Genetic variants and crohn's disease. Some perspective.

[kiny]

Genetic variants associated with crohn's disease are incredibly common in the human populace.

The most common genetic variant that is most closely associated with Crohn's disease is NOD2, one of the receptors involved in recognition of intracellular pathogens, including sensing of mycobateria. Intracellular pathogens are pathogens that invade cells of the host. So your common foodborne pathogens like E Coli and Salmonella, but also mycobacteria like MAP, TB and Leprae for example.

The second most commonly discussed gene, ATG16L1, participates in the autophagy process. Again related to the processing of intracellular pathogens, that need to be delivered to the lysosome. Xenophagy is a special type of autophagy that breaks down intracellular pathogens.

Even with all this data, that associates these variants to crohn's disease, the genetic link is still absolutely weak.

1 in 10 caucasians for example carry this NOD2 variant, a tiny tiny fraction ends up developing crohn's disease. The large large majority of people with this NOD2 variant do not develop crohn's disease. And many caucasians with crohn's disease do not even carry the NOD2 variant, in non-caucasian demographics this link between NOD2 and crohn's disease is often non-existent.

The links for other variants, including the ones discussed in those recent studies, are much weaker still and are not even specific to crohn's disease, unlike NOD2 and ATG16L1 that are.

The overwhelming risk factor for developing crohn's disease is not genetic, but the environment and environmental clustering. Genetically there is a very weak association, but this association is very interesting nonetheless since it gives us very valuable clues.

 

[Soryan]

If compromised innate immune response and xenophagility is a key factor of CD pathogenesis, do you think resetting them by means of something like vaccines or reprogrammed immune cells can help eliminate the entrenched pathogens (e.g. AIEC) that were able to evade xenophagy? Somewhat like Car-T on adaptive immune?

 

[kiny]

Stimulating innate immune function in crohn's disease patients has been mostly done with growth factors, cytokine that stimulate the growth of certain cells.

M-CSF, Macrophage colony-stimulating factor, has been tried in both chronic granulomatous disease and in crohn's disease, to try to support the innate immune function, with some success.

People with chronic granulomatous disease often develop crohn's disease (this is hardly the only problem these patients suffer from, these patients often develop serious infections). But like crohn's disease, there is an innate immunodeficiency at play, which results in delayed neutrophil recruitment for example.

EN like Modulen contains growth factors like TGF-β2, a very important cytokine that can help control inflammation and seems to help promote intestinal healing of the epithelial barrier, itself part of our innate immune defense.

 

[kiny]

People with crohn's disease sometimes have Vitamin D receptor gene polymorphisms.

Adequate vitamin D is important for crohn's disease patients, this has been shown in many studies (be always careful you only take what is recommended, vitamin D is fat soluble and excess tends to be stored and doesn't easily leave the body, unlike for example vitamin C).

People who suffer from crohn's disease flares, have consistently lower vitamin D status. And this does not seem to be only the result of lack of vitamin D uptake during a flare, inadequate vitamin D seems to be a precursor to a flare, not the result. Institutions have also consistently reported higher cases of crohn's disease patients needing help during winter months.

 

[Soryan]

If Crohn’s is in nature immunodeficiency, do you think it is primary or secondary?

In other words, is the impaired immune response inherited or acquired? If it’s acquired, how is it acquired?

Like you said, genetic susceptibility alone has no causal effect towards development of CD. So there must be an “environmental factor” contributing to such immune impairment. But what could that be?

Could it be caused by a pathogen like what HIV does to AIDS or what M.Tb does to Tuberculosis?

Or is it weakened barrier function (like the leaky gut cult says, and thus links to food additives and ultra-processed food) the main contributor?

So there shouldn’t be one single suspect to blame but any enteric infection can cause a cascade of inflammation and bacterial colonisation?

In view of the rather late onset age and high(er) prevalence, it seems more logical to treat Crohn’s as a secondary immunodeficiency disorder?

But for very early onset cases, it could be an interplay of both primary and secondary immunodeficiency? i.e. Inborn error + environmental trigger which makes that a more severe phenotype?

 

[Soryan]

M-CSF, Macrophage colony-stimulating factor, has been tried in both chronic granulomatous disease and in crohn's disease, to try to support the innate immune function, with some success.

