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New vaccine possibility (not MAP)


This reminds me of the Qu Biologics approach, which is based on an immune deficiency model of Crohn's. In this study, the researchers injected mice with flagellin in order to promote anti-flagellin antibodies in the gut. Mice which received the flagellin vaccine did not develop gut inflammation under conditions that normally cause inflammation.
 
Thanks.

The approach is the same as the FimH blockers that are in development for crohn's disease.

You also have crohn's medication in development that supports tight junctions.

And bacteriophage therapy.

Why all of these developments are exciting, is because the mechanism of action is specifically intervening at the bacteria-mucosa-junction level, which would make them much safer than a lot of the treatment that is available now.

And because these treatments are so specific, you don't have any of the potential side effects you see with broad spectrum antibiotics, diets, fecal transplants, etc.

You don't want to disturb the existing ecosystem, the large large majority of intestinal bacteria are not trying to enter tissue, they help outcompete pathogenic ones by depriving and outcompeting them for nutrients, and macrophages can easily deal with them if they enter tissue by accident through a lesion.

You just want be able to interact with the offending bacteria at the mucosa and lamina propria level, the ones that do cause harm, they do try to enter tissue, and cause chronic inflammaton by exploiting weaknesses in the immune system at the macrophage level. You want to target those, without the treatment resulting in dysbiosis or side effects for the patent. And there are only a handful, and they use similar mechanics to enter intestinal tissue, there's no need to disturb the whole ecosystem once we can target those handful of bacteria.
 
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In this study, the researchers injected mice with flagellin in order to promote anti-flagellin antibodies in the gut.
Flagella makes bacteria motile, it allows them to move into intestinal tissue. Other bacteria can't enter that physical barrier since they lack the invasion and adhesion properties that bacteria like AIEC have.

Bacteria without invasion properties that end up in tissue did so not through their own will. They were sampled by peyer's patches, they entered through a lesion, etc. They are generally also easily dealt with by the immune system.

It is the invasive bacteria that are the problem in crohn's disease. They are not part of the regular microbiome, even though they often compete with commensals for nutrients.


Crohn's disease patients have IgG to flagellins, specific antibodies to those flagellins. Controls without crohn's disease don't have them.

Controls without crohn's disease don't harbor the bacteria that chronically invade intestinal tissue (or not in great numbers), so you don't find those IgG.

One of the easiest ways to check if the treatment would work, is simply check if the people with crohn's disease receiving the treatment, have lowering inflammation, combined with lowering of IgG against flagellin. If you can do that, you have a treatment that is highly effective, likely without any significant side effects.
 
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the FimH blockers that are in development for crohn's disease.



 
One of the reasons why there was commotion about that Nissle 1917 probiotics, that was then taken off the market and basically banned...was because of its flagellum.

You don't want to commercialise a probiotic with a strain of bacteria that has invasive properties.

Probiotics contain bacteria that are non-invasive, and if they do enter tissue, they are easily dealt with by the immune system.

They are non-pathogenic, non-pathobiont, that also requires not having invasive properties.

That's not to say probiotics are harmless, if you have an open lesion, you don't want thousands of bacteria to enter the mucus barrier.

If you are going to take probiotics, at least take them when you don't have active inflammation.
 
The basis for the theory that a healthy gut microbiome would help crohn's disease patients is not because commensals can kill invasive species. It's the idea that they will outcompete invasive species when it comes to nutrients and growth.

But when you take a sledgehammer to the problem and administer broad spectrum antibiotics or use fecal transplants, you don't get the results you want. You cause so many changes within the microbiome, that pathogenic species are actually the ones thriving at the end of the treatment. Those harmless commensals are under way more stress due to the treatments, than the pathogenic species you try to remove. Any initial benefits are undone when those pathogenic species end up exploiting the environment the treatment created.

What you want is highly specific treatment, going after the invasive properties of a handful of bacteria, and leave the ecosystem as a whole...alone and undisturbed.
 
