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

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.



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!
 
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.


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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
 
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@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).
 
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.
 
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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.
 
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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?
 
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.
 
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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.
 
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.
 
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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.
 

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.''
 
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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.
 
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! :)
 
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
[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

-----

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

 
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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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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.

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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.
 
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)?
 
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.


''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).''
 
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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?
 
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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.
 
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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.
 
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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.
 
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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.

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.
 
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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].


 
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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.
 
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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.
 
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:

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.
 
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''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.
 
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.
 
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kiny, could you comment on this article?

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


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.


Another one:

 
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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.
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).


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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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rapamycin for Crohn’s
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.


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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.



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.


 
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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.
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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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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my little penguin

Moderator
Staff member
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.


Of note remember the genes for juvenile spondyloarthritis arthritis overlap a lot with genes for crohns
 
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.
 
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
 
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?
 
"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 (58) 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:

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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 (3033). 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.


 
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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.”

 
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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...
 
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.
 
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.
 
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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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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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.
 
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
 
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.
 
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.
 
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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

 
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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. :)
 
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 ''commensal, 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.
.
 
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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.
 
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.
 
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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
 
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.
 
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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.


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.
 
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.
 
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.
 

More information:



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).
 
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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.
 
(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.)
 
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.
 
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.

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.


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

Some of the threads:







 
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.
 
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.
 
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:
  1. 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.
  2. 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.
  1. Cucino C, Sonnenberg A: Occupational mortality from Inflammatory Bowel Disease in the United Stated 1991-1996. Am J Gastroenterol 2001; 96:1101-5
  2. 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
  3. Hermon-Taylor J. Mycobacterium avium subspecies paratuberculosis, Crohn’s Disease and the Doomsday Scenario. Gut Pathogens 2009; 1:15
 
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.
 
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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."
 
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.
 
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.
 
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.

 
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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.
 
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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.
 
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.
 
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.

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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 relative 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]
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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.
 
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.
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.
 
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.
 
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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.


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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.
 
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.
 
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.
 
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.
 
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