Discussion with Dr. Mark Sundrud

[artheta]

A couple of things I got from this were the need for personalised treatments, and that dietary interventions (via interactions with bile acids) are likely to be much more impactful in small bowel Crohn's, and bacteria-centric therapies in colonic Crohn's (and UC). I already knew that diet was more important in Crohn's, and bacteria in UC, but of course Crohn's can affect the colon as well. So maybe colonic Crohn's can be treated similarly to UC.

I'd be interested to hear his thoughts on AIEC in particular, although I get the impression he would think they're not the whole story. At least, not in everyone.

Definitely enjoying the format of these videos. People are doing the science, but it's not always communicated very well, or very clearly. So we need more of this.

 

[kiny]

"the inflammatory response is sparked by antigen derived from gut bacteria, the trillions of gut bacteria"

No, this theory has been debunked countless times.

If the inflammatory response was directed at the gut flora, crohn's disease patients would have superficial inflammation all over the intestine, including the colon, everywhere the gut flora comes into contact with the epithelial cells, there should be inflammation. That is not the case in crohn's disease, crohn's disease involves patchy and deep tissue inflammation.

Only deep transmural inflammation in crohn's disease can lead to fistula and strictures in patients. The response is targeting pathogenic bacteria that have entered tissue.

Granuloma seen in crohn's disease should be enough by themselves to discredit the microbiome theory, granuloma in intestinal disease happens in response to tissue and macrophage penetration of bacteria, it happens in diseases like intestinal TB, it happens during foodborne infections, it happens in every disease that involves a response to a tissue bacteria. Including crohn's disease.

Crohn's disease early endoscopic signs involve inflamed ulcers where M cells reside, which point to specific macrophage penetrating bacteria that have entered tissue and set off macrophages in the lamina propria.

Genetic predispotion in crohn's disease point to an incompetent bacterial recognition in NOD2, and an incompetent xenophagy response in ATG16L1, which again point to intracellular bacteria exploiting phagocytosis incompetence.

Early crohn's disease does not involve dysbiosis, dysbiosis comes later in response to inflammation. Dysbiosis resolves itself when crohn's disease patients take anti-inflammatories. The suggestion that crohn's disease patients came down with the disease because one day, the immune system suddenly decided to lose tolerance to the microbiome and mount an immune response for no reason is a popostrous suggestion.

If the immune response was directed at the dysbiotic microbiome in crohn's disease, fecal transplants would work, they don't.

"diets / vitamins / bile acids"

Crohn's disease will not be solved with diets and vitamins. The inflammation does not start at the epithelial border, it starts in the lamina propria where macrophages are chronically activated, failed clearance of bacteria by phagocyte leads to chronic inflammation. Vitamins or special diets won't change that.

Only elemental nutrition leads to remission, which is a consequence of nutrient deprivation due to high bioavailability and uptake, it has nothing to do with any local effect in the intestine, every single EN works just as well. It's also something no diet will ever be able to replicate. EN are specifically engineered to be bioavailable and to have uptake high in the GI tract.

IV feeds as a dietary intervention work also, by the same mechanic EN do, nutrient deprivation, it lowers bacterial load. Intravenous feed solutions are made by the same companies making EN.

The way EN and IV feeds work is thanks to advances of the last decades that allow us to manipulate nutrients, no diet can recreate this.

After decades of research, there are no known "dietary triggers" in crohn's disease. It does a disservice to crohn's disease patients to put forward the idea that there are, because patients get the dangerous idea in their head that they can manage their own disease if they go on "SCD" or "Paleo", or if they don't eat this or that. The idea that they can manage their own disease without seeking help. If there was a dietary trigger in crohn's disease, we would have found it by now.

 

[Mommabear]

No, this theory has been debunked countless times.

If the inflammatory response was directed at the gut flora, crohn's disease patients would have superficial inflammation all over the intestine, including the colon, everywhere the gut flora comes into contact with the epithelial cells, there should be inflammation. That is not the case in crohn's disease, crohn's disease involves patchy and deep tissue inflammation.