Gastros are thankfully increasingly aware that you don't want to disturb this delicate balance.

The microbiome doesn't cause disease in crohn's disease, gastros that say this have no idea what they're saying, the microbiome didn't ''turn on patients'' for the heck of it one day. The disease is caused by invasive pathogens.

But what many gastros are right about, is that that microbiome is delicate and those commensals help prevent those invasive species from thriving.

Most gastros are aware that you should administer antibiotics for non-intestinal infections, through an IV if possible in CD patients, that anti-fungal medication that is administered topically is better than letting the patient swallow pills, you basically want to leave the microbiome alone. You don't want to antagonise it with antibiotics or fecal transplants, especially not because all the offending agents are enterobacteria and what antibiotics and fecal transplants usually do is kill harmless gram positive bacteria instead by disturbing the whole ecosystem, bacteria that were controlling the growth of pathogenic species.
 
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you basically want to leave the microbiome alone
This idea that you can ''modulate'' the microbiome and help patients is offensive to the complexity and the millions of species that live in the intestine.

Gastros that give broad spectrum antibiotics, fecal transplants, specific diets...and what have you....to crohn's disease patients...in a fruitless effort to play God by trying to bring about changes in the micriobiome...are reckless. These patients all relapse after any initial improvement, and they relapse much worse than before the treatment.

The microbome is 100% capable of modulating itself, it doesn't need help. Once inflammation subsides in crohn's disease patients, the microbiome changes back to a homogenic state.

What will work, instead of trying to modulate millions of species, is going after the handful of offending pathogens, by studying them, detailing their invasive mechanics, and find solutions, without causing havoc on the delicate microbiome.
 
Location
San Diego
In 2018 Takeda signed a deal with Enterome to buy a stake in the EB8018 FimH drug, which is a good thing. Because Enterome is a small French start-up, basically a "virtual company" without the resources to get a major new drug across the regulatory finsih line and onto the market by itself. Takeda can provide both the money and the know-how to make it happen (assuming the drug works).





 
It's a ''good thing'' that the invasive bacteria found in crohn's disease are enterobacteria that you also see in other diseases. There is some overlap between the invasive E coli found in crohn's disease and those found in UTI for example, at least when it comes to adhesion. FimH blockers developed for crohn's disease would overlap with those used for UTI, so it's an attractive development path for pharma companies due to the broader potential market.

FimH blockers are also interesting because you could just give them to crohn's disease patients by themselves or on top of the existing treatment they are on. It's not an immunsuppressive, so it has no cumulative effect.
 
Then again, if bacteriophages can just lyse the bacteria, you don't need the FimH blocker to begin with. Phages would also be able to take out the bacteria within macrophages, where FimH blockers won't be useful.

The inflammation in crohn's disease doesn't happen in the lumen you see, it hapens in the lamina propria, the inflammation starts when bacteria enter the lamina propria and tissue macrophages respond (as they should).

Inflammation in crohn's disease happens ''inside out'' like Marcel Behr described it. The inflammation starts deeper into tissue, the inflammation at the mucosa is the secondary event.

The inflammation is coming from pathogens that ENTERED tissue, it's not coming from the microbiome. FimH blockers block bacterial motility you see, which limits their ability to enter tissue.

If you give the FimH blocker, you're not going to see immediate resolution of inflammation, you'll prevent new bacteria from migrating into tissue, but you won't kill the ones in activated macrophages in tissue. Bacteriophages will, they'll enter macrophages and just lyse them. Bacteriophages would be able to stop actuve inflammation, while FimH blockers would be able to stop the migration of bacteria accross the intestinal barrier.
 
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The inflammation in crohn's disease doesn't happen in the lumen you see, it hapens in the lamina propria, the inflammation starts when bacteria enter the lamina propria and tissue macrophages respond (as they should).
This is why the inflammation in crohn's disease is transmural, can causse fistula, and doesn't just subside quickly.

