CRP in Outpatients with Inflammatory Bowel Disease Is Linked to the Blood Microbiota

[kiny]

 

[kiny]

Until very recently, the assumption was that blood was sterile under normal conditions that did not involve acute infections. But we know that in crohn's disease a large number of bacteria are able to translocate accross the epithelial barrier during periods of inflammation which causes luminal content to enter tissue. (indiscriminate broad spectrum antibiotics can drastically lower inflammation in crohn's disease by bringing down bacterial load). It is not that surprising then that these bacteria could end up in blood vessels, and abundance would correlate with CRP.

 

[kiny]

A condition under which one can donate blood is of course that the blood is sterile. But regular blood tests are insufficient to detect a blood microbiome. Of course, people with crohn's can't donate blood in most countries, but the arguments for this are not related to blood microbiome contamination, but because of other reasons like anemia or medication.

But the assumption that donated blood is sterile from luminal infection just because one doesn't have crohn's disease, is false. Because of course there are people with undetected foodborne infections where luminal content would enter tissue that would never be detected in regular blood tests.

The first study that suggested blood was contaminated with a blood microbiome was from the 60s, but it was often dismissed as sample contamination. It was not sample contamination.

 

[kiny]

I don't think this has any diagnostic value. Any number of infections can cause luminal content to enter tissue.

But it does show how easy luminal content enters tissue, and how permeable the intestinal barrier is.

A recent Nature study from march showed that around 14 percent of patients who had given blood samples for routine hospital controls had luminal content of bacterial origin in the blood sample. Undetected by regular tests.

It would be interesting to see these studies in animals too. It is often assumed that animals naturally have microbiomes, due to the sheer amount of studies coming out. But this is untrue, many animals are functionally lacking a microbiome, and many have transient microbiomes. The percieved benefits for humans is vastly overstated too. Large reductions in bacterial load with dietary intervention like EN, do not result in nutritional defficiencies, but instead drastically lower inflammatory markers in crohn's disease.

 

[asadmom]

I don't think this has any diagnostic value. Any number of infections can cause luminal content to enter tissue.

But it does show how easy luminal content enters tissue, and how permeable the intestinal barrier is.

A recent Nature study from march showed that around 14 percent of patients who had given blood samples for routine hospital controls had luminal content of bacterial origin in the blood sample. Undetected by regular tests.

It would be interesting to see these studies in animals too. It is often assumed that animals naturally have microbiomes, due to the sheer amount of studies coming out. But this is untrue, many animals are functionally lacking a microbiome, and many have transient microbiomes. The percieved benefits for humans is vastly overstated too. Large reductions in bacterial load with dietary intervention like EN, do not result in nutritional defficiencies, but instead drastically lower inflammatory markers in crohn's disease.

What do you mean by "many animals are functionally lacking a microbiome, and many have transient microbiomes"?

 

[kiny]

What do you mean by "many animals are functionally lacking a microbiome, and many have transient microbiomes"?

A gut microbiome is usually lauded for its benefits to the host, rarely is the cost for the host dicussed.

The cost to the host is that a microbiome competes with the host for nutrients and becomes pathogenic when commensal bacteria or fungi cross the epithelial barrier.

The benefit/cost analysis is poor for many animals, so they either completely lack a microbiome, or have transient microbiomes where bacterial load is very low. Many bird species, panda species, host only small or transient microbiomes.

This is likely a result of evolution and diet, where the microbiome became a risk factor in their survival.

There is a cost to humans too. Crohn's disease doesn't develop where there aren't any bacteria, crohn's disease develops in the ileum, colon and mouth where the bacteria and fungi reside.

When bacteria and fungi cross the epithelial barrier in crohn's disease, immune cell in the lamina propria set off an immune response and you get deep transmural inflammation. But if one drastically changes the diet with EN, it deprives the microbiome of nutrients which lowers bacterial load, and lowers the cost we pay for hosting a microbiome.