This looks interesting. Just a thought though, could it be that the wide use of immune-directed drugs e.g. biologics / thiopurines that pulls up a dampened effectiveness of this kind of immune stimulating therapies: M-CSF, GM-CSF, site-specific immunomodulator etc.? They can hardly find immunosuppressant naive subjects nowadays, albeit trying to exclude those who are receiving TNF-a or IL-23 blockers…

Are there some more studies in this area you can happily share or novel treatment options that you find promising?

 

[kiny]

If Crohn’s is in nature immunodeficiency, do you think it is primary or secondary?

It is a primary immunodeficiency of macrophages.

In other words, is the impaired immune response inherited or acquired? If it’s acquired, how is it acquired?

It's inherited. Best comparable to chronic granulomatous disease.

So there must be an “environmental factor”

Crohn's disease onset is caused by an environmental factor, and inflammation is maintained by an environmental factor we don't fully understand (EN causes remission, rare cases go into spontaneous remission, aphthous lesions come and go, etc).

Crohn's disease is highly geographically clustered, within specific areas and within households:
https://crohnsforum.com/threads/the-very-high-level-of-clustering-of-crohns-disease.87089/

Acute foodborne infection often precedes onset of Crohn's disease:
https://crohnsforum.com/threads/the...ute-infections-to-crohns-disease-onset.87316/

Could it be caused by a pathogen like what HIV does to AIDS or what M.Tb does to Tuberculosis?

Yes. These NOD2 and ATG16L1 variants leaves one more susceptible to intracellular pathogens, with some specificity for mycobacteria (large genetic risk overlap between Western CD patients and Asian leprosy patients).

Or is it weakened barrier function (like the leaky gut cult says, and thus links to food additives and ultra-processed food) the main contributor?

If crohn's disease was caused by ultra-processed foods, we would know by now. You can't get much more processed than EN. Glucose syrups and maltodextrins made from hydrolysis of starch, full of emulsifiers, stabilizers and additives. Yet, ultra-processed EN drastically lowers inflammation.

So there shouldn’t be one single suspect to blame but any enteric infection can cause a cascade of inflammation and bacterial colonisation?

An acute foodborne infection can cause a lot of damage to the intestinal lining. People with crohn's disease might be able to clear this initial infection themselves or with antibiotics (infection and use of antibiotics are both linked to CD onset), but damage to the intestinal lining would have allowed lumen content to enter tissue. This lumen content would have come into contact with macrophages that might struggle to clear certain bacteria or fungi. In susceptible individual, the innate immune system would not recruit enough neutrophils and these bacteria would resist phagocytic destruction by macrophages.

One of the defining features of crohn's disease (that sets it apart from UC) is granuloma, also seen in intestinal TB. What are granuloma in crohn's disease, they're a response from the intestine when it can not eliminate a pathogen, they're macrophages trying to shield the intestine from further infection.

In view of the rather late onset age and high(er) prevalence, it seems more logical to treat Crohn’s as a secondary immunodeficiency disorder?

No. NOD2 and ATG16L1 variants point to a failure to timely recognize certain pathogens, and a failure of phagocyte fuction of macrophages, likely due to these autophagy variants.

Crohn's disease does not look like a T-cell disorder for example, it's looks like a failed innate immune response of macrophages, similar to chronic granulomatous disease.

late onset age

Well, what is late. Age of onset for crohn's disease is usually around puberty. A lot of immunological changes only happen during puberty. The number and activity of peyer's patches of the small intestine that are often exploited by pathogens through M cell entry, are at their height during puberty. They are much less active in small children.

But for very early onset cases, it could be an interplay of both primary and secondary immunodeficiency? i.e. Inborn error + environmental trigger which makes that a more severe phenotype?

Maybe. I've mentioned before that I have expressed my doubt that very young kids have the same disease as people who develop crohn's disease during puberty. Maybe the cause is similar, but the features of these kids don't match kids who develop CD at puberty. I have my doubts it is the same disease. One reason for my doubts is the lack of peyer's patch activity in small kids.

