression/dysregutation of their innate immune system, which is the reason we think they responded quicker to SSIs. We think that patients who had taken anti-TNFs will respond, we think that it will take them longer to respond (i.e., longer than the 8 week primary endpoint of our last trial). So in our next trial, we will treat for 52 weeks and the first assessment point will be at Week 16.”
> 
> Me:
> Also, what do you think of combining antibiotics and SSI, for those who did not respond to SSI alone?
> 
> Hal
> “I like the idea of combining SSIs and fecal transplant. The challenge with antibiotics is that they kill the healthy bacteria as well as the unhealthy bacteria and can, themselves, cause dysbiosis. QBECO is designed to restore innate immune function – if the innate immune system is functioning optimally, it can clear unhealthy bacteria, including MAP.”











						Crohn’s MAP Support Group | Facebook
					

A growing subset of doctors and researchers from around the world have ample, scientific reasons to believe that Mycobacterium avium subspecies paratuberculosis (MAP) is the root cause of Crohn's...




					www.facebook.com


----------



## Jonny84

Thanks for that - really interesting read!


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## Crohn2357

I find the results encouraging.


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## Guerrero

Yes but results in terms of efficacy is low.... especially for a medication that pretend the theory behind the use of anti-tnf is wrong...


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## Delta_hippo

Guerrero said:


> Yes but results in terms of efficacy is low.... especially for a medication that pretend the theory behind the use of anti-tnf is wrong...


I wish it was 100% efficacy but then again what is.  A step closer to a possible treatment that might work and might not come with the list of biologics side effects is good news in my book.  But yeah, a more glorious leap forward would be nice.


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## Jonny84

Remember patients were only treated for 8 weeks.  Longer treatment will yield even better results.  Especially for those who have already been on anti TNF's.


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## Crohn2357

From Hal Gunn. These clips were uploaded two years ago:


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## kiny

Treatments that can show that manipulation of M1 and M2 macrophage proliferation have a positive effect on the disease, will result in safer and more effective treatment over time. Subcutaneous injection of heat killed E coli  is a blunt approach to try to correct macrophage response in crohn's disease, but as long as it shows promise, it will be iterated upon with other medication.

Outside of the use of GM-CSF, there has been no real medication to try to correct macrophage defficiencies in crohn's disease.

Current available treatment for crohn's disease is suppressing the adative response, which is a lot more dangerous than manipulating macrophage proliferation.


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## kiny

It's still unclear to me what exactly happens in the time between injecting E coli components and what they say is clinical improvement in crohn's disease.

They're simply injecting it under the skin, so tissue macrophages under the skin will react, not intestinal lamina propria macrophages  (LPMs).

The only way it is going to affect macrophage prolifiration in the intestine, is if the treatment is stimulating blood monocyte recruitment that then migrate to the intestine and become intestinal LPMs.


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## Crohn2357

kiny said:


> It's still unclear to me what exactly happens in the time between injecting E coli components and what they say is clinical improvement in crohn's disease.
> 
> They're simply injecting it under the skin, so tissue macrophages under the skin will react, not intestinal lamina propria macrophages  (LPMs).
> 
> The only way it is going to affect macrophage prolifiration in the intestine, is if the treatment is stimulating blood monocyte recruitment that then migrate to the intestine and become intestinal LPMs.


Maybe @Hal Gunn will write an answer.


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## kiny

Crohn2357 said:


> Hal Gunn:
> “There is growing evidence that there isn't a single bacterial pathogen that 'causes' Crohn's disease, but,


There aren't that many candidates of intracellular bacteria that enter through microfold cells and exploit macrophages.

AIEC is identified in LPM of CD patients in study after study.

Timothy R. Elliott
Lamina propria macrophage phenotypes in relation to _Escherichia coli_ in Crohn’s diseas

_E. coli-laden macrophages were commonly identified in mucosal biopsies from CD patients (25/35 *(71 %)*), rarely in UC (1/9 *(11 %)*) and were *not present *in any of 18 healthy controls (Table 3). The presence of E. coli-laden macrophages in CD correlated with endoscopic severity _


----------



## kiny

AIEC is there, it's causing inflammation, cipro is likely killing it, we know it's invading peyer's patches, you can isolate it from biopsies. We can now identify it in the majority of  CD LPM, not in UC, not in controls. Detection and virulence correlates with disease severity. Maybe we should direct some money towards killing AIEC instead of wasting billions on researching the microbiome.


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## kiny

kiny said:


> cipro is likely killing it


If it can just be a number of bacteria, why is cipro much more effective in CD than other antibiotics.

Incidence of CD is increasing in India. When someone in India develops CD, they don't have money for biologics. They have corticosteroids and 5 asa. If that doesn't work they use antibiotics (or they're already on them because they simply diagnosed it as intestinal TB)

Where an antibiotic like cipro is able to induce remission, tripple therapy antibiotics that are used to target MAP and are specific to gram pos bacteria and mycobacteria instead, don't get anywhere near the remission rates of simply using cipro.

Why is cipro the most effective antibiotic used in CD?


*Replication of Colonic Crohn's Disease Mucosal Escherichia coli Isolates within Macrophages and Their Susceptibility to Antibiotics*

*Abstract*
There is increasing evidence that Escherichia coli organisms are important in Crohn's disease (CD) pathogenesis. In CD tissue they are found within macrophages, and the adherent-invasive CD ileal E. coli isolate LF82 can replicate inside macrophage phagolysosomes. This study investigates replication and antibiotic susceptibility of CD colonic E. coli isolates inside macrophages. Replication of CD colonic E. coli within J774-A1 murine macrophages and human monocyte-derived macrophages (HMDM) was assessed by culture and lysis after gentamicin killing of noninternalized bacteria and verified by electron microscopy (EM). All seven CD colonic isolates tested replicated within J774-A1 macrophages by 3 h (6.36-fold +/- 0.7-fold increase; n = 7 isolates) to a similar extent to CD ileal E. coli LF82 (6.8-fold +/- 0.8-fold) but significantly more than control patient isolates (5.2-fold +/- 0.25-fold; n = 6; P = 0.006) and E. coli K-12 (1.0-fold +/- 0.1-fold; P < 0.0001). Replication of CD E. coli HM605 within HMDM (3.9-fold +/- 0.7-fold) exceeded that for K-12 (1.4-fold +/- 0.2-fold; P = 0.03). EM showed replicating E. coli within macrophage vacuoles. Killing of HM605 within J774-A1 macrophages following a 3-h incubation with antibiotics at published peak serum concentrations (C(max)) was as follows: for ciprofloxacin, 99.5% +/- 0.2%; rifampin, 85.1% +/- 6.6%; tetracycline, 62.8% +/- 6.1%; clarithromycin, 62.1% +/- 5.6% (all P < 0.0001); sulfamethoxazole, 61.3% +/- 7.0% (P = 0.0007); trimethoprim, 56.3% +/- 3.4% (P < 0.0001); and azithromycin, 41.0% +/- 10.5% (P = 0.03). Ampicillin was not effective against intracellular E. coli. Triple antibiotic combinations were assessed at 10% C(max), with ciprofloxacin, tetracycline, and trimethoprim causing 97% +/- 0.0% killing versus 86% +/- 2.0% for ciprofloxacin alone. Colonic mucosa-associated E. coli, particularly CD isolates, replicate within macrophages. Clinical trials are indicated to assess the efficacy of a combination antibiotic therapy targeting intramacrophage E. coli.


----------



## Crohn2357

* Tyler Wilson - Full Mucosal Healing from Crohn's - Qu Biologics Experimental SSI Medicine Trial*







*Tyler Wilson's Miracle - Full Mucosal Healing of Crohn's - Qu Biologics SSI Medicine Oct 30, 2018*







*Colleen Miller in 100% Remission from Crohn's since 2012 with QuBiologics Experimental SSI Treatment*







*Natalia is in 100% Remission from Crohn's since 2012 with Qu Biologics Experimental SSI Treatment*







*Bailey in 100% Remission from Colitis since 2013 with Qu Biologics Experimental SSI Treatment*


----------



## Crohn2357

*Qu Biologics With Promising New Treatment for Crohn's Disease - Global TV - May 31, 2013*


----------



## Jonny84

The people in those videos are so lucky - its great for them.  They hit a million to one shot and were the first to be treated with QBECO.


----------



## kiny

It is interesting how reluctant and slow some research is to just name things as they are. AIEC is a pathogen. It is not commensal, it is not pathobiont, it is not part of the normal microbiome.

AIEC is an intracellular bacteria that targets the ileum, enters through M cells in the ileum, infects macrophages, causes inflammation.

AIEC is called AIEC because it adheres to the intestinal wall and invades tissue. Since when are invasive pathogens that activate lamina propria macrophages part of the commensal micriobiome found in the lumen?

We don't call salmonella, also an intracellular bacteria that targets the ileum, targets M cells and infects macrophages a ''c_ommensal, pathobiont or bystander_''.

A bacteria that enters tissue, is taken up by macrophages, and causes dissease, is a pathogen. It enters tissue, it is an infection.

Name things as they are, it greatly helps crohn's disease patients if you just tell them like it is. AIEC is a pathogen, it causes disease in crohn's disease patients.

It took two decades before people started questioning the autoimmune theory. It fell flat on its face when apparently no one could answer the simple question of where the self-antigen response was. All of this was caused by research simply mislabeling things.

Here is a simple question. If AIEC is part of the microbiota (or microflora, even deciding on what to call it is apparently already an issue), what is it doing in lamina propria macrophages in tissue?

Since when did the microbiota include bacteria that are invading intestinal tissue?

Billions spent on microflora / microbiota research. It has never helped a single patient with crohn's disease, and you still can't decide on a name. This is money every patient and taxpayer pays to see results. Where are the results.

AIEC was found in tissue by Bodeau in 1999 in CD biopsies, not through spending billions on futile microbiome research. We went from isolating it from a few patients with ileal crohn's disease, to the majority of them harbouring pathogenic AIEC in just a few years.
.


----------



## Delta_hippo

I found a clinical trial at Liverpool university (Apricot trial) investigating a triple antibiotic combination targeting AIEC.  It’s been running for about ten years so I emailed to see if they had any results yet and the trial coordinator replied saying that are hoping to publish a paper early next year and can’t disclose anything before then.  So who knows.  But interesting it is being researched given the ideas in this thread.


----------



## kiny

Delta_hippo said:


> I found a clinical trial at Liverpool university (Apricot trial) investigating a triple antibiotic combination targeting AIEC.


You generally don't want to use broad spectrum antibiotic therapy to target AIEC, because AIEC is very good at colonizing the intestinal wall if you remove bacteria that compete with it for nutrients and (literally) physical space on the intestinal wall.

You will also run into resistance at some point.

That's not to say that you shouldn't use antibiotics. What is a doctor supposed to do if the patient no longer responds to medication. What is a doctor in India without access to any biologic supposed to do with patients who don't respond to corticosteroids or 5 asa, they use things like cipro.

You also can't keep patients too long on antibiotics, quinolones can not be used for very long. Outside of rifaximin I don't know of any antibiotics that might be helpful against AIEC that can be given long term. (rifaximin is very interesting due to its localized action, which means you can give it for extended periods of time, unlike cipro, of course it is less effective than cipro that is macrophage penetrating).

But we want to target just AIEC specifically with things like bacteriophages in the near future, we don't want to use too many broad spectrum antibiotics because it's known that can potentially worsen the AIEC infection over time.