Only deep transmural inflammation in crohn's disease can lead to fistula and strictures in patients. The response is targeting pathogenic bacteria that have entered tissue.

Granuloma seen in crohn's disease should be enough by themselves to discredit the microbiome theory, granuloma in intestinal disease happens in response to tissue and macrophage penetration of bacteria, it happens in diseases like intestinal TB, it happens during foodborne infections, it happens in every disease that involves a response to a tissue bacteria. Including crohn's disease.

Crohn's disease early endoscopic signs involve inflamed ulcers where M cells reside, which point to specific macrophage penetrating bacteria that have entered tissue and set off macrophages in the lamina propria.

Genetic predispotion in crohn's disease point to an incompetent bacterial recognition in NOD2, and an incompetent xenophagy response in ATG16L1, which again point to intracellular bacteria exploiting phagocytosis incompetence.

Early crohn's disease does not involve dysbiosis, dysbiosis comes later in response to inflammation. Dysbiosis resolves itself when crohn's disease patients take anti-inflammatories. The suggestion that crohn's disease patients came down with the disease because one day, the immune system suddenly decided to lose tolerance to the microbiome and mount an immune response for no reason is a popostrous suggestion.

If the immune response was directed at the dysbiotic microbiome in crohn's disease, fecal transplants would work, they don't.



Crohn's disease will not be solved with diets and vitamins. The inflammation does not start at the epithelial border, it starts in the lamina propria where macrophages are chronically activated, failed clearance of bacteria by phagocyte leads to chronic inflammation. Vitamins or special diets won't change that.

Only elemental nutrition leads to remission, which is a consequence of nutrient deprivation due to high bioavailability and uptake, it has nothing to do with any local effect in the intestine, every single EN works just as well. It's also something no diet will ever be able to replicate. EN are specifically engineered to be bioavailable and to have uptake high in the GI tract.

IV feeds as a dietary intervention work also, by the same mechanic EN do, nutrient deprivation, it lowers bacterial load. Intravenous feed solutions are made by the same companies making EN.

The way EN and IV feeds work is thanks to advances of the last decades that allow us to manipulate nutrients, no diet can recreate this.

After decades of research, there are no known "dietary triggers" in crohn's disease. It does a disservice to crohn's disease patients to put forward the idea that there are, because patients get the dangerous idea in their head that they can manage their own disease if they go on "SCD" or "Paleo", or if they don't eat this or that. The idea that they can manage their own disease without seeking help. If there was a dietary trigger in crohn's disease, we would have found it by now.

Kiny, thank you for your opinion. I always find what you have to say very interesting, thought provoking and valid. Dr. Sundrud mentions he believes that only 10% of folks diagnosed with Crohn's have the issue he discussed. Isn't it possible that for the vast majority, his findings won't apply but for some it will? Not everyone who has Crohn's has the NOD2 mutation, right? That is part of the problem in figuring this thing out, and so incredibly frustrating. It doesn't seem to fit any pattern, and why many are now calling to change the name because the term, Crohn's doesn't reflect the individuality of symptoms.

 

[kiny]

Not everyone who has Crohn's has the NOD2 mutation, right?

Right, and most people with these specific NOD2 and ATG16L1 anomalies don't develop crohn's disease.

These 2 genes are very interesting, because they are a specific risk factor for crohn's disease but confer no risk of developing UC. They offer very specific clues about crohn's disease.

NOD2 anomalies are very specific to Westerners, specifically with disease in the ileum.

Crohn's doesn't reflect the individuality of symptoms

Sundrud recognises that UC and Crohn's are nothing alike. Crohn's involves deep tissue inflammation, presents granuloma, can lead to strictures, fistula, and there is actually little genetic overlap with UC, outside of IL23 anomalies, which aren't very specific. UC is nothing alike, it's a different disease.

Crohn's disease is closer related to chronic granulomatous disease or blau syndrome than it is to UC.



