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Molecular and Phenotypic Characterization of Escherichia coli Associated with Granulomatous Colitis of Boxer Dogs

When they treat the dogs with fluoroquinolones a lot see long lasting improvement. Antibiotics that have shown to be able to induce short-term remission in crohn's disease have always been macrophage penetrating antibiotics that are effective against intracellular and pathogenic E coli, such as cipro. Images of wall thickening of the ileum of those dogs and inflamed peyer's patches look very similar to humans with crohn's disease. Phages and FimH blockers should be just as effective in crohn's disease patients infected with AIEC.
 
The inflammatory cascade in those dogs is just like it is in humans. AIEC invade through peyer's patches (M Cells) in the ileum of the dog, they replicate inside the macrophages in deeper tissue, macrophages release signaling molecules which causes the adaptive inflammatory cascade, you get an intestinal wall that is inflamed, thickened, and looks exactly like an inflamed ileum of a crohn's disease patient.
 
If cipro is effective why is it not curative?

AIEC simply gains resistance to the antibiotic.

Cipro is able to get people into remission, but they don't stay in remission. When cipro is tried again, it generally fails due to the development of resistance due to prior exposure of cipro.

It's the same reason why urinary tract infections involving E Coli respond less and less to antibiotics, due to overuse of antibiotics, they simply developed resistance to the antibiotic.

That's why phage therapy is in development for both crohn's disease and urinary tract infections, to overcome E Coli resistance.
 
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Now, we don't know why people with ieal crohn's disease harbour AIEC. We know they do, because you can isolate AIEC from biopsies, but we don't know how it got there.

One explanation is zoonosis, we got it from those dogs, cats, that harboured it. So one has to ask themselves, if we should actually be giving those animals antibiotics or if we should simply kill those animals instead. If you treat those animals who harbour AIEC with antibiotics, you create extremely resistant AIEC species, and when they jump to humans, you now have humans with crohn's disease that you can no longer treat with antibiotics.

It's a discussion that isn't that interesting to us though, we have crohn's disease, it doesn't matter how we got it, just how we can treat and hopefully cure it.
 
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If the above is all true, another question that arises is if crohn's disease is infectious. You aren't born with these invasive bacteria, you get them from somewhere.

This was a question that would have been laughed at by GI 20 years ago who assumed crohn's disease was an autoimmune disease. But we now know that is not the case, there is no self-antigen, instead the immune system is responding to bacteria (and possibly fungi) in the intestine. In fact every rat model you try to mimmick crohn's disease that doesn't involve a chemcial to inflame the intestine, requires the presence of bacteria. You can't induce inflammation without those bacteria.

We can now even predict, with high accuracy, who will develop crohn's disease later in life by simply looking at the presence of specific E Coli and the presence of antibodies against outer membrane E Coli proteins.

If the disease is infectious, either between humans or through zoonosis, you would expect to see clustering within families or between people who live in close proximity. We have clustering in crohn's disease, Van Kruiningen has shown this in multiple studies I linked. Just type in 'Clustering Van Kruiningen' to find them online. They are very interesting studies.
 
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People will often say 'it's genetic, my dad, uncle, had it'.

There is an undeniable genetic predisposition, but you aren't born with this disease, there are tons of people who also have these genetic anomalies who do not have crohn's disease.

People live for years without this disease, and within days, they suddenly develop the disease, high fevers, night sweats and intestinal inflammation.

There was a (rather acute) event in life that brought forth this disease.

There has to have been some kind of infection. The infection has to be common enough to explain the sheer prevalence of the disease. Foodborne infections that cause substantial damage to the intestinal lining enabling AIEC to enter tissue are a reasonable explanation.
 
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Mine started as a sudden as it can gets. As a child i had fever and took antibiotics (Augmentin).

For myself i cant judge if it was the infection or the antibiotics what triggered it but either of the two.
 
Onset is generally very acute, the fact a substantial number of patients experienced night sweats, fevers, throwing up, points to an acute intestinal infection.
 
AIEC simply gains resistance to the antibiotic.

Cipro is able to get people into remission, but they don't stay in remission. When cipro is tried again, it generally fails due to the development of resistance due to prior exposure of cipro.

It's the same reason why urinary tract infections involving E Coli respond less and less to antibiotics, due to overuse of antibiotics, they simply developed resistance to the antibiotic.

That's why phage therapy is in development for both crohn's disease and urinary tract infections, to overcome E Coli resistance.

First, I love your posts. Very interesting from the academic point of view. If its invasive AIEC as you said, and CIPRO "cures/gets into remission" then why is there a recurrence of Crohns? As with any other invasive, you take the anitbiotic, its gone, you move on with your life. But this comes back.

Is it the odd combination of how AIEC behaves. Does it go dormant such that when you stop CIPRO it comes right back because it was never fully irradiated? This kind of lines up with some other treatment theories requiring ultra long term dosing because the crohns is thought to have an on off life cycle.

As far as the fungus, I read one thought about crohns being caused by malassezia which I thought was a good theory to the point if things go bad for me I was considering asking to be prescribed oral intraconzanole!

I really believe in the invasive species idea. I am pretty sure my crohns developed when I was prescribed an antibiotic for walking pneumonia at the age of 35. Before that happened I could literally eat a battery and have normal stools. I could set my watch by my bowel movements for 35 years.
 
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Does it go dormant such that when you stop CIPRO it comes right back because it was never fully irradiated?
It does. It simply maintains a presence and gains resistance. Subsequent antibiotic use will just result in a more and more resistant species. You also shed these bacteria in stool, the current patients in trials don't have to go through a colonosopy every time, they simply check for the presenc of the bacteria in stool.

I can answer some questions that arise.

Why isn't every crohn's disease patient checked for AIEC?


There's no standardized test that is easy to do. There's no effective treatment yet so why test. I think people should be tested, but ok, the tests will come.

Does everyone with crohn's disease harbour AIEC?

Likely not. AIEC can be isolated in the majority of people with ileal crohn's disease. Far less so in people with colonic disease.

Why the ileum and less the colon?

An interesting difference between the ileum and colon is the presence of peyer's patches in the ileum, the colon doesn't feature peyer's patches. AIEC interacts with these peyer's patches in the ileum with fimbriae. (that's where the idea of FimH blockers comes from that are in development for crohn's disease).

Where does AIEC live?

AIEC adheres to the intestinal wall and is able to colonize macrophages in deeper tissue. AIEC, like most bacteria, live in biofilms and are able to adhere to the intestinal wall. AIEC that reside in deeper tissue are confronted with lamina propria macrophages, they are able to invade those macrophages and they seem to thrive in an inflammatory environment. Macrophages are not competent enough to eradicate them and the result is inflammation.

Why would cipro cause short term remisison in patients and not other antibiotics?

If the inflammation is due to the presence of AIEC, antibiotics would need to be effective against E coli species and be able to penetrate a macrophage. Cipro is able to do this, few other antibiotics can.

Why doesn't cipro cure crohn's disease then?

AIEC is highly resistant. The depletion of the microbiome likely gives AIEC a fitness advantage later on. The antibiotics we have now are neither effective nor specific enough.

So how can we kill AIEC?

Trials are underway to use phage therapy for crohn's disease. Lysis of AIEC living in biofilms shouldn't be an issue. FimH blockers are in development too.
 
some more questions that would arise

Do people who don't have crohn's disease harbour AIEC?

Most do not. The few that do tend to harbour far less pathogenic types.

Are people who harbour them more likely to develop ileal crohn's disease?

Yes, we are able to predict with increasing accuracy who will develop crohn's disease later on, by looking at the presence of pathogenic forms of E Coli.

If we eradicate AIEC completely, is the patient cured?

This is a question I asked myself, and I think it depends on your definition of cure. If we remove the main offending pathogen and inflammation subsides, I think most patients would consider that a cure. That doesn't mean people with crohn's disease aren't vulnerable to intestinal colonization of pathogens in the future, that doesn't mean one can revert genetic anomalies, but I think everyone would agree that if the inflammation subsides, and your life starts to look like the era pre-crohn's, that would be a cure in practice.