 

[asadmom]

A gut microbiome is usually lauded for its benefits to the host, rarely is the cost for the host dicussed.

The cost to the host is that a microbiome competes with the host for nutrients and becomes pathogenic when commensal bacteria or fungi cross the epithelial barrier.

The benefit/cost analysis is poor for many animals, so they either completely lack a microbiome, or have transient microbiomes where bacterial load is very low. Many bird species, panda species, host only small or transient microbiomes.

This is likely a result of evolution and diet, where the microbiome became a risk factor in their survival.

There is a cost to humans too. Crohn's disease doesn't develop where there aren't any bacteria, crohn's disease develops in the ileum, colon and mouth where the bacteria and fungi reside.

When bacteria and fungi cross the epithelial barrier in crohn's disease, immune cell in the lamina propria set off an immune response and you get deep transmural inflammation. But if one drastically changes the diet with EN, it deprives the microbiome of nutrients which lowers bacterial load, and lowers the cost we pay for hosting a microbiome.

Thanks! This makes me wonder if a diet that is diverse should be considered a modern day phenomenon and is helping all kinds of old and new bacteria thriving in the gut which might not be beneficial like what we think it is?

 

[kiny]

There's some evidence in crohn's disease that patients do better on monotonous diets. Most of these animals with low density or transient microbiomes eat very monotonous diets. EN is very monotonous too.

People used to have very monotonous diets, access to food sources outside of your home region is very recent.

In paintings of the 17th century, a pineapple was a status of wealth. It was rare and exotic, most people could not afford to eat it.

 

[Andersen007]

When I read articles like this, I always wonder what it means for me. In my case CRP was never elevated and I do seem to have a mild disease of the ileum so far, that very clearly reacts to the food I consume. But my calpro at a certain point was as high as 1200 (actually after taking Modulen for 1.5 weeks it skyrocketed there from 600, and thats also the only time I felt really sick), and even at that point my CRP was well within normal limits. I wonder if this may indicate a different phenotype rather than the severity of my inflammation.

I always found it weird how much I cannot tolerate EN, even though it feels great to drink it. I even tried elemental drinks although only to supplement a few times but my gut (lol) feeling was it also makes things worse rather than better. Never dared to go all in with that, and of course they are also super expensive. I think monotony has something to do with this, when during spring I ate exactly the same very restricted diet, I was great, no symptoms and 130 calpro. But then on my bachelors party in May, I had a few drinks and ate some different foods (although nothing particularly triggering or unhealthy really), I still didnt recover from that fully. And whenever I make a small deviation things get worse. Its a shame there are no clear guidelines on how to reintroduce stuff safely.

I am recently thinking with all this research coming out implicating the bacteria, to either take the course of rifaximin antibiotics my GI prescribed for SIBO a while ago, or do 5 strict days with only chicken meat broth - soft chicken breast and the broth liquid I can only assume comes close to what EN is supposed to be, obviously without the benefit of having complete nutritional value hence I cannot stay on it too long. I wonder if this could calm my mild flare somewhat.

 

[kiny]

Antibiotics that are broad-spectrum and macrophage-penetrating like quinolones (cipro) can drastically lower acute inflammation in crohn's disease patients. Yet, there's many downsides and they have gone out of favour in most of the Western world. You are bound to create resistant species, many have long term side effects, and because they are so broad, you run the risk of giving more pathogenic species or pathobionts a fitness advantage.

But the fact broad spectrum antibiotics can have such an immediate effect on inflammation in crohn's disease, just underscores how much bacterial species are involved in driving inflammation. Until evidence shows that probiotics and prebiotics have any positive impact, they should be avoided by crohn's patients.

Crohn's disease does not exist in a sterile environment free of bacterial and fungal species. Crohn's disease can not manifest itself in the upper GI tract where bacterial load is exponentially lower than it is in the ileum, colon and mouth.

