# Defective macrophage handling of Escherichia coli in Crohn's disease.



## kiny (Apr 18, 2015)

（hi lovely people, been busy a bit lately)

http://www.ncbi.nlm.nih.gov/pubmed/25809337

*Defective macrophage handling of Escherichia coli in Crohn's disease.*

2015 Mar 23, UK; Department of Gastroenterology, Department of Medicine, University of Melbourne, Australia.

Elliott TR, Hudspith BN, Rayment NB, Prescott NJ, Petrovska L, Hermon-Taylor J, Brostoff J, Boussioutas A, Mathew CG, Sanderson JD.

*BACKGROUND:*

Escherichia coli can be isolated from lamina propria macrophages in Crohn's disease (CD) and their intramacrophage persistence may provide a stimulus for inflammation. To further determine the contributions of macrophage dysfunction and E. coli pathogenicity to this, we aimed to compare in vitro functioning of macrophages from patients with CD and healthy controls (HC) in response to infection with CD-derived adherent-invasive E. coli (AIEC) and less pathogenic E. coli strains.

*METHODS:*

Monocyte-derived macrophages were cultured from patients with CD and HC. Intramacrophage survival of E. coli strains (CD-derived adherent-invasive (AI) & non-AI strains and laboratory strain K-12) was compared. Macrophage cytokine release (TNFα, IL-23, IL-8 and IL-10) and monocyte phagoctyosis and respiratory burst function were measured after E. coli infection. For CD patients, laboratory data were correlated with clinical phenotype, use of immunomodulation and CD risk alleles (NOD2, IL-23R, ATG16L1 and IRGM).

*RESULTS:*

Attenuated TNFα and IL-23 release from CD macrophages was found after infection with all E. coli strains. There was prolonged survival of CD-derived AIEC, CD-derived non-AIEC and E. coli K-12 in macrophages from CD patients compared to within those from HC. No abnormality of monocyte phagocytosis or respiratory burst function was detected in CD. Macrophage dysfunction in CD was not influenced by phenotype, use of immunomodulation or genotype.

*CONCLUSIONS:*

CD macrophage responses to infection with E. coli are deficient, regardless of clinical phenotype, CD genotype or E. coli pathogenicity. This suggests host immunodeficiency is an important contributor to intramacrophage E. coli persistence in CD.


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## rollinstone (Apr 18, 2015)

Hopefully this births new treatments or even a way of correcting this dysfunction, maybe that'll cure people.


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## wildbill_52280 (Apr 19, 2015)

Interesting, they observed attenuated tnf-a levels in CD cells, so much for inhibiting tnf-a right? just a small contradiction I guess. I'm about seriously confused though with this Immunodeficieny/hyperactive immunity mumbo jumbo, its a kind of wishy washy science with these overly abstract terms. They are trying too hard to generalize and simplify the complexity of what is happening, some events are "too much" and some events are "too little", lets just say, a bunch of stuff is messed up and not "normal" haha. It's like we cant clear these pathogens and the immune system doesn't turn off, that can be categorized as BOTH a deficient response and overactive. so why is that? genetics or microbiome disruptions in bacterial diversity? or a pathogen that is so sophisticated as to evade the immune system.


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## HelenMelb (Apr 19, 2015)

Dr Hal Gunn, who is developing the SSI vaccines for Crohn's, talks about innate immune system deficiency that causes an overactive adaptive immune system response as a result.

There is a post on the SSI vaccine thread that links to an interview with Dr Gunn, where he explains his theory really well.


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## JMC (Apr 19, 2015)

A paper on E-Coli from John Herman-Taylor, that alone makes it pretty interesting given he is a strong proponent of MAP being the cause of Crohns


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## xeridea (Apr 19, 2015)

kiny said:


> （hi lovely people, been busy a bit lately)
> 
> http://www.ncbi.nlm.nih.gov/pubmed/25809337
> 
> *Defective macrophage handling of Escherichia coli in Crohn's disease.*


Hi Kiny, nice to have you back, have missed reading your posts of late.

The defective macrophage model is convenient because it fits somewhat nicely with anecdotal recounts of antibiotic use being their cause of Crohn's. In particular, subjects with this dysfunction will be pre-disposed to other infections, which increases antibiotics use, and later by some accounts, is associated with onset of Crohn's.

Here's a couple papers I hang on to regarding this topic. I'm going to add yours my list of references on this subject.

*Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease*
http://jem.rupress.org/content/206/9/1883.full

*Revisiting Crohn's disease as a primary immunodeficiency of macrophages*

http://jem.rupress.org/content/206/9/1839.full

They're both a few years old but what they suggest seems consistent with the more recent paper you cited in your post.