But ileal crohn's disease is very specific, and all patients with ileal involvement (the majority of CD patients) have extremely similar symptoms.

Sundrud mentioned that crohn's disease involves the small intestine with a lower bacterial load than the colon.

Well, let's be more specific, crohn's disease extremely rarely involves the duodenum and jejunum. It involves the ileum, where bacterial load is extremely high. That's why the ileum has peyer's patches and the duodenum and jejunum do not.

Some argue that crohn's disease can manifest itself anywhere in the GI tract. Well no, in 99% of cases it manifests itself in the ileum and/or colon, with sporadic aphthous mouth ulcers.

Some argue that crohn's disease can be diagnosed at any age. Well no, in the large majority of cases, age of onset is during puberty, when peyer's patches are most active.

While UC is very different from crohn's, ileal crohn's disease is very consistent among patients, especially Westerners. You can't really put people with ileal crohn's in different categories, age of onset, granuloma, deep tissue inflammation, response to treatment, people with ileal crohn's heave markedly similar features.

 

[kiny]

I don't believe there are multiple explanations for crohn's disease. What is true is that in diseases that involve an infectious agent, there is always a smaller subset of people where you either can't find the offending pathogen, or it involves an unknown pathogen.

The bacteria suspected in crohn's disease belong to 1 group, Enterobacteriaceae. E Coli, foodborne bacteria (Salmonellas, campylobacter, listeria) and Klesbiella. A mycobacterial agent seems less likely to me.

There aren't that many bacteria that are capable of causing disease in the ileum, to cause disease in the ileum they need to have invasive properties and they need to interact with M cells to enter peyer's patches.

The microbiome is not invasive, they have lived in harmony with humans for millions of years. They don't feature flagella, they have no desire to enter tissue. TLR built tolerance for them. The microbiome can never explain the deep tissue inflammation in crohn's.

There are a handful of pathogenic bacteria involved in crohn's, I believe crohn's disease is much less complicated than it seems, you can only explain the activation by tissue macrophages in the lamina propria if you invoke pathogenic bacteria that can enter tissue, and there's only so many that do this on a wide enough scale to explain the prevalence of crohn 's disease.

 

[kiny]

The fact that anti-TNF work in crohn's disease shows the inflammation happens in tissue in the lamina propria, not just at the epithelial border. The inflammation is not directed at lumen content, TLR are very tolerant to the microbiome.

What TNF-alpha blockers do is block the TNF-alpha signaling molecules released by macrophages, macrophages that reside in the lamina propria and were activated by a pathogen in tissue.

Macrophages don't just randomly active to content in the lumen, tolerant TLR prevent this from happening. What is happening is that a pathogen (like AIEC for example) has entered tissue, and activated a lamina propria macrophage, phagocytosis incompetence and bacterial clearance fails, this macrophage uses signaling cytokines like TNF-alpha to mount an adaptive response. As long as the bacteria is not removed, the inflammation remains chronic.

 

[kiny]

The suggestion that a food intolerance, or dietary triggers causes the inflammation in crohn's, can not be taken serious.

Crohn's disease features deep tissue inflammation, so intense that at times it causes fistula. There are no "food intolerances" or "dietary triggers" that causes such deep tissue inflammation that it causes fistula or strictures.

Disease that cause the deep transmural tissue inflammation and pockets of granuloma full of macrophage that try to shield off the intestine, are only seen in acute and often deadly infections. They're seen in uncontrolled intestinal TB in 3rd world countries. That's what crohn's disease looks like. It doesn't look like UC, or a food intolerance, it looks like intestinal TB.

The suggestion that crohn's is caused by a dietary trigger makes light of the seriousness of crohn's. It's not caused by a dietary trigger.

 

[my little penguin]

Some argue that crohn's disease can be diagnosed at any age. Well no, in the large majority of cases, age of onset is during puberty, when peyer's patches are most active.