 

[kiny]

Regarding the immune response in the small intestine. The small intestine has defense mechanics against pathogens, that are not seen anywhere else in the body. Peyer's patches and Paneth cells are distinct and defining features of the small intestine. In the ileum, the sheer number of immune cells present in the lamina propria and peyer's patches is unmatched anywhere else in the intestine.

It is a response to all the ways pathogens consistently evade these mechanics. These pathogens have learned how to avoid antibody coating, they have learned how to avoid mucosal defenses by entering through M cells, they learned how to avoid phagocytosis by macropahges, etc.

The primary function of the ileum, nutrient absorption, comes with considerable risk of infection. The ileum developed into a very complex immunological fortress to prevent pathogens from entering tissue, and to eliminate them.

So that's why I am highly critical of these people who try to use probiotics or fecal transplants in crohn's disease. It is no wonder whatsoever that this does not work, and increases inflammation. The goal should be to limit direct contact with pathogens, limit stimulation of bacterial metabolites, consume easy to digest low residue food, easy to absorb glucose and fats, limiting bile acids. Limit stress on the small intestine and allow it to heal and give it the nutrients to do this.

 

[Veske]

Regarding the immune response in the small intestine. The small intestine has defense mechanics against pathogens, that are not seen anywhere else in the body. Peyer's patches and Paneth cells are distinct and defining features of the small intestine. In the ileum, the sheer number of immune cells present in the lamina propria and peyer's patches is unmatched anywhere else in the intestine.

It is a response to all the ways pathogens consistently evade these mechanics. These pathogens have learned how to avoid antibody coating, they have learned how to avoid mucosal defenses by entering through M cells, they learned how to avoid phagocytosis by macropahges, etc.

The primary function of the ileum, nutrient absorption, comes with considerable risk of infection. The ileum developed into a very complex immunological fortress to prevent pathogens from entering tissue, and to eliminate them.

So that's why I am highly critical of these people who try to use probiotics or fecal transplants in crohn's disease. It is no wonder whatsoever that this does not work, and increases inflammation. The goal should be to limit direct contact with pathogens, limit stimulation of bacterial metabolites, consume easy to digest low residue food, easy to absorb glucose and fats, limiting bile acids. Limit stress on the small intestine and allow it to heal and give it the nutrients to do this.

Can you elaborate more on the last section?
Or maybe you have some post that you have already written about this in the past that you could refer to?

 

[wild_one353]

Yes! as far as I was aware, many with risk genes still don't develop crohn's. These observations strengthen the focus on the microbiome.

 

[Waldo]

In the last decade I have seen more focus on family related (emotional) trauma / neglect as a causal factor.

I asked ChatGPT this:

What is the trend in research into whether adverse childhood experienced (ace) is a causal factor in inflammatory disease? Is more or less research being published these years? What does the research conclude?

This is the reply:
Research into the link between adverse childhood experiences (ACEs) and inflammatory diseases has been growing in recent years. Here is an overview of the trends and conclusions:

### Trend in Research

1. **Increasing Volume**: There has been a notable increase in the volume of research focusing on the relationship between ACEs and inflammatory diseases. This rise can be attributed to a growing recognition of the long-term impacts of childhood trauma on physical health, alongside advances in understanding the biological mechanisms that underlie this connection.
2. **Interdisciplinary Approach**: More studies are employing interdisciplinary approaches, combining insights from psychology, immunology, and epigenetics to explore how early life stressors contribute to inflammation and subsequent disease.
3. **Longitudinal Studies**: There is an increasing number of longitudinal studies that track individuals over time to establish stronger causal links between ACEs and inflammation-related health outcomes.

### Research Findings and Conclusions

1. **Biological Mechanisms**: Research indicates that ACEs can lead to chronic activation of the stress response system, resulting in sustained inflammation. Key mechanisms include:
- **Dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis**: Chronic stress from ACEs can dysregulate the HPA axis, leading to altered cortisol production, which in turn affects immune function and inflammation.
- **Epigenetic Changes**: ACEs can induce epigenetic modifications that alter gene expression related to immune and inflammatory responses.
- **Autonomic Nervous System (ANS) Dysregulation**: ACEs can impact the ANS, leading to chronic inflammatory states.