If phage therapy works, we simply give people who are recolonized with AIEC the phage therapy again. Unlike antibiotics, bacteria seem unable to gain resistance to phages.
 
So one could guess that long term (2 years) treatment with CIPRO could possibly work assuming they never used it before. OF course re population could occur again but I think one could argue that the new occurrence could just be treated with CIPRO again assuming it was completely eradicated during the first treatment.
 
Well, Cipro is rarely given long term because of the serious side effects it can cause if you give it long term. It's generally 2 or 3 weeks maximum.

Giving antibiotics long term can also end up damaging the microbiome which would give pathogenic bacteria, including AIEC, a fitness advantage. Bacteria in the intestine are in a constant battle with their host and between themselves to attain enough nutrients for their survival. You don't want to disturb that ecosystem.

Cipro is fascinating to me, but not because it is an effective treatment, it's not. Cipro has an incredibly good track record of inducing short term remission in crohn's disease patients, but the remission does not last in patients.

Cipro is fascinating because it is able to induce short term remission in crohn's disease patients where other antibiotics fail. It shows the inflammation in crohn's disease is directed at enterobacteriaceae (very likely E Coli in most cases), and likely bacteria that have entered tissue and were taken up by macrophages.
 
There's no reason to suggest anyone in 2020, in a developed country with access to anti-inflammatories should take cipro, or any antibiotics, to treat crohn's disease, unless one has run out of options.

When anti-inflammatories fail, yes, cipro should definitely be used, but it should not be a first line therapy. Cipro can save patients who are non-responsive to anti-inflammatories or EN. Cipro is highly effective in inducing remission, you just can not give it long term because you will create resistance and you risk serious side effects in patients. There's no point in inducing short term remission just to create resistant bacteria if anti-inflammatories work.

There will be ways to treat AIEC infection, it just won't be in the form of antibiotics, it will be in the form of phages, FimH blockers, anti-adhesion molecules, etc.
 
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We have a good idea that in Crohn’s the immune system is responding to bacteria with inflammation, perhaps especially AIEC. However, AIEC is not necessarily the cause per se if it doesn't normally have this effect on most people. My guess is that the bacterial infiltration that results in Crohn's inflammation is enabled by damage to the intestinal tissues, and AIEC is particularly good at growing in damaged regions. One can get rid of the AIEC or other bacteria that may be causing inflammation, but the problem will just come right back if you don't get healing of the tissue damage that allowed the bacterial colonization in the first place.

Implication: wound healing should be a central focus of Crohn’s treatment
 
I think the most interesting study that helps us understand the disease is Rutgeerts his study I have linked before.

If you bring a fecal stream of a crohn's disease patient into contact with a previously unaffected part of the intestine, you get inflammation.

If you remove the fecal stream, healing occurs.

If you use an ultrafiltrate to filter out the bacteria from that fecal stream, you get no inflammation whatsoever.
 
Kiny your statement seems to say that you don't think its about healing more about eliminating bacteria. People have been totally healed by using EN or a bag but the moment they reintroduce food inflation starts. Maybe that is because AEIC goes dormant for long periods if time and just addressing the healing is not fixing the issue. This matches up with some cases where people had chemo that irradiated everything and that killed the infection and they have had no reoccurence.
 
Yes, you need the continued supply of bacteria for the inflammation to keep going (which is why intestines usually improve when the fecal stream is diverted), but of course we can't make the fecal stream sterile and permanent diversion is not ideal. I think if you can get certain focal points to heal (which you can determine when you see mucosal healing plus bowel wall thickness normalization), you might be able to introduce a normal fecal stream without further inflammation. Alternatively, there's surgery to take out damaged portions--there are some interesting papers out there indicating that early surgery may have better long-term results.
 
It is unfortunate that some people have started to say that crohn's disease can manifest itself anywhere along the digestive tract.

This is a complete misrepresentation of crohn's disease. Dalziel who first accurately described crohn's disease, defines it as chronic interstitial enteritis, inflammation of the small intestine, specifically the ileum.

The large majority of people with crohn's have inflammation of the ileum, a smaller group have colonic inflammation.

Inflammation in crohn's disease happens in areas of high bacterial concentration, ileum, colon and aphthous ulcers in the mouth. It does not happen in the duodenum or stomach where bacterial concentration are negligible due to low PH and lack of epithelial adhesion. The duodenum also lacks peyer's patches and therefore M cells like the ileum.

I have sympathy for people who have inflammation in other areas of the digestive tract, like the duodenum, but these people don't have crohn's disease. You can't just start describing every type of undiagnosed inflammation along the digestive tract as crohn's disease.
 
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Or it is an autoimmune disease and has nothing to do with E coli.
Autoimmunity requires the identification of an adaptive response towards a self-antigen. This has never been identified in crohn's disease patients. Nor does it make any sense, mutations in ATG16L1, specific to crohn's disease and related to bacterial clearance (xenophagy), has no overlap whatsoever with autoimmune diseases. Autoimmunity in crohn's disease is a dead theory.
 
The highest concentration of bacterial mass in the human body is in
-the ileum
-the colon
-the mouth

Crohn's disease manifests itself in
-the ileum
-the colon
-the mouth

Genetic mutations in NOD2, ATG16L1, strongly linked to crohn's disease, relate to bacterial recognition and bacterial clearance.

We use tests like anti-OmpC (antibodies to outer membrane E Coli) to diagnose crohn's disease.

We can now predict who will develop crohn's disease by looking at pathogenic bacterial populations in the intestine.

We can identify pathogenic species, a macrophage response, and T cell response, when we take biopsies from granuloma.

Bodies at the forefront of bacteriology, like Institut Pasteur, are involved in crohn's disease research.

I am pretty open minded regarding more obscure crohn's disease theories. The cold chain hypothesis, hygiene hypothesis.

But autoimmune theories that can't identify a self antigen, and ignore the bacterial link, are crackpot/conspiracy theories at this point.

The evidence linking bacteria to crohn's disease is beyond overwhelming at this point, it is undeniable.
 
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You need exactly 1 person with crohn's disease where the inflammation subsides after taking antibiotics to disprove autoimmunity and to show the inflammation is directed at bacteria and not a self-antigen, 1 person. The response rate to cipro in crohn's disease patients is over 60%, the inflammatory response is directed at bacteria, end of story.
 
Kiny, we know that the inflammatory response is at least mainly directed at bacteria (though I wouldn't rule out the possibility of fungal, viral, or other microorganism involvement), but I think there needs to be much more examination of *why* these bacteria are causing a problem in Crohn’s patients but not in others. I suspect that everyone is exposed to these bacteria regularly, yet they're only a problem for some people.

My current hypothesis is that in most cases the bacteria are able to infiltrate in Crohn’s patients because of some kind of tissue damage in the gut, which itself could be due to a number of factors including impaired flow through a region of intestine, foods that cause chemical damage to the intestine, trauma, or acute infection.
 
The highest concentration of bacterial mass in the human body is in
-the ileum
-the colon
-the mouth

Crohn's disease manifests itself in
-the ileum
-the colon
-the mouth

Genetic mutations in NOD2, ATG16L1, strongly linked to crohn's disease, relate to bacterial recognition and bacterial clearance.

We use tests like anti-OmpC (antibodies to outer membrane E Coli) to diagnose crohn's disease.

We can now predict who will develop crohn's disease by looking at pathogenic bacterial populations in the intestine.

We can identify pathogenic species, a macrophage response, and T cell response, when we take biopsies from granuloma.

Bodies at the forefront of bacteriology, like Institut Pasteur, are involved in crohn's disease research.

I am pretty open minded regarding more obscure crohn's disease theories. The cold chain hypothesis, hygiene hypothesis.

But autoimmune theories that can't identify a self antigen, and ignore the bacterial link, are crackpot/conspiracy theories at this point.

The evidence linking bacteria to crohn's disease is beyond overwhelming at this point, it is undeniable.
The duodenum lacks peyer's patches but there are in the mouth?
 
