Major cause of IBD found?

[Andersen007]

Media coverage:
https://www.bbc.com/news/articles/c1wwdd6v2wjohttps://www.ft.com/content/06a8ea18-2c92-4606-9b95-e69f614c5c10
Seems like this is the actual study behind it:
https://www.nature.com/articles/s41586-024-07501-1
What makes it quite strange, is the authors do not seem to distinguish between Crohn's or UC very consciously, some part of the study is exclusively about Crohn's, but then they take a lot of the colon samples at one part from UC, etc.

 

[Cross-stitch gal]

I'm afraid that sometimes it's hard to tell the difference between UC and Crohn's. I know that in my case, I was always told that mine was UC and treated as so. However, recently it was scene as Crohn's and supposedly it was possible that my diagnosis should have always been Crohn's anyway. So, I don't know...

 

[Delta_hippo]

Interesting they say about faulty immune system overreaction as I have had hayfever for many years before Crohn’s and I see a lot of people on here complaining of other immune issues too.
5 years until a potential treatment option from the various media articles today so fingers crossed

 

[Guerrero]

Very goood news! Hope it translates into a treatment soon

 

[Jo-mom]

Wouldn't that be wonderful it happened in this lifetime. I would very much like to see my 25 year old son live in a world that will have even better treatment than we do today, however, I'm grateful for what is around today compared to 30 years ago.

 

[Scipio]

Another line of interesting research, but it's pretty early days yet. Nothing from this is likely to see the light of day in my lifetime, but I'm glad they are making progress.

 

[Crohn2357]

Further reading:

https://www.healingwell.com/community/default.aspx?f=38&m=4344174

 

[asadmom]

Tweetorial in more detail from Lee: https://x.com/Dr_James_Lee/status/1799040690225344645

 

[J100]

While the research is interesting and promising, I think we should all wait and watch.

@kiny - What are your views on it? I think this research shows the root cause as a genetic problem. This seems to be at odds with AIEC being a possible root cause.

 

[Scipio]

@kiny - What are your views on it? I think this research shows the root cause as a genetic problem. This seems to be at odds with AIEC being a possible root cause.

Both could still be true. The underlying mechanism of triggering Crohn's could be when a genetically-driven primary defect in macrophage function (identified in the paper cited above) collides with AIEC or other potentially pathogenic gut bacteria resulting in excess production of inflammatory cytokines. The result = uncontrolled inflammation in the gut.

I await further research into this hypothesis.

 

[J100]

Both could still be true. The underlying mechanism of triggering Crohn's could be when a genetically-driven primary defect in macrophage function (identified in the paper cited above) collides with AIEC or other potentially pathogenic gut bacteria resulting in excess production of inflammatory cytokines. The result = uncontrolled inflammation in the gut.

I await further research into this hypothesis.

@Scipio - Thanks for your response. And it seems a plausible explanation that it could be a combination of AIEC along with genetics. The research stated that they are looking at trials in 5 years time. That is a long time. Why should it take that long to test it? Shouldn't they start conducting trials sooner than that?

 

[Scipio]

@Scipio - Thanks for your response. And it seems a plausible explanation that it could be a combination of AIEC along with genetics. The research stated that they are looking at trials in 5 years time. That is a long time. Why should it take that long to test it? Shouldn't they start conducting trials sooner than that?

It's common for new findings to take years to get to clinical trials. And the trials themselves will take years more. They probably need to do several years of more preliminary studies to nail down the details of the biochemical mechanisms that are causing the disease and how best to reverse them. Then they need to use that knowledge to choose the best candidate drug and then to carefully design the formal clinical trials needed to get regulatory approval. Depending on the natural course of the disease, the trials might take years to complete. And no matter what they are, the clinical trials will be horrendously expensive. If no rich pharma company or government is willing to put up the money, the trials might never start.

None of these factors is unique to Crohn's treatments. Developing and getting regulatory approval for new drugs for any serious disease is always slow and costly.

 

[J100]

It's common for new findings to take years to get to clinical trials. And the trials themselves will take years more. They probably need to do several years of more preliminary studies to nail down the details of the biochemical mechanisms that are causing the disease and how best to reverse them. Then they need to use that knowledge to choose the best candidate drug and then to carefully design the formal clinical trials needed to get regulatory approval. Depending on the natural course of the disease, the trials might take years to complete. And no matter what they are, the clinical trials will be horrendously expensive. If no rich pharma company or government is willing to put up the money, the trials might never start.