*Antibiotics Potentiate Adherent-Invasive E. coli Infection and Expansion.*
Oberc AM1,2, Fiebig-Comyn AA1,2, Tsai CN1,2, Elhenawy W1,2, Coombes BK1,2,3.

*BACKGROUND: *
Crohn's disease (CD) is an inflammatory bowel disease with a complex etiology. Paradoxically, CD is associated with the use of antibiotics and with an increased abundance of an unusual phenotypic group of Escherichia coli known as adherent-invasive E. coli (AIEC). However, the impact of antibiotics on AIEC infection has not been well studied in controlled models of infection.

*METHODS: *
We infected mice with AIEC before or after treatment with a variety of different classes of antibiotics. We assessed levels of AIEC in the feces and tissues, AIEC localization by immunofluorescence microscopy, and tissue pathology.

*RESULTS: *
We found that a wide range of antibiotic classes strongly potentiated initial AIEC infection and expanded AIEC in chronically infected mice. We found that the ability of antibiotics to potentiate AIEC infection did not correlate with a stereotyped shift in the gut bacterial community but was correlated with a decrease in overall diversity and a divergence from the pre-antibiotic state. We found that antibiotic-induced inflammation provided a fitness advantage for AIEC expansion through their use of oxidized metabolites in the postantibiotic period.

*CONCLUSIONS: *
Our results show that antibiotics can render hosts more susceptible to initial AIEC infection and can worsen infection in previously colonized hosts. AIEC appears to exploit host inflammatory responses that arise in the postantibiotic period, highlighting a previously unknown interaction between CD risk factors.


----------



## kiny

The dual edged sword of antibiotic use has been confirmed by simply reading the many experiences on this forum.

Antibiotics do lower inflammation in crohn's disease, often spectacularly so with antibiotics that are effective against E Coli like cipro (much less so in trials against mycobacteria).

But the clock resets once AIEC is not fully cleared, has built up resistance. After a few weeks or months, people relapse. Now that resistant AIEC has a fitness advantage in the host, ibecause antibiotics are so broad spectrum.

This is why I am critical of these triple antibiotic therapies against MAP. Borody showed very mild success rate, but a study that tried to recreate any beneficial effect in CD, did not show any improvement.

I don't discount MAP, certainly not, but you have to be able to clearly show that MAP is behind the inflammation. We are much much more successful showing that AIEC is driving the inflammation than MAP. Antibiotics that are effective against gram neg E coli are much much more successful in reducing inflammation in CD patients than antibiotics that are effective against mycobacteria.

What happens if you use antibiotics that target gram pos mycobacteria that are not effective against AIEC, is that you
1) don't kill AIEC
2) give a fitness advantage to AIEC in the post-antibiotic period


----------



## kiny

What we also know is that the oral administration of antibiotics is effective in reducing inflammation in CD, but with non-oral routes (like IV), you don't get that same effect.

IV route is very ineffective. You want to use IV route to treat non-intesinal complications to spare the intestine, but you want to definitely use oral route if the goal is treating CD inflammation itself.

Why is this. An effective treatment against MAP, which resides only in tissue, should be just as effective with IV, but it's not. That tells me the antibiotics is acting on lumen content and tissue, which makes me believe that those tripple macrophage penetrating antibiotic therapies against MAP, are simply (very ineffectively) acting on AIEC that resides in the lumen on the intestinal wall and resides in lamina propria macrophages, instead of MAP. This is then an ineffective treatment.


----------



## kiny

There are trial though, that are trying cipro + rifaximin to target AIEC https://www.centerwatch.com/clinica...se-evaluation-adherent-invasive-e/?&radius=50

Bacteriophages trials are happening too to target AIEC.

It is no surprise they are happening in France which has been at the forefront of AIEC research and which hosts renowned institutes like Institut Pasteur.


----------



## Crohn2357

Delta_hippo said:


> I found a clinical trial at Liverpool university (Apricot trial) investigating a triple antibiotic combination targeting AIEC.  It’s been running for about ten years so I emailed to see if they had any results yet and the trial coordinator replied saying that are hoping to publish a paper early next year and can’t disclose anything before then.  So who knows.  But interesting it is being researched given the ideas in this thread.



Thanks for sharing.



> Brief Summary:
> 
> There is growing evidence that Crohn's disease may be caused by replication of bacteria, perhaps particularly E. coli, within macrophages (a specialized sort of white blood cell). Laboratory studies show that a combination of antibiotics that can penetrate macrophages (such as ciprofloxacin and doxycycline) together with the anti-malarial drug hydroxychloroquine (which makes the contents of macrophage vesicles more alkaline and helps them to kill intracellular bacteria) is particularly effective at killing the E. coli within macrophages.











						Antibiotics and Hydroxychloroquine in Crohn's - Full Text View - ClinicalTrials.gov
					

Antibiotics and Hydroxychloroquine in Crohn's - Full Text View.




					clinicaltrials.gov
				









						LCTC - Research
					

We bring together a wealth of expertise built on the experience of the Liverpool Trials Collaborative which has held full registration status with the UK Clinical Research Collaboration CTU network since its establishment in 2007.




					www.lctu.org.uk
				




A doctoral thesis submitted to the same university (December 2016):

Characterising molecular mechanisms of Crohn’s disease associated Escherichia coli that enable their survival and replication within macrophages

It seems to be worth reading.


----------



## kiny

Crohn2357 said:


> Laboratory studies show that a combination of antibiotics that can penetrate macrophages


It's important that at least one antibiotic is macrophage penetrating. While AIEC attaches to the epithelial wall, they then enter through M cells...meaning they enter tissue.

AIEC don't get killed by phagocytosis, they are able to exploit the macrophage and xenophagy and replicate inside the macrophage.

So one of your antibiotics has to be able to penetrate those macrophages, cipro does this very well.

Now, cipro doesn't cure people, AIEC is a very resistent bacteria and a broad spectrum antibiotic that will give AIEC a fitness advantage in the lumen once it gains resistence. But if you're going to use antibiotic therapy, well, cipro should be looked at.


----------



## Crohn2357

kiny said:


> What we also know is that the oral administration of antibiotics is effective in reducing inflammation in CD, but with non-oral routes (like IV), you don't get that same effect.
> IV route is very ineffective.



That's not true. When a Crohn's patient is hospitalised (due to active Crohn's, abscesses, fistula etc.), he/she is generally given the antibiotics intravenously, even though the patient can take them orally. IV antibiotics work well for Crohn's in hospitalisations to abort the flare-ups (inflammation and/or other Crohn's manifestations) and get into remission again.

IV administration can have lower gastrointestinal side effects, and it achieves higher plasma (thus tissue) levels compared to same dosage of antibiotics taken orally.


----------



## Crohn2357

kiny said:


> There are trial though, that are trying cipro + rifaximin to target AIEC https://www.centerwatch.com/clinica...se-evaluation-adherent-invasive-e/?&radius=50



More information:









						Evaluation of Adherent Invasive E. Coli Eradication in Adult Crohn Disease - Full Text View - ClinicalTrials.gov
					

Evaluation of Adherent Invasive E. Coli Eradication in Adult Crohn Disease - Full Text View.




					clinicaltrials.gov
				







> *Antimicrobial Therapy*
> 
> Antimicrobial therapy aims to alter the composition of the microbiota by reducing the concentration of potentially pathogenic bacteria that may be playing a role in the pathogenesis and disease course of patients with IBD. While the use of ciprofloxacin and metronidazole have demonstrated modest efficacy in inducing and maintaining remission in patients with active colonic Crohn’s disease and in preventing postoperative recurrence in patients with ileocolonic anastomosis, their routine use is not recommended outside of suppurative complications. Display footnote number:  124  Rifaximin, a minimally absorbed antibiotic, has gained attention recently due to its efficacy in other intestinal diseases. Several studies have shown that rifaximin may be effective in inducing and maintaining clinical remission in patients with CD compared to placebo, Display footnote number:  125,126  however studies have thus far failed to show improvement in patients with UC. Display footnote number:  127  Multiple additional trials of Rifaximin for induction therapy in CD patients (NCT02240108, NCT00603616, NCT02240121) and in the prevention of postoperative recurrence in CD patients (NCT03185624, NCT03185611) are currently underway. Additional studies investigating the role of antibiotics in IBD include the use of wide-spectrum antibiotic cocktails with doxycycline, amoxicillin, and metronidazole (NCT02345733) and oral vancomycin, neomycin, ciprofloxacin, lavage with PEG, +/- fluconazole in active CD that is refractory to conventional immunosuppressive therapy (NCT02765256).
> 
> 
> *Antimicrobial therapy targeting specific aberrant bacterial triggers of IBD is currently under investigation. Specifically, the ongoing randomized controlled trial TEOREM (Evaluation of Adherent Invasive E coli Eradication in Adult Crohn Disease) plans to assess whether 12 weeks of treatment with ciprofloxacin and rifaximin is superior to placebo in obtaining endoscopic remission in patients with ileal Crohn’s disease colonized with adherent invasive E coli (NCT02620007). Adherent invasive E coli is a bacteria which has been associated with the pathogenesis of IBD. *RHB-104 (Redhill Biopharma) is a fixed oral antibiotic combination therapy of clarithromycin, rifabutin, and clofazimine with potent intracellular, antimycobacterial, and anti-inflammatory properties that targets _Mycobacterium avium_ subspecies _paratuberculosis_ (MAP). MAP may play a role in the pathogenesis of Crohn’s disease. Display footnote number:  128  RHB-104 has recently completed a phase III clinical trials (MAPUS) in patients with CD (NCT01951326).











						The IBD Therapeutic Pipeline is Primed to Produce
					

Jeffrey A. Berinstein, MD, Calen A. Steiner, MD, MS, Peter D.R. Higgins, MD, PhD, MSc Department of Internal Medicine, Division of Gastroenterology,




					www.practicalgastro-digital.com


----------



## kiny

Crohn2357 said:


> IV antibiotics work well for Crohn's in hospitalisations to abort the flare-ups (reduce inflammation and/or other Crohn's manifestations) and get into remission again.


Oral administration of cipro (with or without flagyl) and oral administration of rifaximin has been shown to help in crohn's disease.

All the others studies I have read (so far) don't show other antibiotics are effective. Especially not if they're given through IV or if they're not macrophage penetrating.


----------



## kiny

(Well, the borody study where he tried the 3  antibiotic cocktail was tried once more by another team and failed to show any improvement. I'm pretty sure Borody used oral administration for what it's worth too.)


----------



## kiny

Wasn't borody using oral clarithromycin, any positive effect he saw (which the other study didn't replicate) was probably because it's macrophage penetrating and was penetrating LPMs with AIEC, instead of what he claimed happened, that it was killing MAP.

And the benefits seen in borody's study didn't last, AIEC creates resistance to clarithromycin pretty easily.


----------



## kiny

kiny said:


> Antibiotics do lower inflammation in crohn's disease, often spectacularly so with antibiotics that are effective against E Coli like cipro (much less so in trials against mycobacteria).
> 
> But *the clock resets once AIEC is not fully cleared*, has built up resistance. After a few weeks or months, people relapse. Now that resistant AIEC has a fitness advantage in the host, ibecause antibiotics are so broad spectrum.


initial improvement on antibiotics is very high, but relapse is also very high

E coli has become a very resistant bacteria (thanks to years of irresponsible antibiotic treatment).