2. **Association with Specific Diseases**: Studies have found significant associations between ACEs and various inflammatory diseases, such as:
- **Cardiovascular Disease**: Elevated markers of inflammation like C-reactive protein (CRP) have been linked to ACEs and increased cardiovascular risk.
- **Autoimmune Diseases**: Conditions such as rheumatoid arthritis and lupus have been associated with higher rates of ACEs.
- **Metabolic Syndrome and Type 2 Diabetes**: Chronic inflammation from ACEs is a risk factor for metabolic dysregulation.

3. **Strength of Evidence**: While many studies suggest a strong association, establishing causality is complex. The evidence points towards a significant link, but it is often mediated by various factors, including lifestyle, socio-economic status, and genetic predispositions.

4. **Intervention and Mitigation**: Research also focuses on interventions that can mitigate the impact of ACEs. Therapeutic approaches such as trauma-informed care, stress reduction techniques, and fostering resilience in children show promise in reducing long-term inflammatory risks.

### Conclusion

The body of research consistently supports the hypothesis that ACEs are a significant risk factor for developing inflammatory diseases later in life. The increase in published studies highlights a growing recognition of the importance of this area. However, while the association is well-documented, ongoing research aims to further clarify the causal mechanisms and develop effective interventions to mitigate these risks.
// end of chat GPT reply.

 

[Waldo]

This meta-study from 2015 on the subject is interesting:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564950/.

The study concludes:

The present meta-analysis finds a significant association between childhood trauma and the inflammatory markers, with effect sizes being greatest for TNF-α (z=0.20, 95% CI=0.10–0.29), followed by IL-6 (z=0.09, 95% CI=0.04–0.15) and then CRP (z=0.08, 95% CI=0.04–0.11). As such, this provides strong evidence that childhood traumatic events significantly impact on the inflammatory immune system, with trajectories reaching into adulthood, thus offering a potential molecular pathway by which early trauma confers vulnerability to developing psychiatric and physical disorders later in life.

Newer studies reach the same conclusions it seems.

 

[Waldo]

Could it be ACE, which causes chronic stress, is the primary environmentel factor? And that our genetic profile results in our gut being the a weak spot, leading to IBD. While other genetic profiles may lead to other inflammatory diseases elsewhere in the body?

 

[J100]

Genetic variants associated with crohn's disease are incredibly common in the human populace.

The most common genetic variant that is most closely associated with Crohn's disease is NOD2, one of the receptors involved in recognition of intracellular pathogens, including sensing of mycobateria. Intracellular pathogens are pathogens that invade cells of the host. So your common foodborne pathogens like E Coli and Salmonella, but also mycobacteria like MAP, TB and Leprae for example.

The second most commonly discussed gene, ATG16L1, participates in the autophagy process. Again related to the processing of intracellular pathogens, that need to be delivered to the lysosome. Xenophagy is a special type of autophagy that breaks down intracellular pathogens.

Even with all this data, that associates these variants to crohn's disease, the genetic link is still absolutely weak.

1 in 10 caucasians for example carry this NOD2 variant, a tiny tiny fraction ends up developing crohn's disease. The large large majority of people with this NOD2 variant do not develop crohn's disease. And many caucasians with crohn's disease do not even carry the NOD2 variant, in non-caucasian demographics this link between NOD2 and crohn's disease is often non-existent.

The links for other variants, including the ones discussed in those recent studies, are much weaker still and are not even specific to crohn's disease, unlike NOD2 and ATG16L1 that are.

The overwhelming risk factor for developing crohn's disease is not genetic, but the environment and environmental clustering. Genetically there is a very weak association, but this association is very interesting nonetheless since it gives us very valuable clues.

Hi @kiny - I am also coming around to the view that genetics is not a reason for the increase in incidence of Crohn's disease. I came across this article in ABC News https://www.abc.net.au/news/health/...y-bowel-diseases-children-australia/103902842. As per this, the rate of IBD is increasing among kids. It can't be suddenly that genes will start causing this. My guess is environmental factor. It could be something in the food chain or a pollutant to which we are exposed and somehow gets passed to children and it is possible that pollutant is passed in mother's milk too. I suspect plastic pollution but it is a hypothesis without any evidence. Apparently, microplastics are omnipresent and that we eat the equivalent of one credit card each week.