None of these factors is unique to Crohn's treatments. Developing and getting regulatory approval for new drugs for any serious disease is always slow and costly.

If we assume that the hypothesis - AIEC and genetic defect cause Crohn's disease is correct, then it seems that a cure is not in sight in the years to come. First because there is no cure for AIEC and no cure for genetic defects. It is a feeling of helplessness.

 

[Andersen007]

If we assume that the hypothesis - AIEC and genetic defect cause Crohn's disease is correct, then it seems that a cure is not in sight in the years to come. First because there is no cure for AIEC and no cure for genetic defects. It is a feeling of helplessness.

I wouldn't be so pessimistic about that. We are really not that far off from being able to do curative treatments when a specific issue in a gene sequence is identified. Look at the recent huge success of the new gene editing therapies for sickle cell disease, previously essentially deemed incurable for instance: https://www.fda.gov/news-events/pre...-therapies-treat-patients-sickle-cell-disease

There is a lot supporting the AIEC or similar pathogen theory, would explain why antibiotics, EEN, certain rigorous diets, can cause a - usually temporary - resolution of Crohn's symptoms / inflammation. I think the main reason why they can't eradicate it yet is because it was never identified as the definite root cause or at least key contributor.

Once the root cause, or a key part of that chain is found, we can intervene, and beyond 2024 we tend to be very successful at this. Biologics do the same, but intervening essentially at the very end of this process. As soon as the role of TNF-s or IL-s were determined, we were rather fast in targeting it, even with technology 20+ years ago.

But, as you rightly say, we are talking multiple years here.

 

[Scipio]

If we assume that the hypothesis - AIEC and genetic defect cause Crohn's disease is correct, then it seems that a cure is not in sight in the years to come. First because there is no cure for AIEC and no cure for genetic defects. It is a feeling of helplessness.

Things aren't quite that bleak. Recall that the A in AIEC stands for "adherent." It is AIEC's ability to stubbornly stick to interior of the gut that makes it so pathogenic. Takeda has a drug in early trials that doesn't try kill AIEC but instead to block its ability to adhere to the gut and thus block its ability to trigger inflammation:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383459/
I have been cautiously hopeful about this approach. However, one limitation may be that AIEC, while it may be a major player, may not be the only bacteria that can trigger Crohns.

 

[Andersen007]

Things aren't quite that bleak. Recall that the A in AIEC stands for "adherent." It is AIEC's ability to stubbornly stick to interior of the gut that makes it so pathogenic. Takeda has a drug in early trials that doesn't try kill AIEC but instead to block its ability to adhere to the gut and thus block its ability to trigger inflammation:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383459/
I have been cautiously hopeful about this approach. However, one limitation may be that AIEC, while it may be a major player, may not be the only bacteria that can trigger Crohns.

Btw did they launch a new study? I only found this one that got discontinued due to lack of participants which is not very surprising as they seemed to only want to include people who go through ileal resection surgery and then only take their drug to prevent recurrency? https://clinicaltrials.gov/study/NCT03943446

 

[Scipio]

I don't know whether they are planning a new trial or not. Disease prevention trials are always difficult because you don't know in advance who is going to get the disease or not. So to get enough cases of Crohn's the placebo arm of the the trial to ascribe a statistically significant disease prevention benefit to the subjects receiving the drug, the trial would need to be huge and lengthy - following thousands of healthy subjects for decades to see whether they do or don't develop Crohn's. This is difficulty in proving disease prevention especially true for a relatively rare disease like Crohn's.

That's why they would go for resection patients - because they know those patients are at high risk of developing recurring Crohn's lesions after resection. You could get away with a much smaller (and hence cheaper and faster) study. Too bad the surgery patients didn't sign up.

 

[longzhiwu]

I don't know whether they are planning a new trial or not. Disease prevention trials are always difficult because you don't know in advance who is going to get the disease or not. So to get enough cases of Crohn's the placebo arm of the the trial to ascribe a statistically significant disease prevention benefit to the subjects receiving the drug, the trial would need to be huge and lengthy - following thousands of healthy subjects for decades to see whether they do or don't develop Crohn's. This is difficulty in proving disease prevention especially true for a relatively rare disease like Crohn's.