My current hypothesis is that in most cases the bacteria are able to infiltrate in Crohn’s patients because of some kind of tissue damage in the gut, which itself could be due to a number of factors including impaired flow through a region of intestine, foods that cause chemical damage to the intestine, trauma, or acute infection.
There is a small amount of research suggesting that the intestinal permeability in crohn's disease is a result of a tight junction disorder in crohn's disease patients, which allows bacteria to enter tissue.

A group of researchers believes the tight junction defect is inherent, and not related to active bacterial challenge to the tissue. A second group believes that the problems with tight junctions are related to the inflammation and bacterial translocation. I believe the later.

We also don't really understand how intestinal tight junctions work, we know they have an effect on bacterial translocation across the epithelial barrier, but we don't really fully understand how they work or how they are supposed to work.

There are differences between tight junctions of controls and CD patients, but one would expect there to be differences after bacterial insult to the tissue.
 
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I also believe this has nothing to do with a disorder or some defect in a person. I never had a single symptom in my life for 40+ years. Now, it could be that I just didn't exhibit symptoms, but I don't see how that is likely. I think an event occurs which makes what ever the pathogen is take hold. It could be a combo of bad diet, antibiotics, etc that creates an opportunity for a whatever the pathogen or gen(s) take hold.

It could be highly likely its a combo of pathogens. Malessesiza, AIEC, Map, etc which probably makes more sense, because crohns from patient to patient seems to have a lot of variablity.
 
But, if it is pathogen related then programs like the Jin Protocol or other long term anti/viral/bacterial protocols could be beneficial. So, something like cycling wormood 10 wks on 10 wks off or a bismuth cycle could be effective.

There are several studies showing long term bismuth use had really good remission rates. Bismuth has been shown safe for long term use except for a black tongue!
 
psoriasis from patient to patient varies a lot, For most its on the elbows, for some its on the legs for some its on the nails. I know 4 psoriasis patient in my close vicinity and every one of them looks totally different. I have both crohn's and psoriasis and it was triggered at a different time of my life (crohn's at 11 and psoriasis at 20) and both conditions was triggered very quick. Even the same drugs are used for the two conditions (Humira,Stelara. and hopefully Skyrizi soon).
 
kiny, are you a native speaker of French? Do you follow closely the work at the The Institut Pasteur regarding phages and AIEC? Do you know what they have been doing for the last two years in this area?

Some papers and reports:




Could you also give an update on this, if you know anything about its progress, if you have talked to people who know about it etc.

Edit:
Takeda Pharmaceutical has agreed to license, co-develop, and co-promote Enterome’s lead candidate, the Phase Ib Crohn’s disease candidate EB8018, Enterome said today, through a collaboration that could generate more than $690 million for the French biotech focused on treating microbiome-associated diseases.

EB8018 is a novel, first-in-class, oral gut-restricted small molecule designed to selectively disarm virulent bacteria in the gut that can cause inflammation without disrupting the local microbiome. Enterome has been developing EB8018 since licensing the small molecule for an undisclosed amount from its discoverer Vertex Therapeutics in 2016.

EB8018 is designed to work by inhibiting FimH-mediated inflammation induced by the interaction of pathogenic pro-inflammatory bacteria to receptors in the gut wall, thereby potentially reducing the production of inflammatory cytokines including TNF.

Together with Takeda, Enterome plans to launch a Phase II clinical proof-of-concept trial of EB8018 in 2019. The companies are also partnering on a Phase Ib trial (NCT03709628) that has begun recruiting patients, according to an update posted Friday on ClinicalTrials.gov.

The Phase Ib trial will consist of eight patients and two parts: Part 1 is designed to demonstrate that a single oral dose of EB8018 that is safe and tolerable in patients with Crohn’s disease, while Part 2 will characterize the PK profile when administered as multiple oral doses. The new trial is intended to support the development of EB8018 as an add-on therapy, for the treatment of adult patients suffering from Crohn’s disease.

Enterome said its agreement with Takeda covers the development of EB8018 in Crohn’s disease, with the potential to expand to other unspecified gastrointestinal (GI) disorders and liver diseases.

“We are delighted to sign this agreement for EB8018, our most advanced candidate that represents a non-antibiotic, non-steroidal, non-immunomodulatory approach for the treatment of GI disorders including Crohn’s disease,” Enterome CEO Pierre Belichard said in a statement. “We believe we have a world-class partner in Takeda to deliver the best development and commercialization strategy for EB8018 based on their extensive expertise and focus in Crohn’s disease and GI disorders.”

...

Takeda has agreed to pay Enterome $50 million upfront, and a future unspecified equity investment in the company. Takeda has also agreed to pay Enterome up to $640 million tied to achieving clinical development, regulatory, and commercial milestones with EB8018.

Enterome and Takeda agreed to co-develop EB8018, and if approved, co-promote the treatment in the U.S. under a profit/cost-sharing structure. Takeda will receive an exclusive license to commercialize EB8018 outside the U.S., with Enterome eligible for royalties on net sales generated there.

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

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

Backed by preclinical evidence to justify those hopes, Enterome has landed a deal with Takeda. The French biotech will co-develop EB8018 with Takeda and, if approved, co-promote it in the U.S. That ongoing involvement in EB8018 was part of the attraction for Enterome.
 
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I can read French, most of the AIEC research is from France.

The current research on phages is ongoing, currently tests are done in crohn's disease patients where we can isolate AIEC in stool, and research is trying to determine if there is a reduction in the presence of AIEC in stool after phage therapy. I don't think there are any results yet.

Most researchers are glad to talk to patients, just remember that none of them will be able to reply to treatment questions. If you want a response, just ask questions about the research, and not therapy or their opinoins on your situation, they are not doctors. Avoid 'should I' or 'do you think that I should'.

(A small note, many sites that index papers, reverse the email address to protect researchers from spam. Make sure you have the correct email address if you want to interact with someone.)

I will describe a small timeline.

The first people I know who likely isolated AIEC, are 2 researchers from Leeds, UK, in 1988.

In the BMJ, they accurately describe adhesive properties and fimbriae of pathogenic E Coli isolated in patients, they could not isolate them in any controls. They start to realise this might just be an infection.

"Our finding that a significant proportion of patients with inflammatory bowel disease harboured in their stools E'coli with a nadhesive property resistant to mannose that was reminiscent of that expressed by recognised pathogenic Ecoli suggests that this organism may have a role in the pathogenesis of inflammatory bowel disease."

A year later, in The Journal of Infectious Diseases, 3 researchers from Massachusetts isolate "diarrhea-causing E. coli" with adhesive properties.

The first group that is able to isolate these bacteria in large groups of Crohn's disease patients, and are able to accurately describe these bacteria recovered from ileal tissue in crohn's disease patients, is a group of France, in Clermont-Ferrand, in 1999. That is when the name AIEC starts being used.

They spent 10 years isolating and researching these bacteria. They released about a new study every year, I waited patiently every year until they came out with a new study.

It isn't until 2007 that the rest of the research community starts taking note, AIEC could be isolated from patients all over the world, researchers in the rest of Europe and the US could all recover them from ileal tissue. Now you have a new study about AIEC about every month, but it was that group in France that really laid the groundwork.

In the last couple of years, you see institutions like Institut Pasteur and medical companies, trying to find solutions. In the form of phages, FimH blockers, anti-adhesion molecules, etc.
 
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It could be highly likely its a combo of pathogens. Malessesiza, AIEC, Map, etc which probably makes more sense, because crohns from patient to patient seems to have a lot of variablity. !
Every type of infectious disease has multiple offending agents. In the majority of patients you can identify a specific well defined pathogen, but in around 10%-20%, there are other pathogens involved.

It seems highly unlikely that an intestinal disease that manifests itself in places where there are millions of bacteria and fungi, that there would just be 1 causative agent.

AIEC is often described as "agent provocateur", it is often described as a "troublemaker", it is rarely described as the sole cause, but often as the main cause in a large group of patients. There are clearly some main players, AIEC and Malassezia being two of them. If we could eradicate those troublemakers, we would solve a lot of problems and most of the intestinal inflammation would likely subside.
 
Regarding phages. I think people know my opinion about fecal transplants, I have argued time and time again that they would worsen the inflammation in crohn's disease patients because it simply increases the bacterial load in the intestine. Recent studies have confirmed this, the most recent study had to be halted due to increased inflammation in patients. Fecal transplants are not a solution for crohn's disease and never will be.

