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Thinking about Crohn's wrong has set patients back decades

The near-exclusive focus on Crohn's as an immune disorder has clouded the judgment of doctors and has set back the research on Crohn's by at least a decade. Even today, many if not most doctors consider Crohn's to be an autoimmune disorder, although little evidence in favor of that theory has ever been produced.

Yes, Crohn's is characterized by an immune response (inflammation), but that doesn't mean that the immune system is the root of the problem. Yes, patients can be helped by various kinds of immune-suppressing and immune pathway-blocking drugs, but none of this means that causation starts with the immune system going wrong. The entire industry has been based on this assumption that Crohn's is caused by some kind of immune system problem, even though there's no actual proof.

I believe if doctors had a more appropriate mindset about Crohn's and humility about what we know and don't know about it, patients would receive better treatment. If the pharmaceutical companies hadn't been so laser-focused on blocking the next immune pathway for the last 30 years, maybe we would be seeing more progress toward real solutions.

I don't know exactly what causes Crohn's. I have my favored perspective (damage-oriented), but there are other possibilities. The bacteria-focused theories like MAP and AIEC deserve much more investigation than they've gotten so far. It's just sad that nearly all the focus has been on blocking the immune system for the last 30+ years.
 
I agree with you Pangolin. I try to tell my doctor this and they get upset with me. The money is in the medicine not a cure.
 
Do people suspect Crohn's could be driven by a food sensitivity or allergy causing the immune response? Just curious as I'm newer to the forums and Crohn's.
 

Bufford

Well-known member
Its hard dealing with a GI who has tunnel vision due to the theory of biologics being the only answer. My experience of biologics has left my body in a miriad of horrible side effects. I will have nothing to do with these treatments, and it does not help any when the GI will not look beyond biologics. It leaves the patient helpless. Given the huge costs of administering biologics I feel that it is being driven by big pharma and profits.
 
Do people suspect Crohn's could be driven by a food sensitivity or allergy causing the immune response? Just curious as I'm newer to the forums and Crohn's.
There is no consensus. However, there is a lot of evidence that food has something to do with the causation. Food allergies could be part of the causation in some cases, but my guess is that it's more often related to chemical damage caused by certain food components eg frying oils.

Nothing has really been proven, though.
 

my little penguin

Moderator
Staff member
@James02
True food allergies IgE mediated -occur within two hours of consuming the food
These can cause anaphylaxis or anaphylactic shock and lead to death
These do not cause crohns

food sensitivities are a different ball of wax
They can cause Gi upset among other things and the jury is out on them

cded ,scd ,and een are all peer reviewed accepted “diets “ with intent to treat in crohns
Success varies among folks
Een (exclusive enteral nutrition-formula only no solid foods ) is used a lot in kids to calm inflammation while waiting for meds

cded has been used in kids and adults who were refractory to other meds
Sometimes it works

What is a trigger food can and does change depending on whether your flaring or not
And sometimes just changes for no reason
After 11 years of dealing with my child having this nothing surprises me anymore


good luck
 
Its hard dealing with a GI who has tunnel vision due to the theory of biologics being the only answer. My experience of biologics has left my body in a miriad of horrible side effects. I will have nothing to do with these treatments, and it does not help any when the GI will not look beyond biologics. It leaves the patient helpless. Given the huge costs of administering biologics I feel that it is being driven by big pharma and profits.
All GI’s I have seen have had this tunnel vision. These are the only drugs they ever offer me even when I ask if there is anything else.
 
@James02

cded ,scd ,and een are all peer reviewed accepted “diets “ with intent to treat in crohns
Success varies among folks
Een (exclusive enteral nutrition-formula only no solid foods ) is used a lot in kids to calm inflammation while waiting for meds
Wow - I am reading up on these. That link looks very interesting. I was aware that Paleo's diet was helpful (due to reading on this forum), but I'm not familiar with the CDED, EED. I'll take a peek.

Thank you!
 
Gi or doctor will tend to offer the patient the best medicine they have at the time.

98% of Gi's are not scientists or pharma companies.

20 years ago medicine was very limited, biologics have given them more options.

They are perfectly aware of the disease and all its unknowns. But when a sick patient turns up they do what they can.