Crohn's is not like UC, Crohn's disease is all about macrophages that live deeper into tissue, and respond to invasive pathogens.

That's why crohn's disease patients experience these deep pains during inflammation, it's the tissue macrophage releasing cytokine that cause the pain.

The macrophages don't just release inflammatory cytokine, they also activate pain mechanics, nociceptors, that's why the pain in crohn's disease feels like tissue, the intestine itself that hurts, it,s the macrophages setting off the alarm bells, in response to invading pathogens.

UC is about the superficial mucosa and neutrophil response.

Macrophages live much longer than neutrophils, that's why crohn's disease is so chronic, takes such a long time of treatment to get mucosal healing etc.

Crohn's is nothing at all like UC, but I have said this a million times, IBD is a horrible horrible word that should not be used.

Crohn's is deep tissue inflammation with granuloma, UC is mucosal inflammation...calling them ''Inflammatory Bowel Disease''...is idiotic, because the inflammatory mechanics behind them are completely different. Crohn's is far more like chronic granulomatous disease, crohn's could easily be called intestinal chronic granulomatous disease, or chronic granulomatous enteritis.
 
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kiny, I have a hypothetical question for you. If there was a safe and effective method of eradicating AIEC from Crohn’s patients, never to return, would that cure Crohn’s?

Imagine the patients take a pill, it kills all the AIEC in the patients’ body and the AIEC won’t ever come into the body of the patients. What would you expect from that? Cure?
 
kiny, I have a hypothetical question for you. If there was a safe and effective method of eradicating AIEC from Crohn’s patients, never to return, would that cure Crohn’s?

Imagine the patients take a pill, it kills all the AIEC in the patients’ body and the AIEC won’t ever come into the body of the patients. What would you expect from that? Cure?
Probably not cure, but greatly reduce inflammation in patients with an AIEC infection (which is a majority of people ileal crohn's). To the point that it might be experienced as a cure in some individuals.

The reason why it likely wouldn't completely cure crohn's is because people with crohn's have some innate defficiencies at the mucosal barrier, increased permeability, tight junction and macrophages anomalies.

The inflammation in crohn's is caused by pathogenic and pathobiont bacteria entering tissue, which results in intestinal inflammation, that is undeniable at this point. Why they are able to enter tissue is due to innate immunodeficiencies, that manifest themselves in increased intestinal permeability at tight junctions, uptake of bacteria by peyer's patches and macrophage defficiencies. If you are able to remove the most offending pathogens, AIEC being one of them, you will greatly reduce the inflammation, you might not completely cure the disease because you still have macrophage and intestinal barrier disfunctions, but patients would be largely free of inflammation is my belief.
 
I don't think anyone really is looking to cure crohn's disease, or that the quest for a cure is beneficial. A cure would involve stemm cell therapy or other drastic and potentially dangerous therapies to permanently correct innate barrier and macrophage deficiencies.

All a crohn's patient really needs to be technically cured is to remove the most offending pathogens , and to restore competent intestinal barrier function so the chronic entry of antigen into the lamina propria is stopped.

I think in the near future that will be possible with bacteriaophages and FimH blockers that go after the most offending of pathogens, and medication that supports tight junctions and growth factors like TGFb that decrease intestinal permeability.

Even ''healthy'' people are not free from intestinal inflammation, the intestine is simply designed to be permeable to a point, to allow entry of nutrients. The ''cure'' for crohn's disease is simply bringing down that inflammation with safer and more effective medication.
 
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What AIEC, Malassezia and a handful of other pathogens do is simply make the inflammation much much worse.

The innate immune deficiencies in crohn's disease are ... innate. You are born with them. While it might be possible to manipulate blood monocytes and tissue macrophages, you can not simply cure an innate barrier or macrophage dysfunction that has its basis in genetics, without resorting to drastic and dangerous therapies like stem cell therapies.