However, fecal transplants do work for C difficile infections. But a recent study has tried a fecal transplant for C difficile without any bacteria. All the bacteria were removed with an ultrafiltrate.

Shockingly, the fecal trasnplant without the bacteria, was just as successful as the one with bacteria. The only reasonable explanation, is that the phages (which are much smaller, and go through the ultrafiltrate) in the fecal transplant are killing C Difficile.

Human intestines are full of bacteriophages. Everywhere where there are bacteria, there are phages.
 
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I have also argued to please be careful with probiotics. This story about 'good' and 'bad' bacteria is the story being told in a petri dish, it is not the story we see in patients, quite the opposite.

Decreasing bacterial load in general seems to help crohn's disease patients, including a reduction in so called 'good' bacteria. Drinking down millions of bacteria when we know the inflammation in crohn's disease is likely the result of bacteria entering tissue, is not a great idea.

When a bacteria enters tissue, macrophages do not make a difference between 'good' and 'bad' bacteria, macrophages will not accept any bacterial presence in tissue. One of the features of the innate immune system is that it is non-specific. When those millions of bacteria you just drank down, start entering tissue because you have a compromised epithelial barrier, it will cause inflammation. It might not cause the level of inflammation of an E Coli or salmonella entering tissue, probiotics are chosen due to their non-invasive properties, but these bacteria certainly have the potential to make the inflammation worse.

Maybe they'll invent some very specific probiotic one day that can antagonize a genotype closely related to an offending pathogen found in crohn's disease, but until then, I would not recommend anyone take them. There is no evidence they are effective, and increasing evidence they are harmful.
 
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I never had a single symptom in my life for 40+ years
I don't think either doctors or researchers appreciate the fact that almost no one had intestinal issues prior to their disease.

I also don't think that people who don't have crohn's disease realise that the road to crohn's disease was not gradual, it was acute and happened in a matter of days.

You can make all sorts of hypotheses about genetics, innate barrier function, hiegene theories, stress, etc. But none of these theories explain the acute event leading up to crohn's disease.

When patients describe that acute event, they mention fevers, night sweats, throwing up, acute intestinal pain. Those descriptions describe an acute intestinal infection.

Researchers who have talked to patients, and I think more should, talk about that acute event, they talk about a trigger, they realise something very specific took place in a short amount of time.
 
I don't think either doctors or researchers appreciate the fact that almost no one had intestinal issues prior to their disease.

I also don't think that people who don't have crohn's disease realise that the road to crohn's disease was not gradual, it was acute and happened in a matter of days.
For what it's worth, my son had intestinal issues from birth, so I'm pretty sure there's a connection to the later Crohn’s, which seemed to come on gradually. Of course, most people's experience may be completely different.
 
anti-adhesion molecules
What do you mean by these, specifically? I know only Natalizumab, which was notorious for its increasing the risk of JC virus infections. Do you know of any other in this class that is in development, promising, and safer for Crohn’s disease?
 
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Location
San Diego
What do you mean by these, specifically? I know only Natalizumab, which was notorious for its increasing the risk of JC virus infections. Do you know of any other in this class that is in development, promising, and safer for Crohn’s disease?
Entyvio (vedolizumab) is also an anti-adhesion molecule (integrin) antibody. It's is approved for Crohn's disease, although some regard it as primarily a UC or Crohn's colititis medication, since it works better in the colon rather than the small bowel. Entyvio also has a pretty good safety profile.
 
What do you mean by these, specifically? I know only Natalizumab, which was notorious for its increasing the risk of JC virus infections. Do you know of any other in this class that is in development, promising, and safer for Crohn’s disease?
Urinary tract infections and Crohn's disease both feature adhesive forms of E coli that stick to the host's cells. You can isolate adhesive E Coli in the urine of people with UTI, you can isolate adhesive E Coli in the stool of people with Crohn's.

The anti-adhesive molecules for crohn's being considered would be something very similar to D-Mannose being used to treat UTI. In UTI the E Coli attaches to the D-Mannose instead of the host cell, so it loses its invasive capacity.

The fact these molecules are in development is the result of antibiotic resistance.
 
The A in AIEC stands for adhesive. They directly adhere and interact with enterocytes.

The inner part of the intestine has the mucus layer which we all heard of.

Below the mucus is a giant layer of enterocytes, cells responsible for taking up all sorts of nutrients, if you are lactose intolerant, or fructose intolerant it is related to those cells. Those cells are held together by tight junctions I mentioned before. It is the adhesion of AIEC to those enterocytes that allows them to be 'virulent', it allows them to colonize and invade.

Below that layer is the lamina propria, this is where all those macrophages I keep mentioning live, macrophages reside all over the intestine. There are so many and they play a critical role in the intestine, that some researchers even question if they all derive from blood monocytes.

(there was this treatment mentioned a year or so ago on this forum, where the treatment would create competent macrophages by challenging them with heat killed E Coli or whatever it was...it is based on the idea that lamina propria macrophages are all derived from blood monocytes, I don't think that is necessarily the case) Anyway.
 
I've posted this image before, you see that image on the left. It's an image from that research team in Clermont-Ferrand in France that I mentioned before.

Those little dots marked LF82 is AIEC, it is adhesive E Coli sticking to enterocytes isolated from a crohn's disease patient. The outer border is called brush border because it would look like a brush if you zoomed it, they're the microvilli.

You can argue all day about the cause of crohn's disease, but we consistently find AIEC sticking to the intestinal lining of crohn's disease patients, all over the world. We see antibodies related to them, we can now predict who will develop crohn's disease by looking for them, and we see disease that looks like crohn's disease in animals that harbour them.

uouououo.PNG
 
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And just to be clear, bacteria adhering to enterocytes is pathogenic behavior, no bacteria are supposed to be there. Commensal E Coli do not do this, AIEC are 100% pathogenic species. They're not pathobionts, they're pathogens.

This is an infection, a majority of people with ileal crohn's disease are infected with AIEC. We can now consistently confirm this.
 
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It would be rather interesting to hear from someone who has had both crohn's disease and a UTI and was on D-mannose treatment. D-mannose treatments are very new (for UTI at least), but D-mannos is often given to UTI patients. We know D-mannose has an effect on AIEC adhesion, it has just never been used in a study for CD. But there have to be at least some people who have both CD and hard to treat UTI were given such a treatment. (this isn't an invitation for anyone to try it, we have no idea what it does at this point and it could be dangerous in high doses). AIEC is likely to be resistant to D-mannose in vivo, but it would still be interesting to hear accounts of people who had both UTI and crohn's disease.
 
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And just to be clear, bacteria adhering to enterocytes is pathogenic behavior, no bacteria are supposed to be there. Commensal E Coli do not do this, AIEC are 100% pathogenic species. They're not pathobionts, they're pathogens.

This is an infection, a majority of people with ileal crohn's disease are infected with AIEC. We can now consistently confirm this.
How common is the AIEC bacteria in the wild though? Is everyone being exposed all the time to this stuff, but it's only causing problems in Crohn’s patients? Or is it something rarely encountered that can induce Crohn’s in healthy people if they get exposed?
 
Kiny, D-mannose , the readily available supplement? I remember reading something about that a while ago and put it in my supplements to try book. It is approved for over the counter consumption, so the safety profile is known, but not at high doses as you stated. Treatments are highly dose dependent so it could be that the otc dose does nothing.
 
How common is the AIEC bacteria in the wild though? Is everyone being exposed all the time to this stuff, but it's only causing problems in Crohn’s patients? Or is it something rarely encountered that can induce Crohn’s in healthy people if they get exposed?
Well, remember that AIEC has no easily identifiable genetic marker, if it did tests would not be so time consuming and it would be much easier to test. There is a lot of genetic overlap between AIEC and commensal E Coli.

But where commensales and non-pathogenic E Coli species won't cause issues, AIEC found in crohn's disease on the other hand, are extremely adhesive and invasive, they are pathogens, they manage to attach themselves to the intestinal wall, they penetrate peyer's patches and invade macrophages.