After resistance, colonisation rebounds, due to the fitness advantage of a resistant bacteria that no longer has to compete for nutriens, it will easily outcompete competitors on the intestinal wall, especially in an inflammatory environment. AIEC thrives in inflammatory environments.

Bacteriophages are so interesting because they should run into less resistance and they are specific, you don't give AIEC any host specific advantage, unlike in the post antibiotic stage.









						Antibiotics Potentiate Adherent-Invasive E. coli Infection and Expansion - PubMed
					

Our results show that antibiotics can render hosts more susceptible to initial AIEC infection and can worsen infection in previously colonized hosts. AIEC appears to exploit host inflammatory responses that arise in the postantibiotic period, highlighting a previously unknown interaction between...




					www.ncbi.nlm.nih.gov
				



_Our results show that antibiotics can render hosts more susceptible to initial AIEC infection and can worsen infection in previously colonized hosts. *AIEC appears to exploit host inflammatory responses that arise in the postantibiotic period*, highlighting a previously unknown interaction between CD risk factors. _









						Bacterial biofilm suppression with antibiotics for ulcerative and indeterminate colitis: consequences of aggressive treatment - PubMed
					

The suppressing effects of antibiotics on the mucosal flora are accompanied by massive rebound effects. The concentrations of mucosal bacteria are dramatically increased as soon as 1 week after cessation of antibiotic therapy, remaining at a level that is at least one power higher over a period...




					www.ncbi.nlm.nih.gov
				




_The suppressing* effects of antibiotics on the mucosal flora are accompanied by massive rebound effects. The concentrations of mucosal bacteria are dramatically increased as soon as 1 week after cessation of antibiotic therapy, remaining at a level that is at least one power higher over a period of 5 months as compared to the group without antibiotic treatment.*_


----------



## Crohn2357

kiny said:


> Bacterial biofilm suppression with antibiotics for ulcerative and indeterminate colitis: consequences of aggressive treatment. - PubMed - NCBI


Swidsinski's work has been discussed a lot in HW's UC board.

Some of the threads:






						Biofilms Biofilms Biofilms
					

Biofilms need their own thread.Perhaps why we are sick and why we can't heal.Trying to dig out good science a bit difficult, lots of blogs, any way th...



					www.healingwell.com
				









						Radical Induction Theory-Time to re-visit
					

I urge you all to read and understand, not a real difficult read. Good chance it might be the metabolic cause of UC. Of course we are still left as to...



					www.healingwell.com
				









						Defective mucus sugar. Chicken or the Egg problem perhaps solved
					

Don't want you to miss this one. What has gone wrong is the question.How to fix is perhaps the bigger question, see my other thread on strengthening t...



					www.healingwell.com
				









						Maltodextrin
					

The hits just keep on coming. FYI another possible,this has not been discussed much.Seems like it might not be safe to eat much packaged food.Old Mike...



					www.healingwell.com
				









						Bacteria rebound after antibiotics for UC
					

Thought you might find this interesting. I also believe this is why antibiotics dont work well for UC, biofilms. Old Mike Bacterial biofilm suppressio...



					www.healingwell.com
				









						Cloves/Eugenol thickens inner mucus
					

At least in mice.Don't over do, can be liver toxic. This is a great study the mice were given low dose in drinking water 13ugm/ml.I am always looking ...



					www.healingwell.com
				









						The fundamental basis of inflammatory bowel disease
					

Here Mike  The fundamental basis of inflammatory bowel disease: www.jci.org/articles/view/30587 It's a little dated (2007) but a little back and forth...



					www.healingwell.com


----------



## kiny

Well, for all intended purposes, all bacteria form biofilms (very few exceptions). It's just that AIEC is particularly good at it. Still, bacteriophages seem to have no problem dealing with biofilms, they wouldn't be very effective at their job if they couldn't deal with biofilms (unlike antibiotics).

It's pretty normal that bacteriophages can penetrate biofilms so effortlessly compared to antibiotics, they have coexisted with bacteria for thousands of years, killing bacteria is their only function and they have become very good at it.


----------



## Crohn2357

Some videos explaining biofilms:


----------



## Pangolin

kiny said:


> Why don't farmers have higher rates of crohn's disease, they should have spectacularly higher rates of crohn's disease but they don't. Why don't people who drink lots of milk have higher rates of crohn's disease.


Just a thought, but why don't milkmaids get smallpox? 
Because they've been infected with cowpox, of course. 

Perhaps the version common in cattle (which, as you note, presents differently from Crohn's) is different from the version common in humans and confers mild immunity to farmers.


----------



## Crohn2357

> *Why don’t dairy farmers and vets get Crohn’s Disease more often?*
> 
> You might expect that occupations resulting in frequent exposure to MAP-infected animals, such as dairy farmers and vets, would be associated with a higher risk of Crohn’s Disease, but in fact, data from the US show that these occupations are associated with a significantly reduced death rate from Inflammatory Bowel Disease1. Children exposed to farm animals, particularly cattle, in early life also subsequently have a lower incidence of CD2, and in many countries Crohn’s Disease is more common in towns and cities than in the countryside.
> The explanation of this apparent paradox lies in the fact that _Mycobacterium avium_ subspecies _paratuberculosis_ (MAP) can exist in (and switch between) two forms:
> 
> The ‘extracellular’ form (i.e. adapted to live outside of other cells) has an outer ‘capsule’. It is easy to see under an ordinary light microscope because the capsule soaks up and retains a special red stain called Ziehl-Neelsen (ZN) stain, commonly used in medicine to identify Mycobacteria in particular. This form of MAP, excreted by the trillion by heavily infected animals, is not one to which humans are particularly susceptible and exposure to it is likely to confer some natural immunity against disease. It has been shown that occupational exposure to MAP is associated with raised levels of antibodies against MAP. The urban preponderance of CD is probably not that townsfolk have an increased susceptibility to CD but rather that country folk have some natural protection3.
> The ‘intracellular’ form (i.e. adapted to live inside other cells) sheds its capsule and in doing so becomes invisible to ZN staining procedures, since it is the capsule which picks up the stain. This ‘naked’ form, which is still very tough, is more virulent to humans and is the form found in people with Crohn’s disease. MAP adopts this form after being taken up into white blood cells in the animal’s bloodstream and tissues. These white blood cells containing MAP bugs then pass into the milk. After a while, MAP in the environment also gets taken up by single-celled amoeba-like organisms called ‘protists’ which again enhances virulence to humans. Humans are therefore exposed to the virulent intracellular form of MAP both via milk from infected cows and via water supplies from contaminated rivers.
> As with almost everything to do with MAP, the truth is more complicated than it first appears and what actually happens turns out to be the opposite of what you would expect.
> 
> Cucino C, Sonnenberg A: Occupational mortality from Inflammatory Bowel Disease in the United Stated 1991-1996. Am J Gastroenterol 2001; 96:1101-5
> Radon K et al. Chronische Autoimmunerkrankungen und Kontakt zu Tieren: Contact with farm animals in early life and juvenile inflammatory bowel disease: a case-control study. Pediatrics 2007; 120:354-61
> Hermon-Taylor J. Mycobacterium avium subspecies paratuberculosis, Crohn’s Disease and the Doomsday Scenario. Gut Pathogens 2009; 1:15











						Crohn's Disease & MAP Frequently Asked Questions - Crohn's MAP Vaccine
					

Q & A on Crohn's Disease, Mycobacterium avium subspecies paratuberculosis (MAP) and the Crohn's MAP Vaccine.




					www.crohnsmapvaccine.com


----------



## kiny

I always said MAP is interesting, because

-Well, crohn looks like johne's disease doesn't it, ileal granulomatous inflammation. It's the first thing that popped in Dalziel's mind in 1913. It's chronic granulomatous enteritis.

-Crohn's genetic susceptibility leave patients particularly vulnerable to bacteria, but specifically mycobacteria.

In a disease with deep transmural inflammation...you would expect to find this bacteria in the same place you would find it in its bovine counterpart...you would expect to find it in intestinal tissue close to these inflammatory lesions,  in lamina propria macrophages, somehwere within that tissue you need to consistently find this bacteria.

But, ...in general..., (unlike AIEC) you do not find MAP consistently enough in those areas in CD patients to claim it is MAP that is driving the inflammation.

Is there a smaller subset of patients with MAP, maybe, I don't know. But you can not consistently isolate MAP like you can AIEC.


----------



## Pangolin

kiny said:


> Crohn's clustering is very common (and underreported). You can't explain this clustering without a localised infectious agent in the food or water supply.


I've noticed clustering in my own neighborhood (and family), enough to be concerned, eg, meeting a group of 20 people containing 4 people with Crohn's disease. Thinking back to your earlier comment on "organic" food and a very bad experience I had once after eating inadequately washed veggies from the farmer's market, I'm wondering if the common factor is a local, hippie-ish tendency to eat more "organic" and farmers' market veggies. 

I know many people with Crohn's don't tolerate salads well, possibly because they are physically rough, possibly because of the bacteria on them; my husband used to eat lots of salads and has been feeling quite a bit better since he stopped. Personally, I've been much more careful about my raw veggie consumption since the incident, including things like raw tomatoes at restaurants. I can definitely see the possibility for a slightly more mild version of an incident like mine to trigger long-term disease. 

When I've brought up this seemingly very high rate of local Crohn's disease with my son's gastro, though, I've just gotten answers that amount to "whites get more Crohn's disease and our city has more white people."


----------



## kiny

Pangolin said:


> Thinking back to your earlier comment on "organic" food and a very bad experience I had once after eating inadequately washed veggies from the farmer's market, I'm wondering if the common factor is a local, hippie-ish tendency to eat more "organic" and farmers' market veggies.


The geographic area responsible for the clustering disease is called ''focus of infection''.

Disease clustering doesn't require a focus of infection, but in foodborne diseases you can usually map out geographic hotspots and actually find the source of infection like they did in the
famous cholera example where the water well was infecting people.

Van Kruiningen is especially interested (a healthy obsession) with these clusters of crohn's disease. If you look for his name, you will find many studies about clustering and his possible explanations (including foodborne infections). I don't advise to read his lymphatics studies too much, they can be somewhat depressing to read from a CD patient perspective.


----------



## kiny

Legionella is a good example of this too, even though it's not a foodborne infection but a waterborne infection, it enters the lungs if you inhale water droplets.

When there are legionella outbreaks, you need to specifically find the focus of infection on a map linking all the known cases in the area. It's often coming from a very specific cooling tower. You need to find the specific cooling tower, this happens all the time.


----------



## kiny

kiny said:


> Van Kruiningen


While we're talking about MAP, Van Kruiningen is not a fan of this theory, to say the least.

But he always makes good points. My apprehension about MAP involvement in crohn's disease came from a lack of evidence isolating these bacteria in places where you would expect them to be. The theory made sense until you try to find studies of MAP in intestinal tissue of CD patients.

Just like Van Kruiningen, I can not find enough studies that consistently isolate MAP from patients. I only read Van Kruiningen studies for his very interesting clustering studies at first. I can find studies isolating AIEC consistently, so I became more interested in AIEC I would say.

I don't discount MAP as strongly as Van Kruiningen. I consider and think about it, but I also have doubts.


----------



## kiny

There's been studies where what he says has later been supported. He talks about contamination of  biopsy samples and the irrelevance of them to detect a pathogen when the inflammation is transmural.

There was a study for example that found MAP in biopsies of patients, and then subsequently found them in healty controls, and eventually isolated them in the water supply of the hospital. The patients were simply getting the MAP from the water of the hospital probably, it contaminated samples most likely.