 

[Soryan]

It is a primary immunodeficiency of macrophages.

It's inherited. Best comparable to chronic granulomatous disease.

I see. But what makes macrophages compromised in the first place? Is it an inborn defect (primary ID)? Or is our innate immune depleted by the environmental factors (secondary ID)?

If it's inborn, then why aren't genetic variants commonly shared in most disease population?

Crohn's disease onset is caused by an environmental factor, and inflammation is maintained by an environmental factor we don't fully understand (EN causes remission, rare cases go into spontaneous remission, aphthous lesions come and go, etc).

An acute foodborne infection can cause a lot of damage to the intestinal lining. People with crohn's disease might be able to clear this initial infection themselves or with antibiotics (infection and use of antibiotics are both linked to CD onset), but damage to the intestinal lining would have allowed lumen content to enter tissue. This lumen content would have come into contact with macrophages that might struggle to clear certain bacteria or fungi. In susceptible individual, the innate immune system would not recruit enough neutrophils and these bacteria would resist phagocytic destruction by macrophages.

So what you mean is: pathogens only perpetuate and aggravate CD but can't single-handedly cause it? Then a sole suspect (e.g. AIEC/MAP) may not even exist for causing the disease like what HIV does to AIDS or m.leprae does to Leprosy patients? Instead, there can be more than one or a collection of invasive bacteria/fungi that take advantage of our defective immune and colonise as they may?

Put it another way, even if "healthy" individuals with normal macrophage function are exposed to high quantity of these pathogens, they won't easily develop CD like us do?

Second, there have been evidences that mucosal and histological healing can predict a so called "deep remission", changing the prognosis of CD. I wonder if just by (1) eradication of the pathogens and (2) repair of intestinal mucosal and epithelial function (e.g. by means of a prolonged course of EEN / some effective antimicrobial drugs or phage cocktails) can bring us cross this tipping point and completely fence off potential pathogens and inflammation in the future?

Or owing to our subpar innate immunity, these environmental triggers because they are everywhere and getting more common nowadays, would make intestinal damages hard to avoid? A sustained pathogen eradication and mucosal recovery is simply impossible in that sense and a little bit of such trigger can kick us back into the vicious cycle again?

To my understanding, CGD is caused by gene mutation hence an enzymic defect. If CD is similar with macrophages its victims this time, I find it quite sad because there won't be an easy fix. The ultimate treatment, be there any at any time soon, won't be a straightforward one like taking some antibiotics for certain period or having one or two shots of vaccines etc.

 

[kiny]

Then a sole suspect (e.g. AIEC/MAP) may not even exist for causing the disease like what HIV does to AIDS or m.leprae does to Leprosy patients?

Leprae is a bit different in the sense that it is a relatively rare infection that doesn't use a mucosal surface as a point of entry. There is some genetic risk overlap with leprosy and CD, but you can only observe this in underdeveloped countries.

But most infections use the large mucosal surfaces of the human body to cause infection, which is surprisingly easy to do for both viruses and bacteria. The largest mucosal surfaces are the small intestine, and respiratory tract. Foodborne infections and respiratory infections are incredibly common among people who are perfectly healthy, the mucosal surface poses little challenge to most pathogen. TB doesn't even need to enter through intestinal mucosa, it just enters through the lungs and ends up infecting the intestine through the lymphatic system and people develop intestinal TB.

Crohn's disease onset is very often preceded by an acute foodborne infection. I posted these large studies before. These can be salmonella, E coli, campylobacter, listeria and yersinia, all capable of causing severe damage to the mucosal surface in the small intestine.

It's not that surprising that we're not just looking at one canidate pathogen, we're not dealing with a skin lesion that would give leprae an entry point, we're dealing with the small intestine with a large mucosal surface that is a daily entry point for pathogens and commensals, in healthy people just as much as in people with CD. People with CD might simply be going into remission by limiting the bacterial and fungal load of the fecal stream, as people on EN and intravenous feeds go into clinical remissions with full mucosal healing.

 

[kiny]

Or owing to our subpar innate immunity, these environmental triggers because they are everywhere and getting more common nowadays, would make intestinal damages hard to avoid? A sustained pathogen eradication and mucosal recovery is simply impossible in that sense and a little bit of such trigger can kick us back into the vicious cycle again?