All you really want to do is bring patients back to a homogeneous state where pathogens are not exploiting a permeable intestine, bring patients back to a pre-crohn's state. That's all you need, stop the chronic entry of antigens into the lamina propria, restore barrier function, and you have a technical cure that will effectively be experienced as a cure by patients.
 
Do you feel hopeful about the qu biologics idea? From what I understand they are trying to increase deficient immune response which hopefully would result in reduction of pathogens. I’m interested in your view as there is talk on the website of a European trial this year.
 
Also, do you think there is any worth in some of the intestinal permeability “cures” on the internet, I.e. drinking endless bone broth?
 
Also, do you think there is any worth in some of the intestinal permeability “cures” on the internet, I.e. drinking endless bone broth?
The small intestine uses mainly arginine, glutamine, and growth factors (TGFβ, macrophage signaling) to recover after intestinal inflammation. You get these from regular diets. Not sure specific diets help crohn's, I think several do more harm than good by excluding many nutrients.
 
Do you feel hopeful about the qu biologics idea? From what I understand they are trying to increase deficient immune response which hopefully would result in reduction of pathogens.
We've tried stimulating innate immune responses with GM-CSF, which wasn't very successful.

While the innate immune response is incompetent in crohn's disease, it is also the innate immune response that causes the tissue damage and inflammation.

Stimulating an innate immune response in crohn's disease patient could lead to more intestinal damage too if there's no resolution. It has to result in mucosal healing so the pathogens are not just cleared effectively, but innate barrier function is restored too.

The important reason why anti-TNF work, is because they are able to cause rapid mucosal healing.
 
Location
San Diego
The small intestine uses mainly arginine, glutamine, and growth factors (TGFβ, macrophage signaling) to recover after intestinal inflammation. You get these from regular diets. Not sure specific diets help crohn's, I think several do more harm than good by excluding many nutrients.
Nestle came up with dietary treatment formula about 5 years ago that was high in those amino acids for treatment of mild to moderate Crohn's - the theory being that boosting the dietary intake of the key amino acids would strengthen the mucosal barrier and decrease the disease. Didn't work. It flunked the clinical trials and thus never made it to the market.
 
Nestle came up with dietary treatment formula about 5 years ago that was high in those amino acids for treatment of mild to moderate Crohn's - the theory being that boosting the dietary intake of the key amino acids would stengthen the mucosal barrier and decrease the disease. Didn't work. It flunked the clinical trials and thus never made it to the market.
EN are made with protein sources that contain a lot of growth factors and nutrients that are conditionally required. Nestlé's modulen is TGFβ enriched for example, growth factors in EN likely contribute to mucosal healing.

https://onlinelibrary.wiley.com/doi/abs/10.1177/01486071050290S4S126

There have been several trials in CD patients that used glutamine enriched diets, we know the small intestine requires a lot of glutamine. Rutgeerts (Donth) his study showed no appreciable benefits. But the patients likely had no glutamine shortages. We know glutamine can be non-essential in certain subjects, but become conditionally-essential in others.
 
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The hopeful thing is that we are starting to understand crohn's disease and where the inflammation is coming from. It's not autoimmmune (not directed at a self-antigen), it is not directly targeting the lumen microbiome either.

The inflammation is directed at microbes entering intestinal tissue. Those bacteria, pathogenic ones that actively enter tissue like AIEC and pathobionts from the micriobiota that enter unwillingly through lesions, set off a chronic immune response. They are not effectively cleared by the innate immune system (macrophages) so you get chronic inflammation in many patients.

All the treatments that have an effect on the disease course are either causing mucosal healing (anti-TNF) which limits the bacteria from entering tissue, or they are actively lowering bacterial load directly (antibiotics) or indirectly through diversion of the fecal stream high in bacterial load (TPN, fecal diversion) and nutrient deprivation through highly bioavailable formulations (EN).