You don't get these issues with AIEC detection simply because you find them so consistently in lamina propria macrophages.

We have also known that people with crohn's disease have serum anti-OmpC  for years, in fact it's used to diagnose people.

All the supporting evidence for AIEC involvement, is largely missing in the case of MAP.

 But you don't want to completely discount MAP...well...because, for the reasons I already mentioned. Completely discounting a mycobacteria that could have zoonotic potential is foolish, MAP clearly has the potential to cause disease, but is it the cause of crohn's disease...well...it's put in doubt if you fail to isolate it consistently in patients.


----------



## kiny

kiny said:


> All the supporting evidence for AIEC involvement, is largely missing in the case of MAP.


And this is important right. Not just from an academic standpoint, this difference has consequences when doctors prescribe antibiotics for crohn's disease.

AIEC is a gram negative E coli bacteria, the other is a gram positive mycobacteria...what antibiotic are you going to use.

Generally doctors don't isolate either bacteria. Testing for AIEC is time consuming until tests become standardized (which will happen), and testing for MAP generally doesn't happen at all (in fact you're better off going to a vet lab).

So which antibiotic do you use.


----------



## Crohn2357

Manipulating AIEC in Crohn's patients
					

Arabinoxylans, inulin and Lactobacillus reuteri 1063 repress the adherent-invasive Escherichia coli from mucus in a mucosa-comprising gut model...



					crohnsforum.com


----------



## kiny

It's really specifically xenophagy that is relevant. There are a lot of things you can do that will probably induce autophagy but won't have any effect on crohn's disease. Xenophagy, that is selective autophagy degradation of intracellular bacteria, is what you would somehow want to induce. All ''natural'' components that can induce xenophagy in intestinal tissue, and there are some (not going to name them, I don't want people taking stuff on my account) generally don't digest very well and probably cause more harm than good.

What you can do is of course to promote xenophagy, is make sure you have enough vitamin D.


----------



## kiny

https://www.ncbi.nlm.nih.gov/pubmed/30587114

*Genetic diversity of Escherichia coli in gut microbiota of patients with Crohn's disease discovered using metagenomic and genomic analyses.*


Taxonomic composition of gut metagenomes in Crohn’s disease patients is characterized by the pronounced presence of Escherichia/Shigella. The heatmap shows relative abundance of microbial genera (columns) in microbiota samples (rows). The genus levels are provided in percentages of the total bacterial abundance.


''_One of the most obvious differences between the CD patients and the healthy populations from Russia and other countries was the *order of magnitude increase in the Escherichia coli r*elative abundance in the stool samples (2.4% ± 16.5% vs. 0.2% ± 7.7%, one-tailed Mann-Whitney test p = 0.00167). 

Interestingly, the hierarchical cluster analysis of the AG profiles showed a high level of genetic diversity of E. coli in the CD metagenomes (Fig. 3) *suggesting that CD-associated E. coli are not a homogenous group but rather consist of multiple genotypes* with diverse genomic repertoires (clustering by the above-mentioned 17 virulence genes also showed diversity, see Additional file 1: Figure S2). 

Here, for the first time, we demonstrated the genomic heterogeneity of E. coli within the same CD patients. This understanding is eye-opening for clinicians because it implies the need to carefully revise the treatment for Crohn’s disease as follows:* an antimicrobial therapy scheme targeted against one biotype of E. coli might be ineffective against the other biotypes associated with the condition and may cause collateral damage to both the commensal microbiota and organism of a patient.* In particular, there is a need to use a diverse set of organisms as part of probiotic treatment scheme as the experimental evidence shows that *multiple E. coli pathotypes occupy significantly different ecological niches* [77]_.''


----------



## Crohn2357

> *David Chapman:*   For the doctors and researchers out there, can you explain the science behind how you think SSIs work?
> 
> *Dr. Gunn:*  Macrophages are important cells of the body’s innate immune system.  One of their primary roles is to engulf (through phagocytosis) dying or dead cells, in order to clear/recycle these dead and dying cells.  The cells of the tissues in our body have a natural life cycle, measured in days, weeks or months depending on the tissue.  When a cell reaches the end of its natural life cycle, it signals to macrophages that it is dying, a process called apoptosis, inviting macrophages to engulf and recycle the cell.  When this happens, the macrophage engulfs the cell and sends out anti-inflammatory and ‘tolerance’ signals so that the adaptive immune system (the other major arm of the immune system) doesn’t react against the antigens of the dying cell.
> 
> However, if there is a defect or deficiency of macrophage function (i.e., innate immune system), especially if there is an environmental trigger such as stress or chronic infection that overwhelms macrophage function, macrophages don’t clear dying or dead cells efficiently.  As a result, not all dying or dead cells are cleared by macrophages and, when they aren’t cleared, these dead cells necrose (i.e., break apart) releasing their internal antigens to which the adaptive immune system reacts, resulting in antibodies against these self-antigens and autoimmune disease (such as Crohn’s disease).  In other words, while symptoms of autoimmune disease are generally understood to be a result of an over-reactive adaptive immune system response, we hypothesize that the underlying trigger/cause may be a defect or deficiency in the innate immune system (macrophage function).
> 
> Based on our preclinical research, we’ve found that SSI treatment results in recruitment of macrophages to the targeted organ or tissue (for example, the gastrointestinal tract) with stimulation of their phagocytosis function, which we believe relieves the defect or deficiency that may underlie Crohn’s disease.  SSIs are made from killed bacterial components.  Injected subcutaneously (i.e., just under the skin), we’ve shown that SSIs stimulate an innate immune response in the organ or tissue in which the bacteria commonly causes infection.  An SSI made from E. coli stimulates an innate immune response in the gastrointestinal tract and thus, we are using an E. coli derived SSI in our Crohn’s disease clinical trials.








						Interview with Dr. Hal Gunn, the Founding CEO of Qu Biologics and Developer of "Site Specific Immunomodulation" (SSI)
					

Crohnsforum.com was lucky and managed to (virtually) sit down and have an interview with Dr. Hal Gunn, the founding CEO of Qu Biologics.  Qu Biologics is a Canadian company developing an exciting potential treatment for Crohn's disease called, "Site Specific Immunomodulation" (SSI).  David...



					crohnsforum.com


----------



## Crohn2357

kiny said:


> 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 said:


> What we will see is specifically designed bacteriophages that target specific bacteria found in crohn's disease. It will hopefully lead to more personalised therapy, where a stool sample or biopsy serves as a guideline to determine which bacteriophage might be useful.
> 
> Bacteriophages Targeting Adherent Invasive Escherichia coli Strains as a Promising New Treatment for Crohn's Disease. - PubMed - NCBI
> There are currently ongoing trial underway with bacteriophages to treat crohn's disease. It might be helpful in people who harbour invasive E coli.
> 
> What the benefit of bacteriophages is over antibiotics is of course their specificity, the fact they don't have any known side effects, and unlike antibiotics they don't suffer from resistance.
> 
> Broad spectrum antibiotics that are used currently, have no such specificity, and they create resistance.











						Biologists turn eavesdropping viruses into bacterial assassins
					

Molecular biologist Bonnie Bassler and graduate student Justin Silpe found a virus that can listen in on bacterial conversations — and then they used that to make it attack diseases including salmonella, E. coli and cholera.




					www.princeton.edu


----------



## kiny

kiny said:


> That permeable bowel is then chronically being invaded by bacterial content from the fecal stream


J Natl Med Assoc. 1998 Aug;90(8):491-2.
*Highly destructive perianal Crohn's disease.*
Shetty AK1, Udall J Jr, Schmidt-Sommerfeld E.
*Author information*

Abstract
This article reports a case of highly destructive perianal Crohn's disease in a 15-year-old boy who presented with fecal impaction and incontinence. Both upper and lower gastrointestinal tract endoscopy were unrevealing. Treatment with intravenous prednisolone and broad-spectrum antibiotics supplemented by enteral feeding with an elemental diet resulted in prompt recovery. However, healing of his perianal lesions began only after a diverting colostomy. Awareness of this uncommon entity is important because prompt recognition can lead to early institution of appropriate treatment and avoid further morbidity.


----------



## kiny

Oxford England 1985



			https://gut.bmj.com/content/gutjnl/26/3/279.full.pdf


----------



## kiny

Inflammatory response in this old 1985 study to fecal matter was (just like the other study I already posted) around *1 week* after contact with effluent.





Flaring from failed microbiota transplantations in crohn's disease *happens 1 week after the transplantation.*


_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. _


----------



## kiny

Doctors performing fecal micriobiota transplant on CD patients need to get their head checked.


----------



## Delta_hippo

In the absence of innate immune stimulating drugs presently, is there anything other than (or in addition to) EEN that might help, e.g. probiotics that might compete with AIEC or foods or supplements that would make the intestines less hospitable?  Other than the vitamin D already mentioned.


----------



## Delta_hippo

I suppose I'm thinking about preventative/ risk reduction measures for direct relatives due to the genetic link as well as anything that might help those of us suffering with this disease.


----------



## kiny

Delta_hippo said:


> In the absence of innate immune stimulating drugs presently, is there anything other than (or in addition to) EEN that might help, e.g. probiotics that might compete with AIEC or foods or supplements that would make the intestines less hospitable?  Other than the vitamin D already mentioned.


Supplements probably do much more harm than good.  Enteric coatings consist of particles that are bigger than 0.22 micron filter, it's both bacteria in the fecal stream and large particles that sets off inflammation.

Regarding probiotics, well, you would need to know if they compete for space and nutrients with relevant bacteria implicated in crohn's disease. Just because you can show this outside of the host, doesn't mean that these bacteria do this in the host too. I don't know, I don't think they are very helpful.


----------



## kiny

Delta_hippo said:


> I suppose I'm thinking about preventative/ risk reduction measures for direct relatives due to the genetic link as well as anything that might help those of us suffering with this disease.


Nothing you can really do. Maybe tell them to get enough vitamin D, watch out for foodborne infections and don't use antibiotics when it's not needed. Other than that you can't proactively prevent this disease I think.


----------



## Crohn2357

kiny said:


> All the data on treatment supports the (well established by now) theory that inflammation in crohn's disease is directed at pathogens (with a possibly minor role for *fungi*) within intestinal tissue.


A few years after my Crohn's diagnosis, I had oral and oropharyngeal candidiasis due to corticosteroid use. It didn't go away with liquid nystatin so I had to use a more systemic and powerful antifungal (fluconazole) to treat that.  I found it interesting to find out that fluconazole was also helping my intestines to a considerable degree.


----------



## kiny

It will be much easier to block AIEC than to treat the fungi, but I think fungi are only a minor player in crohn's disease.

Treatment against AIEC will become a reality, simply due to the fact that you have increasingly resistant E Coli bacteria.

Also simply due to the urinary tract infections where the E Coli is clearly using fimbriae to avoid being removed during urination in patients. In Crohn's disease AIEC uses fimbriae to attach to the intestinal wall.

Anti FimH are in development for both urinary tract infections and crohn's disease.

_''Takeda has paid $50 million (€44 million) upfront to co-develop Enterome’s early-phase Crohn’s disease candidate EB8018. The deal gives Takeda a stake in a small molecule designed to disarm virulent bacteria and thereby treat gastrointestinal disorders.