Well, it's all relative. These primary immunodeficiences might make some more susceptible to crohn's disease. But all things considered, these NOD2 and ATG16L1 anomalies do not seem to cause most people severe health issues. Limiting bacterial load and contact with the fecal stream through EN or IV, seems to be all that is needed to induce remission.

This is in contrast to Chronic granulomatous disease that leads to serious infections, and makes it a lot more likely you develop crohn's disease. People with CGD often have a whole host of infections at once, it has just become less common in the West to see this, patients get a laundry list of vaccines.

Interestingly, people with primary immunodeficiency disease like CGD, suffer mostly from bacterial and fungal infections, less so from viral infections. Still, we can also give preventative treatment for pneumonia for primary immunodeficiency, we know when and how to dose antivirals to stop recurring herpes infections, etc. But it's very intesting that viral infections seem much less common.

CGD predisposes people to develop CD, and makes them more vulnerable to certain mycobacteria, but we should be thankful most of us do not have CGD, and Crohn's disease is manageable.

 

[kiny]

I am also coming around to the view that genetics is not a reason for the increase in incidence of Crohn's disease. I came across this article in ABC News https://www.abc.net.au/news/health/...y-bowel-diseases-children-australia/103902842. As per this, the rate of IBD is increasing among kids. It can't be suddenly that genes will start causing this. My guess is environmental factor

Right, Crohn's disease incidence increased way too fast in the West, but even more so in developing countries. This can not be explained through genetics. Genetic anomalies simply gives you a, relatively small, predisposition.

When Moroccans migrated to France and Belgium, the incidence of their relatives who stayed in Morocco stayed the same, but these migrants developed rates of crohn's disease similar to the population in France and Belgium.

Whatever causes this disease, it is in the environment, it is a disease with geographical clusters, and incidence increases in migrant groups to match the local population in the West in just a few years.

 

[kiny]

Could it be ACE, which causes chronic stress, is the primary environmentel factor? And that our genetic profile results in our gut being the a weak spot, leading to IBD. While other genetic profiles may lead to other inflammatory diseases elsewhere in the body?

I remember I posted a study where ruminants were put under psychological stress for several days, just to see what would happen to their immune function and intestinal biome. Certain viral infections like herpes are known to reactivate when people are stressed. Crohn's disease is still more common in urban settings, a French study recently said it is specifically more common in people who live alone. I'm sure all these factors contribute in some way.

 

[kiny]

Just wanted to note. If the immune response in crohn's disease targets pathogens, that doesn't completely rule out that these pathogens did not enter through the gastrointestinal tract, but through the lungs or another site, and traveled to the intestine through dissemination from the bloodstream or lymphatics.

Intestinal TB looks a lot like crohn's disease, with granuloma and deep transmural inflammation. But intestinal TB is the result of a primary infection of the respiratory system, not the intestine.

I think the chance is small that this is the case in crohn's disease, because removing the fecal stream in crohn's disease leads to robust remission, but it can't be discounted.

 

[Opieshuffle13]

I have ALWAYS felt that my whole Crohn's journey began at an afternoon barbecue unsuspectingly eating uncooked meat when I was 15. Could it be coincidence? Maybe... but I don't think so based on the articles that all mention salmonella and E coli. AND... stress definitely triggers a lot of weird things to happen in my guts. Which is why I wish I could retire and at least eliminate that part of the equation!

@kiny what I find interesting is the mention of immune function: I was always the healthiest person in my family, school etc. I never got sick when everyone else was laid up. Even now... I watched people get COVID and get sidelined badly, but I just got a head cold from it. Seems my body would be better at fighting off pathogens? or am I mis-reading what you're saying?

 

[kiny]

It's just that you end up discussing bacteria and fungi when you talk about NOD2, not viruses. Also because NOD2 variants are most closely associated to crohn's disease.

The NOD2 gene is the body's instruction manual on how to make the NOD2 protein.

The innate immune fuction recognizes pathogens because they are simply different from host cells (your own cells). Specifically, so-called PRR do this (pattern recognition receptors).

These PRR specifically identify patterns that enable pathogenic behavior, so these pathogens can not mutate and make these patterns disappear to avoid detection. If they do, they lose their pathogenic potential.