So I don't think it can be taken out on the patient facing Gi.

Outside of the gi world science and medicine/pharma is very complex.

Subjects like this raise awareness power of the people.

I know lots of scientists and Gi's are hopeful newer and safer medicine will come for our disease.

There is a really huge amount of work being done in the IBD area now. We may have hope, but not for another decade I don't think at least.
 
Do people suspect Crohn's could be driven by a food sensitivity or allergy causing the immune response?
A food allergy or sensitivity would evoke an immune response everywhere where the allergen comes into contact with the epithelial cell wall.

That is not the case in crohn's disease, crohn's disease occurs exclusively in areas with high bacterial load like the ileum and colon. The oral cavity is the only other area with high bacterial load, and not surprisingly people with crohn's disease frequently develop aphthous ulcers in their mouth.

In places where bacteria live and are able to penetrate into deeper lamina propria tissue, crohn's disease manifests itself. In places with low bacterial load, like the upper GI tract, crohn's disease is completely absent.

Early symptoms of crohn's disease features patchy skip lesions in ileal tissue surrounding points of entry for bacterial antigen, like the peyer's patches.

Crohn's is bacterial.

Immunosupressants control the cascading inflammation due to bacterial entry into tissue and the proliferation of bacteria like AIEC that replicate inside macrophages, but it does not address the cause. The cause being pathogenic bacteria that are able to enter tissue, evoking a chronic immune response due to the inability of the immune system to clear these bacteria.
 
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What you can argue of course is that Western diets promote an environment whereby pathogenic bacterial populations in the intestine gain the upper hand.

But this is something very different from a food allergy, an allergen creates inflammation everywhere it comes into contact with tissue immune cells. If you skin is allergic to nickel your nickel watch will cause an immune response regardless if you put the watch on your wrist or around your ankels. A nut allergy will cause an immune response everywhere the allergen comes into contact with epithelial cells, from the epidermis of your skin to the epithelial cells in your throat.

This is of course not what is going on in crohn's disease.

Crohn's disease features very specific skip lesions in areas with high bacterial load, it's not caused due to an allergy against some foods. If it was an allergy, you would have inflammation everywhere, you don't.
 
If you ask yourself what crohn's disease looks like, it doesn't look like an allergic reaction, it certainly doesn't look like UC.

What it does look like is intestinal TB, it looks like chronic granulomatous disease, it looks like a chronic foodborne infection. You can see inflamed peyer's patches, you can see granuloma featuring macrophages trying to shield off bacterial entry. You can see the innate immune system with activated macrophages release cytokine like TNF-alpha, you can see a very active and chronic adaptive response.

What I see, is an unresolved bacterial infection that became chronic.
 
What crohn's disease also is not, is an immune response against the microbiome. For one, you would have inflammation everywhere where the microbiome touches the epithelial wall, that is not the case. And secondly, the microbiome surrounding early ulcers in crohn's disease, is not dysbiotic, dysbiosis developes later (likely due to the inflammatory conditions). This dysbiosis largely dissapears in people in remission, but it does not cure the disease. Nor do fecal transplants or microbiome interventions cure the disease (they tend to make the inflammation worse). Dysbiosis is a feature of crohn's disease, likely due to the inflammatory condition, but it is clearly not the cause and the inflammatory response is clearly not targeting the microbiome.

What is the most likely explanation, is that a pathogenic bacteria gained entry into tissue (either through tight junction failure or M cells), and set off a tissue immune reponse in the lamina propria.

As long as these bacteria manage to evade the immune system and are not cleared, inflammation will persist. Not very different from how some people in remote areas of the world with intestinal TB would suffer for years before treatment cleared the bacterial infection.
 
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As far as possible candidates for those pathogenic bacteria, there aren't that many bacteria that can enter through peyer's patches and evade the immune system.
-pathogenic E Coli (AIEC)
-klebsiella
-foodborne infection like salmonella, campylobacter
-mycobacteria
-fungi

A viral infection is very unlikely simply because there is no precedent for this. Bacteriophages have evolved in harmony with humans, I have never heard of them actively causing disease, they don't infect cells. Viral gastroenteritis doesn't look like crohn's disease at all.
 