*EB8018 blocks the activity of FimH*, a lectin expressed by enterobacteriaceae such as Escherichia coli. Research suggests the lectin activates TLR4 and thereby encourages the production of TNF-alpha, a cytokine that is the target of Crohn’s drugs such as Humira and Remicade. Enterome hopes EB8018 will prevent production of the cytokine by blocking the local inflammatory cascade.''_


----------



## kiny

Also interesting that in 3rd world countries, you often have kids being infected with certain strains of E Coli early in life, and they somehow gain resistance to it. Somehow they become quite resistant to very virulent strains of E Coli that cause a lot of disease in the West.

Now you can argue that this is normal, because the infections simply resulted in acquired adaptive immunity through the activation of memory T cells.

But it's not that simple, they seem to have developed anti-adhesion immunity against E coli, which protects them from very virulent strains of E coli.


----------



## Crohn2357




----------



## Crohn2357

Qu Biologics press release (July 23rd, 2019):                         



> At the time Qu initiated the first CD trial, the Crohn’s Disease Activity Index (CDAI) was the instrument of choice to evaluate how well a treatment was working in patients with CD. However, the bar for evidence is shifting, and there is now a greater emphasis on obtaining objective evidence for mucosal healing in the intestinal tract via endoscopy. Qu is currently running a follow-on trial, which is enrolling at three sites across Canada, to evaluate mucosal healing with SSI treatment. This follow-on trial is 85% enrolled, but interested patients with moderate-to-severe CD can still inquire about participation.  Dr. John Marshall, Director of Gastroenterology at McMaster University, who is a co-author of the recently published study, is one of the principal investigators of the current trial. He discussed in an earlier interview how very different the SSI approach is to current CD treatments and his patients’ experience to date with SSI therapy.








						Qu Biologics publishes potentially paradigm-shifting results of their first randomized-placebo controlled trial for the treatment of Crohn’s disease - Qu Biologics Inc
					

Vancouver, British Columbia – July 23rd, 2019 – Qu Biologics Inc. (Qu), a biopharmaceutical company developing Site Specific Immunomodulators (SSIs), a unique platform of microbial-based immunotherapies designed to restore the body’s innate immune system, is pleased to report that the results of...



					www.qubiologics.com
				




Others: https://www.qubiologics.com/news-investors/news/


----------



## Crohn2357

kiny said:


> I don't know how QUbiologics, the company some people keep mentioning, got around the idea of injecting E coli into the skin to treat crohn's disease, but they of course read that study.


In this new interview, Hal Gunn mentions his recent conversation with Anthony Segal.


----------



## kiny

Crohn2357 said:


> In this new interview, Hal Gunn mentions his recent conversation with Anthony Segal.


Anthony Segal is a very smart person.

Rutgeerts et al. showed that the fecal stream was driving the inflammation. But that still didn't explain why the disease featured patchy granuloma in the form of skip lesions, not much different from the skip lesions that are a feature in intestinal TB.

Anthony Segal showed innate immunodeficiencies in crohn's disease and pointed out to me that foodborne infections also lead to patchy inflammatory lesions. I have read countless stories about crohn's diseae patients on this forum, and what patients (including myself) first experienced are all the symptoms of an acute foodborne infection. The patient has acute abdominal disstress, fevers, night sweats, throwing up, etc,.

These acute fevers and night sweats don't generally present themselves later in the disease, the acute infection seems to have been overcome, but it would leave a permeable bowel behind. They also wouldn't find them during diagnosis, by the time they check biopsies or test for foodborne infections in stool, it is too late to find the offending pathogen. The studies that show a link between salmonella infection and crohn's disease are not based on early intervention in crohn's disease. But the lesions that might lead to chronic disease are still there.

Bodeau in 1999 showed that E coli, especially invased E Coli named AIEC, exploits this inflammatory environment and chronically invades those inflammatory lesions.

(there was a team before Rutgeerts that showed the fecal stream was driving inflammation also, but I can not find it, but Rutgeerts references it, maybe I'll find it if one of these days)


----------



## kiny

The studies by Van Kruiningen that show crohn's disease happens within specific geographic regions, in clustering patterns, is also easy to explain with Anthony Segal's theory. They simply ate the same food infected with the same foodborne pathogens.

That crohn's disease is primarily diagnosed in patients 15-24 of age, is also fairly straightforward to explain with this theory. 15-24 is simply when peyer's patches are most active and the offending pathogen that causes the initial infection invades peyer's patches through M cells.


----------



## kiny

The explanation for the dysbiosis is also straightforward now. The dysbiosis happens due to the inflammatory environment. It's not the cause of the disease itself, dysbiosis is simply a result. Under inflammatory stress, some bacteria will thrive (like AIEC), and others will not. Dysbiosis is much less during remissions and only manifests itself during active disease.

Targeting the opportunistic bacteria like AIEC with anti-FimH or bacteriophages, might not technically cure the patients, but it should make flares and inflammation much less common.


----------



## kiny

M cells simply don't seem to have any mucus covering them. Salmonella and AIEC are specifically targeting ileum entry through the few hundred peyer's patches.

It explains why even after complete mucosal healing in patients, the patient isn't necessarily cured. When AIEC regains entry through M cells and reactivates tissue macrophages, patients relapse.

Restoring innate immune function would need to be combined with anti-FimH, bacteriophage or antibiotic therapy, to have higher success rates.


----------



## kiny

Crohn2357 said:


>


I don't know who this woman is, but it is of course insane to suggest flares are just fine and a normal thing if you go off medication, and you should just let it happen and treat Crohn's naturally. Half the video is quackery.

No one should be playing their own doctor, it's a very bad idea to simply drop your medication. Immunosuppressants serve a purpose, they limit tissue damage from cytokine expression.

Even if one could restore innate immune function, you would still expect inflximab to be used to treat acute phases of inflammation to limit tissue damage. 

Regarding the lady from QuBiologics saying that medication has a poor record for mucosal healing. I don't know what she means by that, Infliximab has a very good record of mucosal healing.


----------



## kiny

Just because researchers point out the double edged sword of immune suppression in a disease that is hallmarked by immunodeficiences, doesn't mean they suggest you should change your medication.

The lady from QuBiologics said that medication for crohn's disease has a bad track record for mucosal healing. This isn't true, Infliximab has an excellent track record for mucosal healing.

Before biologics, there was nothing doctors could give crohn's disease patients to treat acute forms of cascading inflammation.

Back when Dalziel treated patients, they had nothing at all. People with crohn's disease had no treatment and it was surgery or death for them.

Just because people question the chronic use of immunosuppression, doesn't mean that infliximab isn't helping people. There is nothing as effective as infliximab to get people in remissions. If one agrees with the chronic use of it, is a different question.


----------



## Jonny84

So Kiny you are basically saying that initially inflix is very effective in causing mucosal healing but in the long term it actually makes things worse - I understand that from reading this thread but how does long term infliximab use effect mucosal healing then?


----------



## Crohn2357

@kiny, could you put the oral aphthous ulcers seen at the onset of Crohn's into a perspective? I had them right before my diagnosis. After I got hospitalised, diagnosed and received treatment, they were immediately gone and they never recurred; even though I have never been in remission for years

I think I am not the only one who experienced the same.









						From Aphthous Ulcer to Full-Blown Crohn’s Disease
					

At onset, Crohn’s disease (CD) is characterized by transmural inflammation with mucosal ulcerations. In its earliest phase the lesions are mainly aphthous ulcers. The ulcers then become larger, a nodular pattern develops and penetration of the deep ulcers leads to fistulas and collagen...




					www.karger.com
				






> Studies have shown that around 60% of patients with Crohn’s disease present with oral manifestations including cheilitis, oral ulceration, fissuring and glossitis and this may be the first sign of the disease in 5-10% of cases.











						Oral Manifestations of Crohn's Disease
					






					www.bmj.com
				




Are those an epiphenomenon, or a manifestation of Crohn's aetiology (maybe in line with your thesis that CD is first triggered by an acute infection)?

What I find interesting is the fact that they never recurred.


----------



## kiny

Jonny84 said:


> So Kiny you are basically saying that initially inflix is very effective in causing mucosal healing but in the long term it actually makes things worse - I understand that from reading this thread but how does long term infliximab use effect mucosal healing then?


As long as infliximab can suppress the adaptive response by blocking TNF-α patients won't relapse. But when patients build resistance in the form of antibodies, or when the body starts to upregulate other inflammatory cytokine in response, treatment stops working.

When patients relapse on immunosuppressants, one assumes the relapse will be far more pronounced in some patients because it will very hard to deal with bacterial content when the immune system has been chronically downregulated for so long.


----------



## Jonny84

kiny said:


> As long as infliximab can suppress the adaptive response by blocking TNF-α patients won't relapse. But when patients build resistance in the form of antibodies, or when the body starts to upregulate other inflammatory cytokine in response, treatment stops working.
> 
> When patients relapse on immunosuppressants, one assumes the relapse will be far more pronounced in some patients because it will very hard to deal with bacterial content when the immune system has been chronically downregulated for so long.


Ok that makes sense - thanks. 

Ok so what about Qu finding that patient who were previously treated with anti TNF taking longer to respond to their treatment? In other words does long term anti TNF use do permanent damage to the immune system?


----------



## kiny

Crohn2357 said:


> Ok so what about Qu finding that patient who were previously treated with anti TNF taking longer to respond to their treatment? In other words does long term anti TNF use do permanent damage to the immune system?


No, the immune system recovers eventually.

It's just that people on anti-TNF have a diminished response to infections. Patients won't recruit as many neutrophils, blood monocytes and the adaptive response will also be weaker.

A response to subcutaneous injection of heat killed E Coli, or whatever they use, would be much slower with patients recovering from anti-TNF treatment.

If the immune cell recruitment is slowed down, the QuBiologics treatment won't result in the same blood monocyte and neutrophil response, until the patient recovers.


----------



## kiny

That's why when people start infliximab they get a mantoux test first.


----------



## kiny

Crohn2357 said:


> @kiny, could you put the oral aphthous ulcers seen at the onset of Crohn's into a perspective? I had them right before my diagnosis. After I got hospitalised, diagnosed and received treatment, they were immediately gone and they never recurred; even though I have never been in remission for years


Aphthous ulcers in the mouth seen in crohn's disease are the same type seen in chronic granulomatous disease. People with UC don't get them.

The early inflammation you see in early CD intestine, are little inflamed lymphoid follicles, small red dots that look like the aphthous ulcers in people's mouths.

The M cells of peyer's patches are being compromised and it results in small inflamed spots of inflammation. It's either the peyer's patches sampling bacterial content or, what is more likely, M cells being invaded by bacteria.

Why people with crohn's disease have these small inflammatory spots in their mouths too, probably due to immunodeficiencies. We don,t really know what causes aphthous ulcers in people's mouths, but we do know there is a rich bacterial population in people's mouth.



			https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396064/pdf/ijcep0005-0411.pdf


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## kiny

Just because medication blocks the immune response, doesn't mean the body won't recover to a normal state before treatment was initiated if they go off the treatment.

Some people develop lymphopenia on infliximab treatment, but when the treatment is stopped, they tend to recover, it just takes a long time. Some people have neutropenia or lymphopenia due to malnutiriton too, once the malnutrition is dealt with, the immune system recovers, it can just take a very long time.

Exeptions are disease like AIDS, where the lymphopenia is permanent and CD4 keeps dropping and the immune system doesn't recover. But that's different from treatment induced immune changes.


----------



## Crohn2357

@kiny, could you elaborate your thoughts on the significance of granulomatous inflammation in CD's aetiology?