The NOD2 protein is one of those PRR that recognizes pathogens, present in macrophages. Specifically the NOD2 protein is able to identify muramyl dipeptide, which is part of a bacterial cell wall. When it identifies muramyl dipeptide, it knows that what it has identified is not a normal cell, but an invader, since normal cells do not express muramyl dipeptide, so it will ring the immune system's alarm bells.

(recently, we found that NOD2 can likely also recognize chitin, present in the outer wall of fungi, which is why people now are looking into the relationship of fungi and crohn's disease)

I don't think people with crohn's disease have issues detecting viruses. I'm sure NOD2 is involved in viral defense mechanism in some way, but NOD2 variants found in crohn's disease patients, would leave you likely vulnerable to intracellular bacteria, not viruses.

These pathogens would exploit these NOD2 variants, giving them time to avoid detection, which allow for them to colonize, it would limit and delay neutrophil recruitment, etc, and you would get chronic inflammation until the body is able to turn the tide on these pathogens.

 

[kiny]

As far as which specific pathogens would end up being a risk factor when carrying NOD2 variants specific to crohn's disease. It would be intracellular bacteria and fungi.

To be very specific, leprae and TB for example would likely exploit these variants, and we see some evidence of this in developing countries. Good thing these are more rare in the Western world, and good thing people with crohn's disease are given a mantoux test when biologics are considered.

 

[J100]

Right, Crohn's disease incidence increased way too fast in the West, but even more so in developing countries. This can not be explained through genetics. Genetic anomalies simply gives you a, relatively small, predisposition.

When Moroccans migrated to France and Belgium, the incidence of their relatives who stayed in Morocco stayed the same, but these migrants developed rates of crohn's disease similar to the population in France and Belgium.

Whatever causes this disease, it is in the environment, it is a disease with geographical clusters, and incidence increases in migrant groups to match the local population in the West in just a few years.

I agree that it is the environment though what exactly it is in the environment which is the trigger for Crohn's is a billion dollar question. I came across this article about forever chemicals. On the one hand, we have got microplastics and on the other hand, we have got these forever chemicals. Who knows what havoc these are causing and will keep on causing to the human body. Can a colonoscopy detect microplastics and forever chemicals in the intestine?

https://www.smh.com.au/national/nsw...rampant-forever-chemical-20240906-p5k8fj.html

 

[kiny]

You wouldn't find any relevant particles during a colonoscopy. They would be in tissue.

The theory would be that small dietary particles of non-biological origin (like titanium dioxide, silicates or microplastics), including particles you would breathe in (like silica dust), would affect the lymphatic system, they would end up accumulating in macrophages in peyer's patches and intestinal tissue. Because these are inorganic particles that would not degrade, you would have a long chronic immune response to them. Mucosal inflammation would be a secondary event, which allow more lumen content to enter tissue, allowing for more dietary particles to enter tissue. You would develop a chronic immune reponse to these particles. You would not just see this in the intestine, but you would use this as a basis to explain aphthous ulcers for example. Diets free of these particles would relieve symptoms.

The theory of why migrants end up developing crohn's disease, would be their exposure to these particles. As countries develop, their dietary habits would change, and they would be increasingly exposed to products and food additives containing these particles.

When Rutgeerts filtered the fecal stream with an ultrafiltrate, it no longer caused inflammation. But we don't know if bacteria, fungi or certain particles were causing inflammation, or any combination of them. And you can't redo these type of experiments for ethical reasons, because we now know the fecal stream causes inflammation, which is why I called out fecal transplants as UNethical. Not only do they not work, we know the fecal stream causes disease in crohn's disease patients.

There's been trials using low microparticle diets for crohn's disease, they're largely inconclusive. There was 1 study showing a positive result and another showing no such result.

 

[kiny]

Regarding forever chemicals. I don't think there's data showing rates of crohn's disease being higher around chemical plants using forever chemicals, like 3M plants. Or higher rates of crohn's disease among firefighters or people who live close to fire stations. But there's lots of particles in food and food additives we are now exposed to, that wasn't the case decades ago, specifically ultra fine particles that can enter M cells and accumulate in lymphoid organs.