And then when you have chronic inflmation and ulcers, you start eating foods that annoy the tissue even further, pouring alcohol onto cut swollen inflamed tissue, then feeds the fire and leads to further damage.

I feel my dudoneum and ileum talking to each other, as I have a stricture in both, bacteria feels right, if feels often like they are trying to pass the buck to each other.

The lilium will say we are tired, dudboeum please hold the food some longer don't let bacteria down yet, then the duconeum has overload. Then the fight begins with the dudoneum and ilium, that's how I feel it.
 
Kiny, I agree with you that the inflammation in Crohn's is primarily an immune response to bacteria. However, there are many unanswered questions about exactly which bacteria (my guess is it's not just AIEC), why some patients get sick and others don't when most people are probably commonly exposed to these bacteria, how the bacteria are getting exposed to the immune system in certain places, why the problem becomes chronic in Crohn's patients, whether we can eliminate these bacteria, and whether patients have long-term improvement after the bacteria is eliminated.

What is it about Crohn's patients that results in these problems, while other people similarly exposed to bacteria have no problems? I presume that we would notice that Crohn's is infectious if the answer were simply that Crohn's patients get exposed to a specific bacteria and others don't.

I also suspect that the answer to this question is not "Most Crohn's patients have defects of the immune system", because I think that also would have been figured out by now. This is why physical or chemical damage or structural issues in the intestine or wound healing problems come up in my thinking, to explain what it is that makes certain people vulnerable.

On the other hand, maybe it's more like stomach ulcers and H.Pylori, and maybe just getting rid of the bacteria is the key.
 
However, there are many unanswered questions about exactly which bacteria (my guess is it's not just AIEC), why some patients get sick and others don't
We can now accurately predict who has a high chance of developing crohn's disease by using anti-OmpC and anti-flagellin serum tests, that indicate these people carry pathogenic E coli. Note that this only works for crohn's disease, not UC.

https://pubmed.ncbi.nlm.nih.gov/32165208/

What is it about Crohn's patients that results in these problems, while other people similarly exposed to bacteria have no problems?
It's just a roll of the dice.

A lot of infections happen as co-infections, where a primary infection serves as a precursor for the secondary infection.

A bacteria just needs the right conditions to thrive.

We see people often develop crohn's disease after a foodborne infection like campylobacter or salmonella. It leaves the intestine permeable, allowing a pathogenic bacteria to enter tissue.

We see people often develop crohn's disease after a course of antibiotics. Antibiotics gives a fitness advantage to pathogic species. After a course of antibiotics, they are no longer in competition with other bacteria, and can now attach themselves to an epithelial wall and invade tissue.

A number of people with crohn's disease have genetic anomalies that diminish phagocytosis competence of macrophages, which intracellular bacteria exploit.
 
On the other hand, maybe it's more like stomach ulcers and H.Pylori, and maybe just getting rid of the bacteria is the key.
In 1998 a researcher in Clermont-Ferrand in France discovered AIEC. Darfeuille-Michaud.

The reason it took such a long time before this bacteria got the spotlight it deserves, with large studies now found in journals like Nature, is because these bacteria are new, and need to be classified through virulence and adhesion properties because they have no easily identifable genetic marker.

If we can identify the troublemakers in crohn's, remove them with phages or disarm them with fimH blockers or anti-adhesion molecules, we are well on our way to new treatments that will be much more effective.
 
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We can now accurately predict who has a high chance of developing crohn's disease by using anti-OmpC and anti-flagellin serum tests, that indicate these people carry pathogenic E coli. Note that this only works for crohn's disease, not UC.
This proves that the immune system is reacting to certain bacteria, but what we don't know is whether this is a cause or an effect of the inflammation. Perhaps the inflammation (or, say, a defect in the intestinal lining caused by a prior infection) causes changes in the gut that allow bacteria to get exposed to the immune system, which results in the immune reaction. Perhaps a normal intestine doesn't allow the bacteria to become exposed to the immune system in the first place. My guess is you need the bacteria *and* an abnormality that exposes the immune system to the bacteria, and then the process can begin.