Most 'controls' do not harbour AIEC. Either studies don't find any in controls, or in very few controls. The AIEC they do encounter in controls tend to be far less invasive. At that point you can also ask yourself if these species should be called AIEC, since the A and I in AIEC stands for adhesive and invasive.
 
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Crohn's disease is far too common to have some exotic explanation. The fact the disease has spread so readily all over the world, requires the presence of one or more very specific pathogenic species with a lot of genetic overlap to already existing bacteria.

Genetic predisposition gives you a lot of clues that the disease is related to bacterial clearance, it also tells you the bacteria causing issues are intracellular. The most straightforward explanation has always been an intracellular pathogenic enterobacteriaceae that gains access to deeper tissue through ileal peyer's patches. We looked at bacteria like Yersinia and Salmonella, while they could very well be involved in the disease onset, the acute intestinal damage phase, they don't seem great candidates for maintaining inflammation. E Coli on the other hand is an excellent candidate, also because we use anti-OmpC to actually diagnose the disease.
 
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Well, remember that AIEC has no easily identifiable genetic marker, if it did tests would not be so time consuming and it would be much easier to test. There is a lot of genetic overlap between AIEC and commensal E Coli.

But where commensales and non-pathogenic E Coli species won't cause issues, AIEC found in crohn's disease on the other hand, are extremely adhesive and invasive, they are pathogens, they manage to attach themselves to the intestinal wall, they penetrate peyer's patches and invade macrophages.
So the differentiation between non-pathogenic E Coli species and AIEC is made ex post facto, by looking at the behavioural patterns of the bacteria in the presence of the host’s cells?

This is an infection, a majority of people with ileal crohn's disease are infected with AIEC. We can now consistently confirm this.
but we consistently find AIEC sticking to the intestinal lining of crohn's disease patients, all over the world.

Could you cite some of the key studies that show, “consistently”, “AIEC sticking to the intestinal lining of crohn's disease patients, all over the world”?

Could you also cite some of the key studies, again, for the claims of: 1) antibodies related to them (related to what?) 2)prediction, 3) the animals that harbour them (aiec?) having crohn’s-like disease?

We see antibodies related to them, we can now predict who will develop crohn's disease by looking for them, and we see disease that looks like crohn's disease in animals that harbour them.
Well, remember that AIEC has no easily identifiable genetic marker, if it did tests would not be so time consuming and it would be much easier to test. There is a lot of genetic overlap between AIEC and commensal E Coli.

But where commensales and non-pathogenic E Coli species won't cause issues, AIEC found in crohn's disease on the other hand, are extremely adhesive and invasive, they are pathogens, they manage to attach themselves to the intestinal wall, they penetrate peyer's patches and invade macrophages.

Could you cite some of the key studies backing your claim below? Could you also clarify what you mean by “the disease”?

we use anti-OmpC to actually diagnose the disease.
The presence of the anti-ompc antibodies does not indicate an infection, it doesn’t even indicate the presence of live E Coli (let alone the AIEC) within the organism, it just means the host immune system encountered at least fragments of E. Coli outer membrane protein at some point. Any claim besides this based on the anti-ompc would be further from what the antibodes indicate, and would be better considered as speculation.


“Anti-OmpC as an isolated assay had low sensitivity for both CD (24%) and UC (11%), and displayed a 5% false-positive rate.”

Zholudev A, Zurakowski D, Young W, Leichtner A, Bousvaros A. Serologic testing with ANCA, ASCA, and anti-OmpC in children and young adults with Crohn's disease and ulcerative colitis: diagnostic value and correlation with disease phenotype. Am J Gastroenterol. 2004;99(11):2235-2241. doi:10.1111/j.1572-0241.2004.40369.x


“We hypothesized that anti-OmpC, in the absence of anti-S cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA), is an assay that overestimates the presence of Crohn disease (CD) and ulcerative colitis (UC).
...
Results: Seven patients between 3 and 20 years of age were discovered to be positive for anti-OmpC but negative for ASCA and ANCA. These patients were determined to have significant medical conditions without combined radiographic, endoscopic, or histological evidence of IBD. Despite the reported 85% positive predictive value of anti-OmpC for IBD, none of the 7 patients with isolated anti-OmpC had a diagnosis of CD or UC.
Conclusions: Anti-OmpC, in the absence of ASCA and ANCA, is a serological pattern noted in a subset of medically complex cases in children and young adults without CD or UC.”

Davis MK, Andres JM, Jolley CD, Novak DA, Haafiz AB, González-Peralta RP. Antibodies to Escherichia coli outer membrane porin C in the absence of anti-Saccharomyces cerevisiae antibodies and anti-neutrophil cytoplasmic antibodies are an unreliable marker of Crohn disease and ulcerative colitis. J Pediatr Gastroenterol Nutr. 2007;45(4):409-413. doi:10.1097/MPG.0b013e31812f7f6e
 
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Could you also cite some of the key studies....

Could you cite some of the key studies...
Well, if you want more info, I have made a whole topic with every relevant link about AIEC.

You'll find answers to most of your questions there.

 
So the differentiation between non-pathogenic E Coli species and AIEC is made ex post facto, by looking at the behavioural patterns of the bacteria in the presence of the host’s cells?
No, you identify them through PCR tests (to identify virulence genes), antibiotic resistance tests, and through phenotypic traits.
 
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Regarding your anti-OmpC comment. It is one of the few reliable diagnostic biomarkers we have and large studies show much higher specificity than the study with barely 7 patients you cherry picked. Not going to argue about this, not worth my time, be thankful we actually have these tests available to us instead.
 
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Image of a Crohn's disease macrophage infected with LF82 AIEC, in case you doubt the ability of AIEC to be highly pathogenic.

Yes AIEC is infecting a substantial part of crohn's disease patients, including pediatric patients. Yes AIEC is inducing inflammation in those patients. That's not even a discussion anymore.

The discussion is now...how do we identify AIEC easily on a large patient scale, without doing time consuming tests...and how do we treat this infection.

b vvnvnvnv.PNG
 
Instead of providing relevant citations as evidence for your claims for the members of this community that follow the thread and communicate in it, posting a link with a bunch of articles and saying read all of them is disrespectful for the community.

Is this how you contribute? By making a lot of claims and being immature when you are asked to provide evidence for them.

Not going to argue about this, not worth my time, be thankful we actually have these tests available to us instead.
So, providing evidence for your claims is “not worth your time”?

“Not going to argue” when you are challenged to provide the key studies as evidence for your claims? Did being kindly asked to provide evidence for your claims, for the betterment of the discussion, hurt your ego so much?

Good luck with your dogmatism and infantile reactions.

I won’t communicate with you any further before you acknowledge your misbehaviour.
 
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For what it's worth, the OmpC data was in the Index I made and linked.

All you had to do is do CTRL+F in your browser and type in OmpC and you had the answer to your question.

My threads are mostly my own thoughts about studies, I don't expect anyone to enjoy or like them. If you find information in them, great, if you think they are useless, that's great too. I don't care, I write them mostly for myself and the handful of people who do enjoy them.

Sntre.png
 
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I appreciate all insights on this topic, as there is no cure the cause is not known. thus everything is conjecture at this point. I view these discussions as academic and I don't think this is a place to argue, but learn.
 
I appreciate all insights on this topic, as there is no cure the cause is not known. thus everything is conjecture at this point. I view these discussions as academic and I don't think this is a place to argue, but learn.
I agree, that’s why I asked for citations. Providing evidence for your claims is fundamental for making discussions and inquiries meaningful.

A person can make whatever claims he wants in his own blog, when he is “writing for himself”; but when communicating in a forum, i.e. within a community, he should base his claims on evidence if he wants to be taken seriously. It’s first out of self-respect, and respect for the community he is writing in that he does this; insisting on doing the contrary will make him deserving of looked down upon.
 
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If you want more sourced material, most of the Genetics section and AIEC text on the crohn's disease Wikipedia page are written by me. I think my contribution was an impovement, it is one of the few parts of the article that are well sourced.