Research also seems to agree that dysbiosis is not the cause of the disease, but a secondary event. Several treatments like TPN and EN, decrease bacterial diversity, can increase dysbiosis and yet they are effective to cause mucosal healing. What EN and TPN seems to do, is affect bacterial load. When bacterial load is brough down, the bacterial stress at the mucosal barrier is lowered.
 
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Research about dysbiosis and this idea that there are good and bad bacteria, has clouded progress.

People who advocate for manipulation of the microbiome with probiotics and fecal transplants (none of which work), seem so focused on dysbiosis, that they have forgotten, or have not realised, that

-the fecal stream high in bacterial load causes inflammation in crohn's disease
-many people with active crohn's disease have SIBO (small intestinal bacterial overgrowth), somehow these studies end up being completely ignored and overshadowed the dysbiosis arguments

Not sure who mentioned it on this forum, but a fecal transplant for crohn's disease is like throwing gasoline on the fire. It is a good analogy.

All treatments that work for crohn's disease, do the opposite of what probiotics and fecal transplants do. Instead of increasing bacterial load, effective treatments from crohn's disease limit bacterial entry into tissue through mucosal healing, and bring down bacterial load.

Bacteria are not our friends. One can not mimmick crohn's disease in a sterile environment.
 
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What AIEC, Malassezia and a handful of other pathogens do is simply make the inflammation much much worse.

The innate immune deficiencies in crohn's disease are ... innate. You are born with them. While it might be possible to manipulate blood monocytes and tissue macrophages, you can not simply cure an innate barrier or macrophage dysfunction that has its basis in genetics, without resorting to drastic and dangerous therapies like stem cell therapies.
Perhaps CRISPR will be able to eventually “fix” the innate deficiencies?
 
What I find difficult to understand is that although cases are growing in the under 10 age group, the majority of cases don’t appear until late adolescence and early adulthood. If the innate immune system is faulty, why does it take 20 or so years for Crohn’s to appear? The answer to this question also led me to believe MAP had something to do with it since it is a very slow growing pathogen. People become infected long before the symptoms appear. And if a person never encounters MAP they may never know their ability to fight it is compromised. It seems so logical, and maybe it is the same for other pathogens, like AIEC?
 
Yesterday I learned of a very interesting company called Inflammatix. They have created several diagnostic tests using the host immune response to read the Immune system and diagnose specific diseases like sepsis, TB, etc. They can differentiate between viruses and bacteria, and latent and active stages. There is a lab at Stanford linked with the co-founders of this company, working on IBD.
 
Location
San Diego
What I find difficult to understand is that although cases are growing in the under 10 age group, the majority of cases don’t appear until late adolescence and early adulthood. If the innate immune system is faulty, why does it take 20 or so years for Crohn’s to appear?
That's a good question, and perhaps and even harder question is why is there a second spike in the incidence of new Crohn's cases that appears in ages 50s - 60s? One can speculate that there needs to be a second trigger, such as a thinning of the protective mucin coating of the gut over time or other problem, that increases the gut permiability and allowing exposure to the triggering bacteria. But that certainly hasn't been proven.

MAP may well be one of the bacteria that can trigger Crohn's, but IMO it is certainly not the only one. There are too many holes in the MAP theory ( the inability to detect any trace of MAP in many Crohn's patients, the low incidence of Crohn's in dairy farmers, and the reduced risk of Crohn's in milk drinkers for examples) for MAP to be THE one big cause of Crohn's.
 