----------



## kiny

In crohn's disease it's groups macrophages literally trying to wall off bacteria like AIEC from invading intestinal tissue. They're full of E Coli DNA.


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## Crohn2357

How do researches who think CD is an autoimmune disorder explain the existence of granulomas in CD, do you know?


----------



## kiny

Crohn2357 said:


> How do researches who think CD is an autoimmune disorder explain the granulomas' existence in CD, do you know?


They can't.
They can't explain why the inflammation is patchy instead of everywhere on the organ.
They can't explain why it's the ileum or colon, but not higher up in the intestinal tract.
They can't explain why the age onset of disease is 15-24.
They can't explain geographic disease clustering.
They can't explain why antibiotics results in decreased inflammation.
They can't explain why fecal stream diversion results in remission.

They can't explain anything, they can't even prove the basis of their argument, they can't show a self-antigen.


----------



## wildbill_52280

Pangolin said:


> I've noticed clustering in my own neighborhood (and family), enough to be concerned, eg, meeting a group of 20 people containing 4 people with Crohn's disease. Thinking back to your earlier comment on "organic" food and a very bad experience I had once after eating inadequately washed veggies from the farmer's market, I'm wondering if the common factor is a local, hippie-ish tendency to eat more "organic" and farmers' market veggies.
> 
> I know many people with Crohn's don't tolerate salads well, possibly because they are physically rough, possibly because of the bacteria on them; my husband used to eat lots of salads and has been feeling quite a bit better since he stopped. Personally, I've been much more careful about my raw veggie consumption since the incident, including things like raw tomatoes at restaurants. I can definitely see the possibility for a slightly more mild version of an incident like mine to trigger long-term disease.
> 
> When I've brought up this seemingly very high rate of local Crohn's disease with my son's gastro, though, I've just gotten answers that amount to "whites get more Crohn's disease and our city has more white people."


Could just be the whole concept of westernization, germ theory of disease/antibiotic usage, low fiber/high sugar/high fat diets, and a clothed indoor life low in vitamin d, all of this promoting the extinction of microbes and the weakening of immune system. White people are also kind of the epitome of modern western culture, which we impose on the rest of the world through our historical power sometimes for better, sometimes for worse. https://www.cdc.gov/ibd/IBD-epidemiology.htm


----------



## kiny

The clustering is family and geographic clustering confined to small areas. They can not be explained with ''westernisation''' or ''diets''. The likely explanation is what Tony Segal proposed, the fact people with salmonella and campylobacter infection are far more likely to develop CD.

Clustering cases.

_''Two French families were investigated. In the first a husband, wife, and 4 children had Crohn's disease; in the second *7 of 11 children had the disease*. There was no history of Crohn's disease in antecedent generations and no linkage to HLA haplotypes. ''

''A large family of Moroccan immigrants was investigated. In this family the father developed Crohn's disease (CD) after moving from Morocco to Belgium and successively *4 of his 8 children subsequently developed CD*. There was no previous history of familial CD. ''

''Ten pairs of husband-wife couples are reported with inflammatory bowel disease who were seen in the same geographical area in Nord Pas de Calais region of France and in Liège county (Belgium). In one couple, one spouse had Crohn's disease before marriage and the other partner experienced symptoms afterwards. Eighteen children were born to eight of 10 couples. *Five of them developed Crohn's disease but four belong to the same family.* In all cases the affected children were born to parents who both developed Crohn's disease after they had married and were conceived at a time when parents did not yet have symptoms. It is proposed that this pattern of emergence of inflammatory bowel disease suggests a role for an infectious agent yet to be identified. ''

'' *Five affected fathers preceded 9 affected children; 7 affected mothers preceded 10 affected children.* First borns were affected more frequently. Within sibships there were* 21 instances (36%) when an affected sibling was consecutive in birth order with an affected sibling.* ''_


----------



## Crohn2357

kiny said:


> All the data on treatment supports the (well established by now) theory that inflammation in crohn's disease is directed at pathogens (with a possibly minor role for *fungi*) within intestinal tissue.





Crohn2357 said:


> A few years after my Crohn's diagnosis, I had oral and oropharyngeal candidiasis due to corticosteroid use. It didn't go away with liquid nystatin so I had to use a more systemic and powerful antifungal (fluconazole) to treat that.  I found it interesting to find out that fluconazole was also helping my intestines to a considerable degree.



Some research and links:




> *
> 
> 
> 
> The effects of itraconazole on inflammatory bowel disease activity in patients treated for histoplasmosis
> 
> Click to expand...
> 
> *
> 
> 
> 
> S. Samuel E. V. Loftus  W. J. Sandborn
> First published: 06 October 2010
> 
> Sirs, We read with interest the article by Schneeweiss and colleagues studying the risk of bacterial infections in patients treated with infliximab for the treatment of inflammatory bowel disease (IBD).1 We would like to share with the readers some interesting observations following a retrospective database review of histoplasmosis in IBD patients on immunosuppressive treatment.
> 
> Between 2000 and 2009, six patients with moderate‐to‐severe IBD (five Crohn’s disease and one ulcerative colitis) developed histoplasmosis as a consequence of their immunosuppressive regime and received treatment with itraconazole (an azole antifungal agent) and withdrawal of immunosuppression. Four of the six patients (67%) were in clinical and endoscopic remission at the end of itraconazole therapy (6 months median treatment duration) despite being off their immunosuppression (Table 1). The two patients whose IBD was active at the time of initiation of treatment had complete clinical and endoscopic response after 6 and 9 months of itraconazole treatment respectively (Table 1). Majority of our Crohn’s patients had previously experienced intestinal complications (fistulas and/or strictures), and had required multiple prior surgical resections suggesting an aggressive natural history. Despite this, and in the absence of continued biological and/or immunosuppressive therapy, they were able to withdraw immunosuppression and anti‐TNF‐α therapy during the entire itraconazole treatment course and the time to relapse in two of the Crohn’s patients was at least 10 months post‐itraconazole therapy (Table 1).
> 
> Table 1.             Demographic and clinical characteristics of six patients with inflammatory bowel disease and histoplasmosis treated with both itraconazole and withdrawal of immunosuppressives and/or biologics
> 
> ���
> 
> Age§ (years)Type of IBDMontreal classification of IBDImmuno‐suppressive therapyNo. of infliximab infusionsNumber of previous surgical resectionsDisease activity at initiation of itraconazoleDisease activity at stoppage of itraconazoleTime to relapse (after itraconazole therapy)Itraconazole dosage (mg/day); Rx duration (months)Age at diagnosisLocationBehaviourPatient 172CDA2L1B2IFX+AZA163‡Inactive (clinical and endoscopic)14400; 6Patient 237CDA1L3B3IFX+AZA143Active (clinical)Inactive (clinical and endoscopic)10400; 9Patient 344CDA1L2B1IFX400Active (clinical and endoscopic)Inactive (clinical and endoscopic)3 (off immuno‐suppres‐sives still)200; 6Patient 434CDA1L3B3IFX140‡Active (clinical and endoscopic)0400; 12Patient 521UCE2 (Left sided UC)IFX+6‐MP†0‡*0400; 6Patient 651
> 
> 
> 
> 
> 
> CDA2L3B3IFX+AZA31‡Inactive (clinical and endoscopic)3400; 5
> 
> 
> IFX, Infliximab; AZA, azathioprine; MP, mercaptopurine; CD, Crohn’s disease; UC, ulcerative colitis.
> * This patient’s disease flared 4 months into treatment with itraconazole.
> † The number of doses of infliximab received was unknown.
> ‡ Information not available.
> § Age at the time of histoplasmosis diagnosis.
> 
> Although the above findings were unexpected, azole group of drugs inhibit the expression of both various TNF‐α‐induced cell adhesion molecules and angiogenesis and thereby ameliorate colitis in rat models.2-4 This interesting observation should be explored further in controlled studies to assess the effect of itraconazole in patients with IBD. Clinical trials are already underway on the topical use of clotrimazole (another azole antifungal) in pouchitis (http://clinicaltrials.gov/ct2/show/NCT00061282).
Click to expand...

The effects of itraconazole on inflammatory bowel disease activity in patients treated for histoplasmosis





> Malassezia yeasts found in oily skin and scalp follicles are linked to skin conditions, including dandruff. These microscopic fungi also end up in the gut, but it's not known how or what they do there.
> "We were surprised to find that Malassezia restrica was more common on intestinal tissue surfaces in Crohn's disease patients than in healthy people," says co-author David Underhill, Janis and William Wetsman Family Chair in Inflammatory Bowel Disease at Cedars-Sinai in Los Angeles. "Further, the presence of Malassezia was linked to a common variation in a gene known to be important for immunity to fungi -- a genetic signature more common in patients with Crohn's disease than the healthy population."
> 
> ...
> 
> Changes in intestinal fungi such as M. restricta -- and host responses to these fungi -- may be a factor in exacerbating symptoms that contribute to disease in a subset of patients with Crohn's disease, says co-author Jose Limon, a Cedars-Sinai research team member.
> 
> The researchers had originally found that fungi are present in the gut microbiome of mice and that immunity against these fungi helps control gut-based inflammation. In mice, the presence of M. restricta worsened colitis, a type of intestinal inflammatory disease.
> 
> Looking at the mucosa-based intestinal fungi of healthy people and patients with Crohn's disease, a form of IBD, the researchers found several mucosa-associated fungi that were significantly more abundant in Crohn's patients. In particular, M. restricta was elevated in Crohn's patients carrying a genetic variation known as the IBD CARD9 risk allele.











						A fungus usually found on skin might play a role in Crohn's disease
					

A fungus commonly found in human hair follicles also resides in the gut, where it may worsen intestinal disorders such as inflammatory bowel disease (IBD) in patients with a certain genetic makeup, researchers report.



					www.sciencedaily.com
				







> The study was published in the journal _Cell Host & Microbe_, which featured it on the cover of its March issue along with an alcohol-ink painting of fungi created by Andrea Wolf, PhD, a research scientist in the Department of Biomedical Sciences at Cedars-Sinai. Wolf was a co-author of the study, and David Underhill, PhD, the Janis and William Wetsman Family Chair in Inflammatory Bowel Disease at Cedars-Sinai, was the corresponding author.
> 
> Under the headline, "Dandruff Could Be Key to Crohn's disease," the _Daily Mail_ reported: "A fungus linked to dandruff may be a crucial factor driving the chronic stomach condition Crohn's disease, according to a new study. Malassezia yeasts found in oily skin and scalp follicles are linked to skin conditions, including dandruff.
> 
> "Researchers discovered that the fungus commonly found in human hair follicles also resides in the gut. In most of us, it is harmless, but in some people with a certain genetic make-up it appears to worsen their intestinal disorders such as inflammatory bowel disease (IBD)."
> 
> The article by Mia de Graaf, DailyMail.com health editor, quoted Underhill as saying, "We were surprised to find that Malassezia restrica was more common on intestinal tissue surfaces in Crohn's disease patients than in healthy people." De Graaf stated the next steps involve exploring whether eradicating the yeast from the intestinal microbiome clears the patients' symptoms.











						Daily Mail: Dandruff Could Be Key to Crohn's Disease
					

London-based DailyMail.com, which claims more than 12 million daily unique visitors, and ScienceDaily, a widely read online source for research news, recently wrote about a Cedars-Sinai study that linked a common skin fungus to the intestinal disorder Crohn's Disease. The study was published in...




					www.cedars-sinai.org
				





*



			Dandruff could be a crucial factor in Crohn's disease: Scientists discover the hair fungus also resides in the GUT and causes inflammatory reactions in people with digestive diseases
		
Click to expand...