(I wrote a whole part about xenophagy that was truncated because it was too long, but you can still find it on google cache if you want)

I suggest you take a look at the AIEC index I made. it is a trove of information about AIEC, I hand picked every relevant AIEC study since 1988, members of this forum and researchers have made use of that index.

There are plenty of researchers who love nothing more than to talk to actual patients, including about AIEC, but they will expect you to do some work yourself and actually read their study.

will make him deserving of looked down upon
That's great, but I suggest you talk about me in another thread and stick to the topic in this one.
 
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I agree, that’s why I asked for citations. Providing evidence for your claims is fundamental for making discussions and inquiries meaningful.

A person can make whatever claims he wants in his own blog, when he is “writing for himself”; but when communicating in a forum, i.e. within a community, he should base his claims on evidence if he wants to be taken seriously. It’s first out of self-respect, and respect for the community he is writing in that he does this; insisting on doing the contrary will make him deserving of looked down upon.
I don't necessarily 100% agree with you. This is a message board and not a peer reviewed journal article. When someone posts something it is not necessarily required that they post every source. I have read many of Kiny's posts, and Kiny has posted plenty of sources in the past that I don't think it is necessarily required that Kiny post a source with every assertion.

It is incumbent upon the reader to do their own research if they have questions. Kiny isn't getting paid to share thoughts, it is voluntary.
 
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Kiny, is your theory basically:

1. Some people have an innate deficiency related to their macrophages, which allows

2. Persistent infection with AIEC, which results in

3. Persistent inflammation, which can be stopped by killing the AIEC

Patients would be susceptible to reinfection unless they continue to receive treatment to kill AIEC or their immune system gains the ability to fight off the AIEC more effectively (eg vaccine?).

This is all plausible to me, but I question whether #1 has actually been well established. I think something else could take the place of #1 which causes some people to be susceptible to this problem.
 
Kiny, is your theory basically:

1. Some people have an innate deficiency related to their macrophages, which allows

2. Persistent infection with AIEC, which results in

3. Persistent inflammation, which can be stopped by killing the AIEC
Right. Altought just like Segal, I believe there was an event between step 1 and 2. Onset of crohn's disease is a rather acute event that looks like a gastrointestinal infection. Foodborne infections in the Western world have become very common and could easily explain the gastrointestinal infiction.

The foodborne infection leads to ulcers and a permeable bowel which allows AIEC to colonize and invade tissue. The infection is cleared. We wouldn't be able to detect this foodborne infection anymore. While crohn's disease onset is acute, diagnosis is very slow. Giovanni Maconi et al averaged it to 6 months, the offending agent would have long been cleared by then.

This is all plausible to me, but I question whether #1 has actually been well established. I think something else could take the place of #1 which causes some people to be susceptible to this problem.
When I mention NOD2 and ATG16L1, I am mostly talking from the perspective of ileal disease. They are important in differentiating ileal from colonic due to the presence of paneth cells in the ileum that don't exist in the colon. Anomalies in NOD2 are primarily relevant to ileal disease.

I am also talking specifically about patients with a European lineage (Europeans, Americans), not asian patients that don't seem to have these anomalies, yet still develop crohn's disease.

You can debate how relevant these genetic anomalies are when many people in the West who have them don't develop crohn's, when not all CD patients have them and when they're not a feature at all in asian CD patients.

But I think they are very relevant if we want to find the cause behind this disease, because they are very specific to CD and give us a lot of information about what is actually happening when bacteria enter tissue in CD patients.

NOD2, ATG16L1 and IRGM are closely related to the workings of Paneth cells. Paneth cells are small intestine specific, most of them are concentrated in the ileum where most bacteria reside. Their function is wholly focused on early pathogen detection and early elimination, they have TLRs on the surface (that can detect pathogens) and they release AMPs, antimicrobial proteins.

NOD2, part of the the innate immune system, it is required to detect bacterial cell walls in tissue, peptidoglycan, especially in Paneth cells in the ileum. Crohn's disease patients have a very large reduction of a-defensins in the intestine compared to controls because of incompetent paneth cells. Those a-defensins are needed to keep pathogens at bay so they don't enter tissue. Crohn's disease patients have a defensin deficiency. That's not to say crohn's disease patients with a NOD2 anomaly can't detect intestinal pathogens, TLR4 on the surface can still detect pathogens.

ATG16L1 and IRGM are risk allele specific to crohn's related to autophagy, Paneth cells in crohn's are ATG16L1 defficient. The autophagy mechanic is activated in those paneth cells. When people think of autophagy, they generally don't think of bacterial clearance because it has only been recently described in detail (thanks in large part due to crohn's disease research). Autophagy involving bacterial clearance is called Xenophagy. It happens when pathogens invade cells, they are engulfed, the pathogens become nutrient defficient, acidified and die. Any defects in this process during active inflammation will grealy reduce the ability to clear AIEC from the intestinal tissue on the surface.
 
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Regarding other reasons. If you ask a doctor in Japan, they will categorically blame the 'Westernisation' of the diet for the increasing prevalence of crohn's disease in their country, basically the increase in high sugar, high fat diets. I think this is a poor argument.

I don't read a lot about diets, maybe people with low fat and low sugar diets develop less crohn's I have no idea. Maybe it affects microbiota composition and impacts the prevalence of AIEC and other pathogenic species in the pre-Crohn's state, but I don't think it is that relevant to people who have crohn's disease.

There are probably hundreds of conflicting studies out there, one blaming sugar, the other fat, the other smoking, the other stress, hygiene hypothesis that claim we didn't roll around in the mud enough as kids. What have all these studies and money spent on them actually done to help crohn's disease patients.

All these theories put the blame on patients, on past events no one has any control over anymore, and none of them help manage the disease.

Outside of EN, out of the scope of regular diets, I think diet plays a rather minor role in crohn's diseae and I think blaming 'Westernisation' is a bit too easy. Most of the crohn's disease patients I know had a rather healthy diet before developing the disease, including me. Blaming 'Westernisation of the diet' also puts the blame on the patient, which isn't a good way for people to cope with this disease, patients will end up blaming their past eating habits for something they likely had zero control over.
 
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Regarding diet, there are a lot of correlations globally and over time between "Western" diets and Crohn's. Of course, since this is an intestinal disease and since diet can be used as a treatment, we have a variety of reasons to suspect diet as a cause. What we don't know is exactly how diet plays into the causation.

My guess is that the problem isn't really the "western diet" per se, nor is the problem sugars or even fats in a general sense. I think that's probably the wrong way to look at how diet might be playing a role in causation--it's just too vague. I suspect that there may be some specific foods that have become more common that can cause chemical damage to the intestine--more like poisoning than "healthy" vs. "unhealthy" diets.
 
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Nutritional studies and studies about diets seem highly unreliable and conflicting to me. The best example is all the studies about maltodextrin, it supposedly increases intestinal permeability, and increase the growth of pathogenic E Coli. Yet what these studies see in their small petri dish in their lab, is not at all what seems to be happening in patients. When patients take EN, that are all made with maltodextrin, permeability improves and E coli numbers go down in stool. For those nutritional studies to be reliable, they would first have to define what maltodextrin they use, how long hydrolysis was, and where it is taken up in the intestine. If a substance never reaches the ileum because it is absorbed higher up the GI tract for example, all those studies are pointless.
 
Same with studies about added sugars, part of the evil 'Western diet'. Studies done in a tiny petri dish in a lab can show bacteria X and Y grow in the presence of glucose. Ok, but how much of that glucose in your petri dish actually reaches the ileum or colon at all? Glucose and maltodextrins are rapidly absorbed in the duodenum, how relevant is that study in that petri dish for actual patients? There aren't any bacteria worth mentioning in the duodenum, that's not where people with crohn's disease have inflammation. What does it matter what this substance does if it is readily absorbed high in the GI tract.
 
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I know, the nutritional studies are totally incoherent. I don't place any reliability on the idea that sugars have anything causative at all (even if sugar may be bad for you in other ways). However, when you look at the studies together there are a couple of things that do stand out to me: people who get Crohn’s eat less fruit than those who don't, and there may be some reliable correlations with certain fats. This (along with some personal observations) has made me wonder about the role of oxidants and antioxidants.