I understood that it was at times when the immune system is weakened, by stress or a bad cold, etc., and with older people whose immune system is no longer as robust. However I just read yesterday about the cattle vaccine being created at Washington State showing that in MAP, like in TB in humans, relA prevents CD8 T-cells from activating and killing intracellular bacteria: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917596/?fbclid=IwAR3opAHNWyiA3aj4gsH3D5L8TsU7GsYRizQKGumys5dLKtjN4D0rrbIWD9M

The article is quite technical and difficult to understand but interesting. I wonder though, why if scientists have known this about TB, why haven’t they been able to figure out an efficient vaccine? Maybe because as I also gleaned, that CD4 and CD8 T-cells need to simultaneously recognize their respective epitopes?
 
the majority of cases don’t appear until late adolescence and early adulthood. If the innate immune system is faulty, why does it take 20 or so years for Crohn’s to appear?
The most straightforward explanation why crohn's disease generally manifests itself around puberty is the activity of peyer's patches. Peyer's patches are most active and most numerous during puberty, some pathogens are able to exploit peyer's patches that allow them access into tissue.

Peyer's patches are exclusive to the small intestine, it's a straightforward explanation for ileal crohn's, but it of course doesn't explain rarer cases of crohn's with no ileal involvement.

What I find difficult to understand is that although cases are growing in the under 10 age group
Right, there is no explanation why the incidence of CD is rising in kids, long before puberty, it's a rather recent trend. It's hard to argue they don't have crohn's, they have the same rate of granuloma, anti-ompC, anti-flagellin, they have crohn's disease. Why, I have no idea.
 
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MAP may well be one of the bacteria that can trigger Crohn's, but IMO it is certainly not the only one.
The whole intestine is lined from top to bottom with macrophages, they will respond and ingest any bacteria, fungi, organic or inorganic particle they encounter into their vesicle. The fact we have such varying degrees of severity among crohn's disease patients indicates as much.

Over half of people with crohn's disease have granulomatous disease, but not everyone does. A granuloma has historically been a telltale sign of a mycobacterial infection, when you think of granuloma, you think of mycobacteria. But it doesn't have to be the case of course, if bacteria are chronically entering intestinal tissue you'll simply get a granulomatous response, macrophages literally trying to wall off the intestine from further infection.

Granuloma are a sign of chronic infection, persistent infection, delayed clearance, whatever you want to call it. Mycobacterial in most cases, fungal in some rare cases. Bacteria that are resisting phagocytosis. You get a grouping of macrophages and T cells, that you can clearly isolate during endoscopies. It could be AIEC resisting macrophages, MAP, fungi, any resistant bacteria.
 
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Kiny, the formation of granulomas makes sense and it would seem to clearly indicate an infection by a pathogen. But what about the people who don’t have granulomas? Can we still say the same thing? Thanks!
 
The underlying basis for the chronic inflammation is the same in every patient I think. Tissue macrophages in the lamina propria will regard every bacteria that enters tissue as an invading pathogen.

That will result in the formation of granuloma in some, and not in others, likely depending on the bacteria, depending on location, depending on genetic deficiencies, depending on the involvement of peyer's patches.


Researchers have tried to distinguish pathogens from pathobionts, but the innate immune system doesn't make that distinction, the innate immune system is by design, non-specific. Any foreign substance that enters tissue is regarded as pathogenic by macrophages, phagocytes will not tolerate any bacteria in the lamina propria, it doesn't matter if it's a mycobacteria or the supposed ''good'' bacteria from a probiotic.

The argument that crohn's manifests itself from the mouth all the way to the colon is of course not the reality, the disease is concentrated in the ileum and colon. The ileum and the colon is where bacteria are, the higher up you go in the digestive tract the less bacteria there are.

When there is a breakdown of the mucosal layer and disruption of tight junction competence, it allows entry of a whole host of bacteria, including ''supposedly'' good bacteria. We now know fecal transplants worsen disease, and thanks to older studies from Rutgeerts we know the fecal stream itself causes disease due to its high load in bacterial content.
 
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My son’s symptoms first showed up in the mouth. But we didn’t know what it was and he lived with a misdiagnosis and worsening condition for nearly a year. Turns out his mouth was a reflection of his entire digestive tract, and culminated in anal fistula formation. But, more inflammation and ulcers were located in his terminal ileum.
 
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