That's why they would go for resection patients - because they know those patients are at high risk of developing recurring Crohn's lesions after resection. You could get away with a much smaller (and hence cheaper and faster) study. Too bad the surgery patients didn't sign up.

Unfortunately，Takeda and Enterome have gave up it. In the results, nearly 90% of patients experienced recurrence that means the goal has failed. I think the reason may be that FimH can not kill the AIEC hiding in macrophages. Based on these studies, EB8018 is designed to solve the adhesion of AIEC, not eliminate them. Maybe that's not enough.
Ecoactive is a group of bacteriophages designed to kill AIEC,and the trial is still in progress.

 

[kiny]

Genetic variants, "genetic defects" is a bit too harsh I feel. These NOD2 and ATG16L1 variants specific to crohn's disease (not UC), confer a certain disease risk.

But they likely served a function in the past. Mice with Crohn's disease NOD2 variants survive when challenged with certain Yersinia strains while NOD2 "competent" mice do not. In Europe, Crohn's disease NOD2 variants are most common in geographic regions that suffered from plague outbreaks (yersinia pestis), suggesting that these genetic differences were an evolutionary necessity, and crohn's disease in some individuals might be a cost one pays.

The positive news is that these variants do not seem to lead to autoimmunity like some suggested in the past. They're not leading to self-reactive immune cells that target our own cells.

Factors in our control can influence the course of the disease. Put crohn's disease patients on EN for 4 weeks and inflammation goes away completely in the large majority of patients. This does not work with UC at all, where the case for autoimmunity is much stronger.

Immune function of crohn's disease patients seems generally fine, the innate response seems just somehwat delayed and macrophage function is suboptimal. You can only really see these genetic variants at play when you look at neutrophil recruitment, and it just so happens that the intestine is rich in phagocytes so any macrophage reaction that isn't optimal will be magnified in the intestine. But it's not like our immune system is defective, infections do not seem more common in crohn's disease patients when adjusted for medication, intestinal macrophages of crohn's disease can kill common foodborne pathogens. And while certain bacteria (like AIEC and other pathogens) can exploit autophagy incompetence of macrophages associated with some of these CD variants, given the right conditions, people do go into remission, one assumes CD patients can very likely control and kill these pathogens. They exploit inflammatory conditions that lead to a breakdown of intestinal barriers and invade tissue or peyer's patches.

Crohn's disease is receptive to diets like EN, and is likely going to be receptive to treatments that can decrease bacterial and fungal load in the future. The prospects for UC are not that great compared to those for crohn's disease. The use of IBD in articles is unfortunate, very different diseases.

 

[kiny]

That we were able to associate thse specific NOD2 and ATGL16L variants to crohn's disease shouldn't make one feel helpless, it is a very positive thing no.

It greatly narrows down research. It tells us we're dealing with pathogens that exploit innate immmune function, we have chronically activated macrophages that release TNF-a resulting in inflammation. Blocking TNF-a results in resolution of inflammation but does not cure. EN results in resolution of inflammation but does not cure.

We have very good genetic clues, evasion of innate immunity is not uncharted territority, many pathogens are resistant to phagocytosis. We have levers that can influence the course of disease, we have increasingly powerful computers that can map all these interactions between pathogens and immune cells in the intestine. That's a good foundation for an eventual cure.

 

[kiny]

I can't read all articles, but regarding any treatment mentioned in the articles.

Changing how macrophages function is not what current treatment does, and suggestions that macrophages themselves, or genetic pathways need to be treated is dangerous talk.

The "relative" safety of TNF-a blockers is because it's a hands-off approach, and it is dose-dependent. Specifically, TNF-a of macrophages is blocked, meaning only activated macrophages that release TNF-a are affected, inactive macrophages are not affected by TNF-a blockers. TNF-a blockers dampens the immune response and limits neutrophil recruitment, but leaves macrophage function itself in tact, inactive macrophages are not affected, and once treatment is stopped mO TNF-a is back to normal.

If an infection does occur, TNF-a blockers can be immediately stopped, and half-life of these blockers is relatively short.

Trying to manipulate the functioning of macrophages is comparatively a very dangerous idea and completely unnecessary. EN is very safe, TNF-a and IL-23 blockers are relatively safe. Genetics plays an important role as a clue into the role of the innate immune response in maintaining inflammation in patients, but does not serve a role in treatment in crohn's disease.