Perhaps on a related note, we know that certain chemicals can be used to induce colitis in mice. It's conceivable that some people are similarly eating something in particular that's inducing damage or inflammation, perhaps if they eat it in the wrong way or in an unusual concentration.

Of course, as you point out, infection could also easily be what starts up the cycle and allows the chronic AIEC colonization.
 
what really missing in all of this is the control. We are really only analyzing people with crohns against other people with crohns. It would be really helpful if someone could perform some large scale analysis and include a group of people some with crohns others without and try and track the difference. That would give good insight, but I doubt that happens because of cost and quite frankly, if you are well why would you even participate.
 
FimH blocker that targets AIEC enters phase 2.

Some researchers call them FimH antagonists, some call them fimbriae antagonists, antibiotics compounds, etc... I prefer FimH blockers, it's easiest to write and remember.

I haven't seen any details, but my guess would be they are D-mannose derived.

To understand these FimH blockers, you kind of need to understand the role of fimbriae. They're a feature of mostly gram negative bacteria, especially pathogenic forms of Enterobacteriaceae. The fimbriae of bacteria kinda look like tentacles that stick out, they are used to adhere to cells (they are not the same thing as flagella, flagella also look like tentacles, but they are purely there for locomotion).

What AIEC basically does in crohn's disease patients, is use those fimbriae to interact with M cells. M cells are like little domes, they are not covered with mucus and they are part of the peyer's patches.

I explained what peyer's patches do extensively in other posts, but all you need to really know to understand a FimH blocker, is that AIEC is exploiting M cells to enter tissue and a FimH blocker will try to stop AIEC from adhering to tissue.

If you can prevent AIEC from entering tissue by interferring with its adherence mechanics, that would be a really good thing since you can halt inflammation at that point and disarm AIEC. Killing it would be even better, but disarming it is the next best thing.


"https://finance.yahoo.com/news/enterome-announces-first-patient-dosed-070000908.html

Enterome announces first patient dosed in Phase 2a trial of sibofimloc in Crohn's disease

Wed, September 23, 2020

Sibofimloc (EB8018/TAK-018) is a first-in-class, orally administered, gut-restricted small molecule designed to reduce inflammation underlying Crohn's disease

Sibofimloc binds FimH, a novel microbiome-derived therapeutic target validated by Enterome, to selectively disarm virulent bacteria in the gut that can cause inflammation without disrupting the local microbiome

PARIS and BOSTON, Sept. 23, 2020 /PRNewswire/ -- ENTEROME SA, a clinical-stage biopharmaceutical company leveraging its unique knowledge of the microbiome-immunoinflammation axis to develop next-generation therapeutics, today announced that the first patient has been dosed in a Phase 2a clinical trial of sibofimloc (EB8018/TAK-018) in patients with Crohn's disease. Sibofimloc is advancing through clinical development under a 2018 global licensing, co-development and co-commercialization partnership with Takeda Pharmaceutical Company Limited ("Takeda"). "
 
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Another way to think about FimH blockers is that they interfere with the A in AIEC, the Adherent part.

If you can take out the A, you also remove the I, the Invasive part. If they can't adhere to the inestinal wall anymore, they can no longer invade it either. What you're left with if you remove the letters A and I from AIEC, is EC...E Coli that has been disarmed of its virulence. This is at least the theory behind the FimH blockers. They're going to be used increasingly for UTI too.
 
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So are fimH blockers another treatment you would have to take forever?
I would hope not, it's not the case for UTI, it's a few weeks treatment for UTI.

Once you undermine AIEC's ability to use its fimbriae it won't survive very long. They use those fimbriae for attachment to tissue, attachment to each other, and to keep macrophages and DC at a distance. Those fimbriae are central to AIEC's survival.

Once AIEC loses its adhesive capacity, I assume it would be extremely vulnerable, it would no longer be able to enter tissue or colonize the intestinal wall and would likely be outcompeted quickly by other bacteria in the lumen.

The remaining AIEC in tissue would just be killed off by the immune system, CD macrophages can kill AIEC just fine, just not when it chronically invades tissue and overwhelms the immune system. AIEC can't be allowed to have a 'bacterial reservoir'.
 
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IF AIEC is behind the inflammation, and IF FimH blockers or phages are successful, crohn's disease would be no different from any other intestinal infection. It would be no different from foodborne infections, salmonella, campylobacter, traveller's diarrhoea, intestinal TB, etc. You'd just take the treatment for a few weeks, the pathogen would be gone and that would be it. Intestinal infections can be cured rather easily.

If crohn's disease is an overlooked intestinal infection, and more and more evidence points in that direction, it means it can simply be cured too.
 
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so is Enterome the only company trialing a FimH blocker? I read their first trial, but that only talked about safety and didn't discuss any changes in CD for paitents given doses.
 
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It's the first company for crohn's disease afaik. There are multiple for UTI.

FimH blockers for UTI are interesting, because UTI infections are chronic due to a bacterial reservoir of E Coli in the intestine. The intestine serves as the seed, the vector, for the UTI.

What pathogenic E Coli does to survive is it builds reservoirs, groups of bacterial colonies that attach themselves to the intestinal lining, they use fimbriae and biofilms to attach to the intestinal lining and to themselves. In UTI those reservoirs are not in the urinary tract, but in the intestine, they infect the urinary tract through feces.

Pathogenic E Coli is really good at building out colonies in the intestine due to its ability to adhere to cells.
 
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I always said that the idea that crohn's disease is a reaction to the microbiome is completely ridiculous. I argue this because the microbiome does not interact with the epithelial barrier. The little contact it has with the intestine is with the outer mucus layer, it does not come into direct contact with TLRs and if it does, which is an accident, it comes into contact with tolerant TLR4 and not deeper tissue TLRs.

People who say crohn's diseae is a reaction to the micriobiome do not understand how much tolerance there is for the microbiome, there are way too many safeguards in place for the immune system to mount a response to the microbiome. Of course if there is a breach in the intestinal lining, bacterial content will enter, but the inflammation is clearly not caused by the microbiome.

You'd also have inflammation all over if crohn's disease inflammation was a reaction to the microflora. In Crohn's disease there are small pockets of inflammation and granuloma, that is a reaction to specific pathogens, not the microbiome.

Granuloma itself, pockets of macrophages surrounded by lymphocytes, indicate the presence of pathogenic intracellular bacteria. Those granuloma look exactly like the granuloma seen in intestinal TB.

There are also no AMP defects or DC defects in crohn's disease, nor is there a mucus defect, crohn's disease patients have all the tools to build up microbiome tolerance and to keep the microbiome away from the epithelial barrier. The genetic anomalies in crohn's disease relate strictly to the recognition of pathogenic intracellular bacteria and elimination of them.

AIEC is completely different, AIEC has the bility to attach itself to the epithelial barrier, it attaches to tissue, it sets off TLR4 and TLR5 and it invades tissue and sets off macrophages. AIEC is purely pathogenic and therefore a good candidate behind the inflammation of crohn's disease.
 
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If crohn's disease was simply caused by dysbiosis and the inflammation was a reaction to the dysbiosis, fecal transplants would simply cure the disease. Of course it doesn't, it tends to worsen the disease due to the simple fact you are increasing bacterial load.

In people with crohn's disease in remission, the dysbiosis simply disappears, but of course they are not cured at that point. The dysbiosis is simply a reaction to the inflammatory condition, you see dysbiosis in pretty much every intestinal disease that features inflammation, none of them are actually caused by the dysbiosis, neither is crohn's disease.

To explain the deep transmural tissue inflammation you need to find an intracellular pathogen capable of crossing over from the lumen to the deeper lamina propria where it will activate a macrophage response. AIEC is able to do this, so are a few other pathogens, but the amount of pathogens that can do this is rather limited.
 
It also shouldn't be understated that 'healthy people' harbour pathogens too. They are able to keep those pathogens from attaching themselves to the epithelial barrier, but they harbour pathogens.

Some 'healthy people' harbour AIEC, others harbour pathogenic E Coli, other foodborne pathogens, fungi, etc.