 

[asadmom]

It's so interesting that you used the term "broad-spectrum" to describe the spread of bacteria types. It almost sounds like the bacteria groups all operate on different frequencies and respond to attacks that operate on the same.

I definitely bought into the marketing campaign of good prebiotics and probiotics and the doctors do recommend them when patients go through rounds of antibiotics. I've never connected the dots to think that these -biotics all affect our microbiome in some way.

 

[Andersen007]

Btw I think what Kiny says makes a lot of sense, but I recently found this study that basically says chronic inactive gastritis is almost universal in Crohns patients: https://www.nature.com/articles/s41598-022-21630-5

They also noticed a curious phenomenon, about h pylori being much less prevalent in Crohns patients vs controls. But the most curious thing about this is the location being the stomach. Btw I had upper endoscopy 1.5 years before my Crohns diagnosis which came back with the same exact findings, although deemed of questionable clinical relevance.

 

[kiny]

Commensals and probiotics are often described as these low-harm bacterial species without invasive properties.

In a healthy individual with a competent GI barrier these bacteria are kept at bay, the mucus layer is in tact, the epithelial barrier is sealed off between cells with proteins called tight junctions. The barrier lets through nutrients and little else.

In people with crohn's disease who have active inflammation, this is all compromised, likely due to pathogenic bacteria and fungu who enter tissue and set off the immune cells in the lamina propria.

Suddenly those "low-harm" commensals become pathognic (they become "pathobionts" if you wish), they enter tissue through mechanical force, through the fecal stream, and they are no longer harmless.

 

[asadmom]

Btw I think what Kiny says makes a lot of sense, but I recently found this study that basically says chronic inactive gastritis is almost universal in Crohns patients: https://www.nature.com/articles/s41598-022-21630-5

They also noticed a curious phenomenon, about h pylori being much less prevalent in Crohns patients vs controls. But the most curious thing about this is the location being the stomach. Btw I had upper endoscopy 1.5 years before my Crohns diagnosis which came back with the same exact findings, although deemed of questionable clinical relevance.

How do they diagnose gastritis when it's inactive?

 

[asadmom]

Commensals and probiotics are often described as these low-harm bacterial species without invasive properties.

In a healthy individual with a competent GI barrier these bacteria are kept at bay, the mucus layer is in tact, the epithelial barrier is sealed off between cells with proteins called tight junctions. The barrier lets through nutrients and little else.

In people with crohn's disease who have active inflammation, this is all compromised, likely due to pathogenic bacteria and fungu who enter tissue and set off the immune cells in the lamina propria.

Suddenly those "low-harm" commensals become pathognic (they become "pathobionts" if you wish), they enter tissue through mechanical force, through the fecal stream, and they are no longer harmless.

Any other microorganism that could potentially turn harmful when the opportunity presents itself?

 

[kiny]

My view of what is and what isn't crohn's disease is well defined.

Early events, gastroenteritis, fever, night sweats, oral manifestations in the form of aphthous ulcers, general abdominal pain.

Chronic enteritis develops, endoscope will show inflamed lymphoid follicles early on, later on can develop into deep transmural inflammation and large amounts of macrophages shield off the GI tract in the form of granuloma.

The upper GI tract is not involved.

 

[kiny]

Any other microorganism that could potentially turn harmful when the opportunity presents itself?

There's a mouth-gut axis, where species like klebsiella and veillonella that normally reside in the mouth, likely end up in the intestine. These are ingested with saliva. In normal people these would simply be washed away with the fecal stream, in people with active inflammation, these would enter tissue.

 

[Andersen007]

How do they diagnose gastritis when it's inactive?

They did a biopsy on a healthy / normal looking stomach (I also didn't have any symptoms resembling gastritis as far as I could tell, neither did others in the study I linked), and that's when they saw it. There are specific chronic signs histopathologists look for that are distinct from active ones - as far as I understand the presence of neutrophils causing ongoing inflammation distinguishes active from inactive gastritis, while infiltration of lymphocytes in the lamina propria is seen in both.