Environmental factors, not genetics, confer the highest risk of developing CD in multiplex families.

[kiny]

Healthy first-degree relatives from multiplex families versus simplex families have a higher subclinical intestinal inflammation, a distinct fecal microbial signature, and harbor a higher risk of developing Crohn's disease

University of Toronto, Ontario, Canada
2024 Sep

Background & aims: Unaffected first-degree relatives (FDRs) from families with two or more affected FDRs with Crohn's disease (CD, multiplex families) have a high risk of developing CD, although the underlying mechanisms driving this risk are poorly understood. We aimed to identify differences in biomarkers between FDRs from multiplex versus simplex families and to investigate the risk of future CD onset accounting for potential confounders.

Methods: We assessed the Crohn's and Colitis Canada Genetic Environmental Microbial (CCC-GEM) cohort of healthy FDRs of patients with CD. Genome-wide CD-polygenic risk scores (CD-PRS), urinary fractional excretion of lactulose-to-mannitol ratio (LMR), fecal calprotectin (FCP), and fecal 16S ribosomal RNA microbiome were measured at recruitment. Associations between CD multiplex status and baseline biomarkers were determined using generalized estimating equations models. Cox models were used to assess the risk of future CD onset.

Results: There were 4051 participants from simplex families and 334 from CD multiplex families. CD multiplex status was significantly associated with higher baseline FCP (p=0.026) but not with baseline CD-PRS or LMR. Three bacterial genera were found to be differentially abundant between both groups. CD multiplex status at recruitment was independently associated with an increased risk of developing CD (adjusted hazard ratio 3.65, 95% confidence interval 2.18 - 6.11, p < 0.001).

Conclusion: Within FDRs of patients with CD, participants from multiplex families had a 3-fold increased risk of CD onset, a higher FCP, and an altered bacterial composition, but not genetic burden or altered gut permeability. These results suggest that putative environmental factors might be enriched in FDRs from multiplex families.

 

[kiny]

This is a new study that confirms Van Kruiningen his old studies. There is a major environmental factors that contributes to disease risk, which is completely independent and much more important, than genetic predisposition.

The environment is, by far, the strongest risk factor in multiplex families. Familiar disease clustering, caused by the shared environment, independent of genetics.

There need to be exposome studies of individuals and cases of familiar clustering to find the culprit.

 

[Opieshuffle13]

My parents both developed autoimmune issues LONG after I was diagnosed with CD when I was 15. My dad developed psoriatic arthritis and my mom exczema and other skin disorders. All 3 of us are on various biologics to control our issues. My brother has not been diagnosed with any autoimmune disorders however he does suffer sinus issues which I would argue are 'somethin'g (if he ever went to a doctor for any diagnosis!). So the question becomes: what did we eat / breathe / drink / absorb that's led us all to this place?

 

[Waldo]

Some newer studies point to ACE (adverse childhood experiences) as a cause of increased inflammation. This is related to chronic stress, which is a consequence of emotional trauma. If a whole family is dysfunctional (alcoholism, abuse, emotional unavailability etc.), or both parents are severely dysfunctional, it follows that the family members/children are all more succeptible to inflammatory disease (multiplex). Which increase the chance that a first-degree relative is subject to ACE that trigger inflammation.
Whereas if the family/ one parent is less dysfunctional, maybe just the "weakest" individual in that family gets a diagnosis (simplex).
Just a thought...

 

[kiny]

It's popular in certain nations with rising incidence of crohn's disease to blame a certain lifestyle. "Western diets", "Western lifestyles", it's talked about as if it's a lifestyle-related disease. And it's sad to see this, because it puts the blame on the patient.

There's also no proof to back this up. Crohn's disease patients have generally not had unhealthy lifestyles, they have similar or lower rates of obesity compared to the general population prior to disease for example, and there's no indication they ate poor diets at all. There's also no indication they ate less fiber or more fat, that has been debunked in larger studies.

Crohn's disease is very acute, it's a disease with a very rapid onset. It involves acute vomiting in some people, fevers, night sweats, sudden onset of aphthous ulcers in the mouth.

This doesn't indicate a lifestyle-related disease at all.

It indicates an acute event. Ingestion of large amount of food contaminants or toxins for example. Common enough to explain the high incidence of crohn's disease. Infections or poisoning. Foodborne infections with listeria, e coli, salmonella, campylobacter. Or poisoning with mycotoxins, acute dietary exposure of high amounts of deoxynivalenol causing vomiting for example. These can all cause acute intestinal and lymphatic vessel damage in susceptible individuals. There's nothing patients could have done about this, it's a totally random event that has nothing to do with a certain lifestyle.

 

[kiny]

Unlike the "lifestyle" argument, of which there is no proof, there is ample proof acute infections predispose people to developing crohn's disease:

https://crohnsforum.com/threads/the...ute-infections-to-crohns-disease-onset.87316/

 

[J100]

@kiny - I have posted this link in another thread too. Who knows what these toxins are doing to the human body. Sometimes, I think we should go back to 50 years or 100 years back when packaging was a lot simpler and a lot less plastic was used. Again how do we prove the deadly effects of these toxins. Perhaps do a study with one one set of subjects not using any food packaging and the other just using it as per normal but our food chains have changed so much that I think it will be almost impossible to have a set of subjects not using any food packaging or maybe paper packaging.

I came across this article in CNN

https://edition.cnn.com/2024/09/16/health/food-packaging-chemical-toxins-study-wellness/index.html

 

[longzhiwu]

There is a new research about commensal consortia decolonize enterobacteriaceae. In the reseach, F18-mix was also highly effective at decolonizing Klebsiella aerogenes (strain Ka-11E12) and adherent-invasive E. coli (AIEC, strain LF82), both of which have been implicated in IBD pathogenesis. I think this is a further treatment than FMT. By selecting the microbiota that truly treat inflammation, we can achieve more effective treatment than FMT. There have been some similar studies in the past, but now no further news has been released.We hope this research can persist.

Commensal consortia decolonize Enterobacteriaceae via ecological control
https://www.nature.com/articles/s41586-024-07960-6