If you give a person with crohn's disease a fecal transplant, you are not just increasing bacterial load of commensals, but you are very likely infecting them with pathogens. And people with crohn's disease might not have the ability to keep those pathogens at bay. There is no such thing as a 'healthy microbiome', just the ability to keep pathogens at bay.
 
There is no such thing as a 'healthy microbiome'
What it has done, is give some researchers millions in research funds, blaming every disease on the microbiome, without ever having to come up with a single proof that the microbiome was actually responsible for it, nor having provided a single practical solution.

'it's ongoing research'

Yes, it's been ongoing research for a decade now, a lot of money that should have been spent treating AIEC and other pathogens, has been wasted on microbiome research.

You can't cure or treat crohn's disease by altering the microbiome, just like you can't cure intestinal TB with it, or salmonella, or campylobacter, or yersinia. The inflammation happens at the epithelial barrier and in tissue, it does not happen in the lumen.
 
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If crohn's disease was simply caused by dysbiosis and the inflammation was a reaction to the dysbiosis, fecal transplants would simply cure the disease. Of course it doesn't, it tends to worsen the disease due to the simple fact you are increasing bacterial load.

In people with crohn's disease in remission, the dysbiosis simply disappears, but of course they are not cured at that point. The dysbiosis is simply a reaction to the inflammatory condition, you see dysbiosis in pretty much every intestinal disease that features inflammation, none of them are actually caused by the dysbiosis, neither is crohn's disease.

To explain the deep transmural tissue inflammation you need to find an intracellular pathogen capable of crossing over from the lumen to the deeper lamina propria where it will activate a macrophage response. AIEC is able to do this, so are a few other pathogens, but the amount of pathogens that can do this is rather limited.
Okay, so AIEC infect the macrophage, which in response start producing inflammatory cytokines (like IL-23) to harbour the infection. How come IL-23 antagonist treatment is helping crohn's instead of making it worse.

If you are infected with tubercolosis, IL-23 or TNFalpha treatment will make the infection worse and you will have much more worse symptoms.
 
I frankly don't know much about IL-23 blockers and I am not really interested in them. They're not comparable to anti-TNF and they're far less effective in crohn's disease patients.

IL-23 discovery was very recent, it's not described in immunology references and IL-23 medication is barely a few years on the market. It was rushed to market because anti-TNF patents ran out.

As far as IL-23's effects on TB, you'll have to ask someone else, I don't even know if people on IL-23 blockers get a mantoux test. There's probably no records of anyone on IL-23 developing TB either simply because IL-23 have been on the market for barely a few years.

People on anti-TNF get screened with a mantoux test, but that's for latent inactive TB, as a precaution for reactivation, it can cause a disseminated type of infection.
 
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Okay, so AIEC infect the macrophage, which in response start producing inflammatory cytokines (like IL-23) to harbour the infection.
Macrophages and neutrophils take up microbes through phagocytosis, they get killed in the phagolysosome through acidic PH and antimicrobial enzymes.

But many bacteria (including TB you mentioned) are able to circumvent that process. Many foodborne infections are able to do this too, they simply escape the macrophage phagosome.

Xenophagy is the way the macrophage tries to capture bacteria that have escaped the phagosome mechanic, autophagosomes will hand them over to lysosomes for killing.

In the intestine, where most macrophages reside, it happens in the lamina propria, the layers right below the epithelial barrier.

AIEC escapes that phagosome mechanic too, and it is the Xenophagy process where a lot goes wrong in crohn's disease patients. Genetic anomalies in patients are related to that Xenophagy mechanic (NOD2, ATG16L1 and IRGM) and AIEC is able to circumvent innate immune mechanics that happen within macrophage. AIEC thrives in inflammatory conditions and is able to exploit them.

Anyway, what IL-23 has to do with that is anyone's guess. It is a recently discovered cytokine, I have no idea how it is involved if at all. All I know is that IL-23 blockers are no that effective to treat crohn's disease.
 
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Just because there are IL-23 blockers doesn't meant they understand what IL-23 does btw. variants in IL-23 can predispose people to develop crohn's disease, UC and a bunch of other diseases. It is not specific to crohn's disease.

That made it a attractive target to block that cytokine because you can make a lot of money if you can develop medication for multiple diseases. At the same time, patents for anti-TNF were running out so these companies needed something to fill that loss in revenue. So they made an IL-23 blocker. Why...money.
 
If you're wondering what causes the actual damage in crohn's disease, it's the inflammation. To be more specific, it is oxidative stress.

When the innate immune system and macrophages try to kill the bacteria, they use low pH and enzymes to do it. One of those enzymes is phagocyte oxidase, this is what causes the oxidative stress, this is what causes tissue damage in crohn's disease.

The enzymes used to kill bacteria also damage tissue. And because the immune system is unable to kill those bacteria, the intestine is in a chronic state of stress and inflammation.

To stop the inflammation people use anti-inflammatories which stops the release of those enzymes, it heals the intestine, but it doesn't fix the problem of course, the bacteria are still there. The moment you stop anti-inflammatories, the inflammation restarts. The only way to stop it is to do something about those bacteria.

In many infections, anti-inflammatories are actually used, to prevent too much tissue damage.

Anti-inflammatories are used during COVID too.

What happens in crohn's disease is what also happens in chronic granulomatous disease, which is very closely related to crohn's disease. Many people with granulomatous disease develop crohn's disease.
 
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If you go down the list of anti-inflammatories in the pre-biologic age, they were developed to treat infections. Infections cause tissue damage, forms of necrosis, nerve damage, etc. The immune system has the ability to react very violently during infections and can cause severe tissue damage, especially if the infection is chronic. Untreated intestinal TB, untreated crohn's, etc.
 
It seems as time passes, studies shows that the difference between Crohn's and Colitis gets larger and larger.
do you think FimH blockers will work for colitis? or are they Crohn's exclusive ?
in your knowledge or belief, is Crohn's a AIEC infection and Colitis something completely different?
Do you think FimH blockers will work for other areas of crohn's such as the colon? or only ileum?
 
I've always argued UC and crohn's are different because crohn's immune anomalies look like chronic granulomatous disease, and the actual intestinal inflammation in crohn's disease looks like intestinal TB.

Crohn's disease doesn't really look like UC at all, they're both intestinal diseases but that's pretty much where the similarities end. Genetic anomalies (NOD2, ATG16L1, IRGM) found in crohn's disease are completely missing in UC, granuloma are missing in UC, crohn's are patches of inflammation, UC is organ specific, crohn's features deep transmural tissue inflammation, UC superficial mucosal inflammation. Doctors confusing UC and crohn's should probably find another job, they are vastly different.


Now for the AIEC question

People with UC tend to harbour slightly more AIEC than controls, but much less than people with crohn's disease.

UC doens't feature granuloma, and you would expect them to be there in people with UC if AIEC was driving the inflammation in UC. You would expect deeper tissue inflammation too.

You also would expect there to be pockets of inflammation where AIEC has colonized, but UC inflammation is disseminated, it's all over the organ.

Crohn's colitis that is colon sepcific, does feature pockets of inflammation and granuloma, consistent with an infection of an intracellular pathogen, but not UC.


You could counter my argument by arguing that..

...the lack of granuloma and deeper tissue inflammation in UC is because the colon doesn't have peyer's patches and paneth cells, and that explains the superficial mucosal inflammation because it limits the ability for AIEC to enter tissue.

UC, unlike crohn's, doesn't have a problem with neutrophil recruitment, and you could argue shorter lived neutrophils wouldn't cause deep long lasting tissue inflammation like lamina propria macrophages.



Is it possible AIEC is involved in UC? I think so, but I think it is a bit unlikely due to how different the diseases are. If crohn's and UC were caused by a similar pathogen, you would expect there to be more similarities rather than so many differences.
 
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The disease most similar to crohn's disease from an immune perspective is chronic granulomatous disease. An innate immunodeficiency just like crohn's disease.

People with chronic granulomatous disease develop intestinal symptoms that are the same as crohn's disease. Researchers often call it 'mimmicking crohn's', but they simply develop the exact same inflammation, and they respond to the exact same treatment.

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