*


> Researchers discovered dandruff-linked fungus resides in many people's guts, but doesn't cause a reaction in most (left). Some people, however, suffer inflammation from it (right)
> 
> In mice, the presence of M. restricta worsened colitis, a type of intestinal inflammatory disease.
> 
> Looking at the intestinal fungi of healthy people and patients with Crohn's disease, a form of IBD, the researchers found several mucosa-associated fungi that were 'significantly more abundant' in Crohn's patients.
> 
> The findings, published in the journal Cell Host and Microbe, showed that M. restricta in particular was elevated in Crohn's patients carrying a genetic variation known as the IBD CARD9 risk allele.
> 
> The researchers said that the genetic variant enhances the ability of human immune cells to pump out inflammatory cytokines in response to M. restricta.
> 
> 'We found it in some healthy people, and in mice it does not seem to cause disease in the gut by itself.
> 
> 'However, if there is some intestinal inflammation, Malassezia seems to make it worse.'











						Dandruff fungus found in the gut could be driving Crohn's disease
					

LA researchers discovered that the fungus commonly found in human hair follicles resides in the gut. In most, it is harmless, but in some people with a certain genetic make-up, it causes a reaction.




					www.dailymail.co.uk
				












						You’re Covered in Fungi. How Does That Affect Your Health? (Published 2019)
					

Following extensive study of the body’s bacterial occupants, researchers are turning to how our fungal residents may contribute to inflammatory bowel diseases and other maladies.




					www.nytimes.com
				





*



			Malassezia
		
Click to expand...





			Is Associated with Crohn’s Disease and Exacerbates Colitis in Mouse Models
		
Click to expand...

*


> Jose J. Limon Jie Tang Dalin Li Stephan R. Targan Dermot P.B. McGovern David M. Underhill
> Published:March 05, 2019
> 
> *Highlights   *
> 
> 
> 
> •
> _M. restricta_ is associated with the colonic mucosa in Crohn’s disease (CD) patients
> •
> _M. restricta_ exacerbates colitis in wild-type and gnotobiotic mice
> •
> _M. restricta_ is found in CD patients with a disease-linked polymorphism in                _CARD9_
> •
> _Malassezia_-exacerbated colitis in mice requires signaling via CARD9
> 
> 
> * Summary   *
> 
> Inflammatory bowel disease (IBD) is characterized by alterations in the intestinal         microbiota and altered immune responses to gut microbiota. Evidence is accumulating         that IBD is influenced by not only commensal bacteria but also commensal fungi. We         characterized fungi directly associated with the intestinal mucosa in healthy people         and Crohn’s disease patients and identified fungi specifically abundant in patients.         One of these, the common skin resident fungus          _Malassezia restricta_, is also linked to the presence of an IBD-associated polymorphism in the gene for         CARD9, a signaling adaptor important for anti-fungal defense.          _M. restricta_ elicits innate inflammatory responses largely through CARD9 and is recognized by         Crohn’s disease patient anti-fungal antibodies. This yeast elicits strong inflammatory         cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9         and exacerbates colitis via CARD9 in mouse models of disease. Collectively, these         results suggest that targeting specific commensal fungi may be a therapeutic strategy         for IBD.





			https://www.cell.com/cell-host-microbe/pdfExtended/S1931-3128(19)30045-9
		




*



			Malassezia
		
Click to expand...





			Primer
		
Click to expand...

*


> Despite being the most prevalent fungal genera in the human microbiome, _Malassezia_ are little known outside the field of dermatology. _Malassezia_ were first described in 1889, yet it took nearly a century to firmly establish their role in dandruff and seborrheic dermatitis (47). This delay can be attributed to _Malassezia_'s difficulty growing in culture (they require just the right concentration of certain lipids) (48), their extremely high prevalence on the skin (~100% throughout life) (49), and their resistance to fungicides (commonly used antifungal drugs do not completely eradicate _Malassezia_ and their populations rebound once such treatments are discontinued) (50). About 50% of adults have first-hand experience with _Malassezia_-associated symptoms: they use antifungal shampoo to keep their dandruff under control, and whenever they switch back to normal shampoo, _Malassezia_ and dandruff return (47).
> 
> 
> Until very recently, it was believed that _Malassezia_ were restricted to the skin, except in rare immunocompromised or lipid-rich parenteral nutrition cases (34, 51). Due to improved microbe detection techniques, many groups now report finding _Malassezia_ within the body of both healthy adults and immunocompetent patients with various ailments (14–16, 23–25, 33, 52–61). _Malassezia_'s potential role in diseases of internal organs is just coming to light (19, 54, 62–64). It is important to note that _Malassezia_'s presence is not synonymous with disease: in the vast majority of individuals, _Malassezia_ colonize the body without causing symptoms. This means detecting _Malassezia_ in a given organ is far from sufficient to prove their involvement in diseases of that organ. Additional lines of evidence are necessary to implicate them, for example the efficacy of antifungal drugs in treating the disease, immunological evidence (such as antibodies against _Malassezia_) and genetic evidence (such as genes affecting _Malassezia_'s lipid supply or the immune response against fungi).
> 
> 
> Since _Malassezia_ are not well-known in the field of neurodegenerative disorders, this section is included as a primer on _Malassezia_'s suspected role in SD, acquired immune deficiency syndrome (AIDS), Crohn's disease (CD), spondyloarthritides (SpA), and MS. Each of these conditions is informative for PD.
> 
> 
> *Malassezia Are a Necessary Factor in Seborrheic Dermatitis*
> 
> _Malassezia_'s role in SD is now generally accepted (29, 42, 43, 50). Given the right conditions, _Malassezia_ over proliferate on the skin (65), resulting in SD—though specific mechanisms are still open to debate (29, 42, 43, 50). Most SD cases respond well to topical fungicides which reduce _Malassezia_ populations on affected patches of skin to levels tolerated by patients (29, 42, 43).
> 
> 
> SD occurs mainly in lipid-rich skin regions, especially the face, trunk and scalp (29, 42, 43). _Malassezia_ are lipid-dependent fungi: they lack key lipid metabolism genes (including fatty acid synthase, stearoyl-CoA desaturase, and enoyl-CoA isomerase), and thus depend on host lipids for survival (48). Skin lipid production varies during our lifetime, with a peak in the first year of life, followed by a second peak in adolescence (66–68): production is depressed during the rest of childhood, which corresponds to the period of lowest SD risk (69). In adults, the risk of SD increases substantially with age (69). This is unexpected because skin lipid levels slowly decline with age (67), so _Malassezia_ should have increasing difficulty securing lipids in the elderly.
> 
> 
> Azathioprine and cyclosporin, two immunosuppresive drugs which target T cells, substantially increase SD risk (39). Similarly, CD4+ T cell counts are inversely associated with SD risk and severity in AIDS patients (29). Peripheral blood mononuclear cells (PBMC) from SD patients produce less IL-2 and interferon gamma (IFNγ) when exposed to _Malassezia_ antigens as compared to age-matched controls (70), suggesting a weak type 1 helper T cell (Th1) response against _Malassezia_ is a characteristic of SD. In healthy individuals, thymic involution reduces naive T cell production, which results in a slow decline in T cell efficacy over our lifespan (71). This can be observed in part by measuring T cell receptor (TCR) diversity (71, 72). T cell immunosenescence can explain why SD risk increases with age, despite declining skin lipids. SD seems to be mainly due to the combination of ample lipids (29, 42, 43) and weak T cell-mediated control (70, 73, 74) of _Malassezia_, which together allow this fungus to over proliferate on the skin.
> 
> 
> Seborrheic dermatitis (SD) is a well-known symptom associated with PD: PD patients have ~50% SD prevalence, while controls only have ~3% prevalence (44, 45). Though these are the most frequently cited figures, they are based on old studies whose accuracy has drawn criticism (75). We only found one recent study which measured the association between PD and SD (46). It reported that SD increases the risk of a _subsequent_ PD diagnosis (OR = 1.69, 95% CI 1.36, 2.1; _p_ < 0.001). This association remained significant when the SD diagnosis was made at least 5 years before the PD diagnosis, suggesting PD-associated treatments or behavior cannot explain it (46). This study reported an SD diagnosis rate of 4% prior to a PD diagnosis, as compared to 2.5% for age matched controls (46). This low rate of association indicates factors predisposing to SD and PD are mostly different. Of note, this report (46) is only available as an abstract and has not been published as a peer-reviewed article. Specific mechanisms underlying the association between SD and PD are not known (75). Nonetheless, this association suggests that mechanisms allowing _Malassezia_ to over proliferate and cause SD (ample lipids and T cell immunosenescence) should be thoroughly investigated as possible mechanisms underlying PD as well.
> 
> 
> *Malassezia Are a Necessary Factor in Crohn's Disease and Spondyloarthritides*
> 
> Spondyloarthritides (SpA) are a group chronic immune-mediated diseases mainly driven by alpha beta T cells recognizing intracellular peptides through HLA-B*27 presentation (62, 83). Affected organs include the spine, joints, skin, eyes, gut, and prostate (62). Historically, isolated inflammation of the eyes, gut, and skin—respectively acute anterior uveitis, inflammatory bowel disease (Crohn's disease [CD] and ulcerative colitis) and psoriasis—were considered separate diseases unrelated to SpA. However, SpA, acute anterior uveitis, inflammatory bowel disease and psoriasis run together in families (84), and share many polymorphisms in genes controlling T cell activation (85), strongly suggesting that they are the same immunological pathology (84). In particular, the fact that HLA-B*27 increases the risk of each disease strongly suggests the same antigens are being targeted (62). Varied lines of evidence support the presence of an elusive necessary intracellular fungal infection in each affected organ, which is efficiently detected by HLA-B*27 and CARD9 (62). CARD9 is an essential signaling protein for fungal immunity: homozygous loss-of-function CARD9 mutations cause severe mycoses (37). CARD9 polymorphisms are associated with inflammatory bowel disease and SpA (62, 64). Oral antifungal drugs are effective in psoriasis (86–89), psoriatic arthritis (89, 90), and likely in Crohn's disease as well (91).
> 
> 
> In inflammatory bowel disease and psoriasis, strong evidence points to _Malassezia_ as being the causative genus (62). Enteric _Malassezia_ is strongly associated with CD (54, 64) and ulcerative colitis (63). Immune recognition of _Malassezia_ occurs specifically through CARD9 in the gut, and knocking out CARD9 in mice abrogates colitis symptoms following exposure to _Malassezia_ (64). In CD, CARD9 risk alleles increase PBMC secretion of tumor necrosis factor alpha (TNF-α) following _Malassezia_ antigen challenges (64). Antibodies against _Malassezia_ are associated with CD (64) and psoriasis (92, 93). Applying lysed _Malassezia_ to the skin provokes psoriasis lesions in susceptible individuals (94). The only known fungus which is commonly present in the gut (61) and on the skin (49), and thus can explain why Crohn's patients develop psoriasis during vedolizumab treatment (95), is _Malassezia_. Finally, PBMCs in psoriasis react strongly to _Malassezia_ antigens (96). These data suggest that a dysregulated immune response against _Malassezia_ in the gut is causative in CD (64).
> 
> 
> CD and SpA provide three key insights for PD. First, they demonstrate that _Malassezia_ can cause diseases of internal organs in genetically predisposed individuals. Second, the increased risk of psoriasis in overweight individuals (97–100), and the increased risk of CD in carriers of certain _LRRK2_ alleles (101, 102) are most simply explained by enhanced lipid availability (103) which promotes _Malassezia's_ growth by supplying it with lipids [the same _LRRK2_ alleles increase PD risk (101, 102)]. Third, intracellular melanin reminiscent of neuromelanin (104) is associated with inflammation of the prostate (104–106). Though indigenous production of melanin by human cells has been proposed as an explanation (104), a second possible origin would be from _Malassezia_ which have colonized the prostate and CNS. _Malassezia_ produce DOPA-melanin from L-DOPA (107). Both prostate epithelial cells and dopamine neurons contain intracellular lipid droplets which can fulfill _Malassezia_'s requirement for lipids.