The usual problem with these theories, eg MAP, is that we can notice that we find MAP much more commonly in people with Crohn's, but we just don't know if that's merely because MAP thrives in the intestinal conditions of a Crohn's patient, because MAP is causing the inflammation, or because any bacteria will cause the inflammation and MAP happens to be there.

We could test this by attempting to induce Crohn's in healthy test subjects by giving them Crohn's associated bacteria, and we could compare them to people who we induce some kind of intestinal lesions in and then expose them to the bacteria, vs healthy controls given placebo. On second thought, maybe we shouldn't do this.

Of course, we do know that reducing bacteria can help some Crohn's patients, and we know that reducing the inflammatory response can also help some Crohn's patients. Maybe any bacterial or inflammation reduction can help the body heal, which reduces future immune system exposure to bacteria, if complete healing does happen. We're not sure yet if we can target and eliminate AIEC or maybe eliminate the specific immune response to AIEC to get rid of Crohn's, and I'm surprised there's no definitive answer to this considering AIEC has been known about for quite a while. Maybe targeting AIEC will really work, though.

A lot of infections happen as co-infections, where a primary infection serves as a precursor for the secondary infection.

A bacteria just needs the right conditions to thrive.

We see people often develop crohn's disease after a foodborne infection like campylobacter or salmonella. It leaves the intestine permeable, allowing a pathogenic bacteria to enter tissue.

We see people often develop crohn's disease after a course of antibiotics. Antibiotics gives a fitness advantage to pathogic species. After a course of antibiotics, they are no longer in competition with other bacteria, and can now attach themselves to an epithelial wall and invade tissue.

A number of people with crohn's disease have genetic anomalies that diminish phagocytosis competence of macrophages, which intracellular bacteria exploit.
Right, I appreciate all of this research. I think this is all on a much better track than the simpler "let's just block the next immune pathway" school of thought.
 
We could test this by attempting to induce Crohn's in healthy test subjects by giving them Crohn's associated bacteria, and we could compare them to people who we induce some kind of intestinal lesions in and then expose them to the bacteria, vs healthy controls given placebo. On second thought, maybe we shouldn't do this.
In the 90s Rutgeerts and Harper did such experiments. Rutgeerts showed that crohn's disease develops when healthy intestinal tissue from crohn's disease patients comes into contact with intestinal fluids. Harper redid this experiment and came to the same conclusion, but when Harper filtered out all the bacteria from the intestial fluids, no inflammation was observed.

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


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

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

Results: Contact with intestinal fluids for 8 days induced focal infiltration of mononuclear cells, eosinophils, and polymorphonuclear cells in the lamina propria, small vessels, and epithelium in the excluded neoterminal ileum that was previously normal. Epithelial HLA-DR expression increased, and mononuclear cells expressed the KP-1 antigen associated with activation. Marked up-regulation of RFD-7, RFD-9, intercellular adhesion molecule 1, and lymphocyte function-associated antigen 1 was observed after infusion, reflecting epithelioid transformation and transendothelial lymphocyte recruitment. At the ultrastructural level, dilatation of the endoplasmic reticulum and Golgi apparatus occurred in epithelial cells, where also basally located transport vesicles were identified.
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Perhaps a normal intestine doesn't allow the bacteria to become exposed to the immune system in the first place.
Bacteria in crohn's disease patients are either entering through M cells or through incompetent tight junctions. In people with ileal disease, they are almost certainly entering through M cells, because that's where all the peyer's patches are. In people with colonic disease they are likely exploiting a general barrier and tight junction failure.

The bacteria causing disease in crohn's disease are highly pathogenic and have clearly invaded tissue, they have been taken up by macrophages, because the inflammation in crohn's disease is deep transmural inflammation. Crohn's disease inflammation is very different from UC inflammation, inflammation in UC is very superficial, in crohn's disease it is deep tissue inflammation that comes from immune cells in the lamina propria, mostly macrophages.
 
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The fecal stream experiments are great, but they don't tell us why some people are susceptible while others aren't. Would healthy people react the same way to the fecal stream?

Is Crohn's due to ubiquitous bacteria that only affect some people due to particular susceptibilities, or is Crohn's more a result of uncommon exposure to particular bacteria? If the situation is mostly the former, then eliminating the bacteria may not do much because people will just be exposed to it over and over again.
 
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