Then what about very early onset ibd (children under the age of 8 ) diagnosed with Crohn’s disease

 

[kiny]

Then what about very early onset ibd (children under the age of 8 ) diagnosed with Crohn’s disease

None of the cases of crohn's disease described as a form of crohnic enteritis by Dalziel, involved children.

Van Kruiningen did large demographic studies on age-of-onset of crohn's disease in the 90s. The large large majority of cases involve patients with age-of-onset between 15-24, when peyer's patches peak in the ileum.

At 8 years of age, peyer's patches are rare. Very young children who develop intestinal inflammation, years before puberty, and years before the activation of peyer's patches are a mystery to me. They do not have crohn's disease as described by Dalziel.

 

[kiny]

1972 The early histological lesion of Crohn's disease.

Morson describes inflamed peyer's patches as the earliest signs of crohn's disease onset


2006 Peyer's patches and M cells as potential sites of the inflammatory onset in Crohn's disease

Inflamed Peyer's patches are described as the earliest sites of inflammation.


In 35 years, how crohn's disease starts, has not changed. It starts with peyer's patches in the ileum. Likely a bacteria that has invaded M cells.

Why in 2021, there are doctors saying little kids have crohn's disease, even though 8-year-olds have no active peyer's patches to speak of, is something you'll have to ask those doctors, but they are certainly describing a disease that can't possibly look like crohn's disease through their endoscope.

 

[my little penguin]

My child was dx at 7 and biopsies did have chronic and acute inflammatory changes .
Incudling the lamina proper as well a non caseating granulomas in the terminal ileum .
No evidence of chronic granulomas disease
Multiple second opinions at multiple major university based hospitals.
Plus MRE showing thickening in the terminal ileum

there are many kids under the age of 8 who have evidence on biopsy of Crohn’s disease
My kiddo was one of them
He is 18 now .

 

[kiny]

It is a mystery for me, I haven't seen any early endoscopic images of kids with crohn's disease.

A young child might have 40 or 50 peyer's patches, an adolescent willd have hundreds. The presence of M cells is critical for invasive bacteria to enter tissue. I have no explanation why a child with undeveloped peyer's patches would develop deep tissue inflammation as seen in crohn's disease patients.

 

[artheta]

After decades of research, there are no known "dietary triggers" in crohn's disease. It does a disservice to crohn's disease patients to put forward the idea that there are, because patients get the dangerous idea in their head that they can manage their own disease if they go on "SCD" or "Paleo", or if they don't eat this or that. The idea that they can manage their own disease without seeking help. If there was a dietary trigger in crohn's disease, we would have found it by now.

Still, we're seeing the development of new diets like the Crohn's Disease Exclusion Diet (CDED), CD-TREAT diet, and others. I was put on the LOFFLEX diet following EEN. Are you saying that such diets are pointless?

You say that reducing bacterial load is how EEN is beneficial. But surely foods can contribute to bacterial load in differing degrees?

And what about the effects of food additives, like emulsifiers that upregulate AIEC gene expression? For example: https://www.sciencedirect.com/science/article/pii/S2211124720312183 .

If nothing else, some foods are commonly reported as causing worsening symptoms. So it seems to me that there are many reasons to care about diet, even if a diet can't directly induce remission.

 

[westernbuddy]

I think often the food is just making the damage worse not causing the damage.

For instance if you have inflmation cuts and ulcers, spices may make it worse, water may make it better.

By taking away the food and living on entral nutrition it's less fuel for the fire.

I had crohns in my ileum around the age of 14, then the dudoneum around 27.

How it is in both locations I have no idea, its the same disease in both locations I know that, and without doubt its crohns.

My Hospital in the uk, City population is 350k,,, 2k crohns patients, and around 80 with it in the dudoneum.

The inflammation is targeting something, and I think it's bacteria, however I'm not 100% certain. I wish I was more scientific to understand better.


@kiny it's very impressive reading your posts, I hope scientists and pharma are actually reading them too.

I think they are.