						Malassezia and Parkinson's Disease
					

Parkinson's disease (PD) is a common debilitating neurodegenerative disease caused by a loss of dopamine neurons in the substantia nigra within the central nervous system (CNS). The process leading to this neuronal loss is poorly understood. Seborrheic dermatitis (SD) is a common benign...




					www.frontiersin.org
				







> *Our goal is to send Crohn’s, prostate cancer, and hopefully many other diseases the way of dandruff: cured by antifungals. Please watch the videos, share your insights and subscribe.*











						Home | The Malassezia Project
					

The Malassezia Project's goal is to send Crohn’s disease, prostate cancer, and hopefully many other diseases the way of dandruff: cured by antifungals.




					www.malassezia.org


----------



## Gabriel89

It sounds a bit confusing to me, reading their comment as:

"What’s more, the CARD9 protein comes in different variants (alleles) which are passed down from parents to their children. One of these variants (CARD9 rs4077515:A) greatly increases the risk of Crohn’s disease and ulcerative colitis by increasing TNF-α production when _Malassezia_ is detected by the Mincle hook, resulting in immune hypersensitivity to _Malassezia_. "

For me the conclusion is that Anti TNF-α should be the main treatment, and should work for all patients, since the inflammation is in fact because of a hypersensitivity. Just if i follow their logic.
And if one genetic allele rs4077515:A (according to promethease its like 36% of the general population have that) is responsible for this disease then GWAS studies would have already pointed this out long time ago. 

So this concept looks a bit blurry to me, nevertheless i look forward to the results of their trials.


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## Scipio

Gabriel89 said:


> And if one genetic allele rs4077515:A (according to promethease its like 36% of the general population have that) is responsible for this disease then GWAS studies would have already pointed this out long time ago.


Studies have not pointed this out because the notion that one CARD9 allele is alone responsible for Crohn's disease is incorrect.  The majority of Crohn's patients do not have the rs4077515:A allele, including me.  (I have 23&Me and my Promethease report.)

So there is clearly something more going on to trigger Crohn's than one nasty gene.  What that allele does more than cause Crohn's is to make the disease more aggressive.  That gene is much more prognostic than it is diagnostic.  CD patients with that allele are more likely to suffer severe Crohn's, and those without it are more likely to have milder disease.  

One thing that reading the Crohn's research has taught me is that Crohn's is a multi-factorial disease.  It's a mistake to focus trying to find *the* one big cause for Crohn's.  The cause of Crohn's is not genes, although that may play an important role in some or many cases.  The cause of Crohn's is not MAP, although that may play an important role in some or many cases.  The cause of Crohn's is not a primary defect in the immune system, although that may play an important role in some or many cases. The cause of Crohn's is not the western diet, although that may play an important role in some or many cases.  The cause of Crohn's is not emulsifiers or other food additives, although they may play an important role in some or many cases.  And so on....

And what this multiplicity of causes and triggers implies is that a multiplicity of treatments may be needed to cure or even to successfully manage Crohn's disease.  And indeed that is just what we see.  Just skimming the posts by members on this site shows some degree of success (and a lot of failure) for many different approaches to therapy and diet.  But none of them works for everybody.

Whether all this confusion will ever get sorted out into a single unified theory Crohn's disease with a resultant cure that works for everybody looks pretty doubtful at this point.  Those focused on finding the one big answer to Crohn's may well be chasing something that doesn't exist.


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## Crohn2357

kiny, what do you think about this? Could you share your thoughts?



> The primary pathology in most case of CD appears to affect macrophages recruited from the blood as monocytes301. Advances in gene editing with the CRISPR-Cas390,391 technology make the corrective treatment of CD a real possibility in the relatively near future. Once a primary causal mutation has been identified, and validated in animal models, bone marrow could be extracted, edited and reinfused into a conditioned patient in much the same way as is being applied to gene therapy for primary immunodeficiencies392.


Segal AW. Making sense of the cause of Crohn’s – a new look at an old disease [version 2; peer review: 2 approved]. _F1000Research_ 2016, 5:2510
(https://doi.org/10.12688/f1000research.9699.2)

These are the last three articles Segal cited in that quote:

390. Wright AV, Nuñez JK, Doudna JA: Biology and Applications of CRISPR Systems: Harnessing Nature’s Toolbox for Genome Engineering. _Cell._ 2016; 164(1–2): 29–44. PubMed Abstract | Publisher Full Text
391. Shui B, Hernandez Matias L, Guo Y, _et al._: The Rise of CRISPR/Cas for Genome Editing in Stem Cells. _Stem Cells Int._ 2016; 2016: 8140168. PubMed Abstract | Publisher Full Text | Free Full Text
392.  Ghosh S, Thrasher AJ, Gaspar HB: Gene therapy for monogenic disorders of the bone marrow. _Br J Haematol. 2015; 171(2): 155–170. PubMed Abstract | Publisher Full Text_
Edit: I think what’s important in Segal’s statement is the emphasis on the “identification” of a “primary causal mutation” in the future. Based on the current evidence, the possibility of that do not seem high to me.


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## InstantCoffee

The fungal aspect is interesting, I've had recurring fungal issues for most of my crohn's-having life, especially my scalp, but I've had it in the groin area, and in my nose. They tried to treat my nose with topicals + fluconizale but it didn't work. I actually caved and tried tea tree oil diluted in coconut oil and it cleared it in like a week, and I am generally the, "Essential oils are a load of crap" type.

The scalp is especially stubborn and I basically have to avoid any kind of ingredients that could potentially trigger it or I have a flare for a month unless until I use Nizorale daily.

Kind of like my crohn's.

I disagree with the notion that Crohn's being linked to multiple causes means that it is multiple causes requiring multiple treatments. I know Occam's razor is just a philosophic principle but it often holds true. It's more likely that Crohn's is a more specific cause perpetuated by a perfect storm of circumstances that allow it to become worse and propagate. That doesn't mean a singular treatment can't work.


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## Crohn2357

Pangolin said:


> Anti-TNF agents linked to increased risk of IBD. https://www.medscape.com/viewarticle/915613



_“The question then arises as to how anti-TNF drugs can be effective against a condition in which the secretion of TNF and other pro-inflammatory cytokines is impaired? The answer is in the timing of the different components of the immune system. The call to arms of the innate immune system is a very early and explosive secretion of pro-inflammatory mediators, including TNF. If the clearance of faecal material from the tissues is incomplete, it becomes walled off by macrophages, endotoxin diffuses into the circulation, and cells of the adaptive immune system are recruited257. They secrete a wide array of mediators over the next weeks including TNF which acts as an amplifier of the response258. It is of interest that in a recent study of high-resolution gene expression profiling using RNA sequencing of inflamed biopsies from patients with CD, UC and controls, levels of pro-inflammatory cytokines like TNF, IL-1β, IL-6 and IL-23 were all elevated to a lesser extent in CD than in UC259. *The very early secretion of TNF and other mediators is required to prevent the development of the Crohn’s lesions whereas at a later stage it is the TNF and associated mediators that produce the symptoms, which in some cases respond to anti-TNF treatment. This explains why anti-TNF therapeutics can both cause260 and alleviate symptoms of the disease**261*.”_

Segal AW. Making sense of the cause of Crohn’s – a new look at an old disease [version 2; peer review: 2 approved]. _F1000Research_ 2016, 5:2510 (https://doi.org/10.12688/f1000research.9699.2)


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## Crohn2357

Crohn2357 said:


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











						Horror Stories Underscore FMT Risks
					

Two E. coli infections with one fatal, transmitted to trial patients by same donor




					www.medpagetoday.com


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## kiny

E coli have become incredibly resistant bacteria. Those won't be the last deaths from fecal transplants.


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## ce1210

This research doesn’t surprise me at all. Biologics/immunosuppressants all made me 1000x worse, and my GI doctor basically blamed it on me saying I was probably smoking cigarettes, weed, or drinking alcohol and that was what caused them not to work. I was in fact doing none of those things and had gone on an almost exclusively liquid diet. Dropped all the bullshit they were giving me kept up with the liquid diet, then started ingesting very large quantities of thc/cbd oil (1000-1500mg a day of each) and was symptom free with a nice clean colonoscopy 30 days later. Started testosterone injections after finding my levels were incredibly low as well. Those things in combination with cannabis oil and a very clean low fiber diet have not only held me in remission, but have allowed me to get my weight/strength back and I feel great most of the time and have more energy than ever before. Prednisone, sulfasalizine, 6-mp, humira, etc all failed miserably for me and made the disease worse. My colonoscopies as of late have shown little to no inflammation just a lil scar tissue from my 2 big flares that has lessened significantly.


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## ce1210

The role of macrophages in THC-induced alteration of the cytokine network - PubMed
					

Delta-9-tetrahydrocannabinol (THC) has been shown to decrease Th1 responses (cell mediated immunity) while increasing Th2 responses (humoral immunity), both in vitro and in vivo. The addition of THC to murine splenocytes stimulated for 72 hrs with pokeweed mitogen (PWM) increased the detection...




					www.ncbi.nlm.nih.gov


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## westernbuddy

How should infliximab have been intended to be used for crohns.

Currently it's 3 x induction infusions then 8 weekly maintenance.

What was the original so it wasn't used in a chronic way.

First 3 infusions then quit, or 12 months infusions then quit, from what I can see from nhs looks like it used to be 12 months then quit.

But many develop antibodies within 3-6 months

Now they add azathioprine to infliximab.

At what point does infliximab non combined induce musocal healing, 4 months maybe from what I can tell.?

Also what are peoples thoughts on surgery, you have surgery cut the disease out, your In remission fully recovered, then it makes and appearance again always and always In the exact same spot. Usually around 2 years after surgery, then it's back to diet then meds then the circle starts again.

What is the explanation for cutting the disease out then the thing comes right back?


Also infliximab isn't the only biologic about now, what is the favourite one now ?


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## Guerrero

Regarding surgery, you right there may be recurrence, that’s why surgery is the last option (in case of more osbtruction for example…). Also recurrence is not 100% guaranteed.

Not sure there is a favourite biologic. Will depend on your case i guess. Hopefully in the close future dna or other evidences may suggest to doctors what is the best option for any single patient. We not there yet.


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## westernbuddy

Sure when I'm reading this whole thread however and lots of the science and research all points to bacteria.

My question I guess was you end up with surgery they cut the damaged bowl out and a bit extra each side, then crohns always makes a come back, alway makes an appearance again in that very same point, usually 2 years after surgery.

What is the science behind this, if it is bacteria why are they always going back to the exact same location even after cut out?


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## Guerrero

Yeah it’s still a kind of mistery I think, why crohns is active only in few spots and not in the entire bowel tract. So when you cut out one on these spots, it’s very likely the disease will come black near there if it does.


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