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## wildbill_52280 (Apr 19, 2015)

xeridea said:


> Hi Kiny, nice to have you back, have missed reading your posts of late.
> 
> The defective macrophage model is convenient because it fits somewhat nicely with anecdotal recounts of antibiotic use being their cause of Crohn's. In particular, subjects with this dysfunction will be pre-disposed to other infections, which increases antibiotics use, and later by some accounts, is associated with onset of Crohn's.
> 
> ...


I suspect you are proposing the defective macrophages could be primary cause of crohn's. For a moment i would ask why are these macrophages defective, here is a study which suggests the microbiome send signals which regulate macrophage behavior, leading us back toward the microbiome again as a possible sole cause of crohn's. 

http://www.ncbi.nlm.nih.gov/pubmed/24625929


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## xeridea (Apr 19, 2015)

Bill one of the papers was evaluating macrophage response in Crohn's patients subcutaneously so looking at it wholistically and not just looking at response in the gut. So possibly a diffetent angle not involving microbiome!


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## wildbill_52280 (Apr 19, 2015)

xeridea said:


> Bill one of the papers was evaluating macrophage response in Crohn's patients subcutaneously so looking at it wholistically and not just looking at response in the gut. So possibly a diffetent angle not involving microbiome!


yea i have no idea how far the influence of microbiota metabolites goes. I do recall short chain fatty aids produced by intestinal microbes travel all throughout the body and especially influence liver function.


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## wildbill_52280 (Apr 20, 2015)

wildbill_52280 said:


> yea i have no idea how far the influence of microbiota metabolites goes. I do recall short chain fatty aids produced by intestinal microbes travel all throughout the body and especially influence liver function.


also lets not forget about the vagus nerve which scientists estimate the purpose of is to send signals from the microbiota to the brain, 80% of the signal ssent via the vagus nerve is coming from the gut. They have proven this link so that is another example to the far reaching influence of the intestinal bacteria in the bodily systems.


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## kiny (Apr 22, 2015)

wildbill_52280 said:


> For a moment i would ask why are these macrophages defective


Genetics. ATG16L1 NOD2 and IRGM  polymorphisms, the major genetic risk factors for crohn's disease, prevent proper clearance of AIEC from macrophages. Those macrophages cause a chronic inflammatory response, they can't clear AIEC, and keep producing inflammatory cytokine like TNF-α.

Invading peyer's patches and macrophages is AIEC's niche. That's what they're dsigned to do, they have long fimbriae specifically to invade peyer's patches of the ileum.

http://www.ncbi.nlm.nih.gov/pubmed/22309232

_"Impaired ATG16L1, IRGM or NOD2 expression induced increased intramacrophagic AIEC and increased secretion of IL-6 and TNF-α in response to AIEC infection. In contrast, forced induction of autophagy decreased the numbers of intramacrophagic AIEC and pro-inflammatory cytokine release, even in a NOD2-deficient context.

On the basis of our findings, we speculate that stimulating autophagy in CD patients would be a powerful therapeutic strategy to concomitantly restrain intracellular AIEC replication and slow down the inflammatory response."_


That's what vitamin D does.

Vitamin D affects how a macrophage handles intracellular bacteria. It corrects ATG16L1 and NOD2's polymorphism by affecting autophagy, ATG = Autophagy. VDR polymorphism is also a risk factor for developing crohn's disease, VDR = Vitamin D receptor.

http://www.ncbi.nlm.nih.gov/pubmed/20594120


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## kiny (Apr 22, 2015)

wildbill_52280 said:


> Interesting, they observed attenuated tnf-a levels in CD cells, so much for inhibiting tnf-a right? just a small contradiction I guess.


TNF-a secretion is normal during infections and a requirement to clear an infection. What isn't normal is that CD macrophages can't clear the invader. As long as the macrophages can't clear AIEC, they will keep producing inflammatory cytokine, TNF-a. Cytokine signal other immune cells, it's a_ call for help_ from the macrophage.

Giving people TNF-a blockers stops the destructive inflammaton, but it doesn't stop the cause of the inflammation. If you stop anti-TNF, the inflammation just comes back.

As CD patients, we suffer from _*immunodeficiency*_, our macrophages are asked to do the same tasks but with genetic defects and inability to properly clear bacteria, leading to chronic inflammaton.


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## kiny (Apr 22, 2015)

wildbill_52280 said:


> It's like we cant clear these pathogens and the immune system doesn't turn off, that can be categorized as BOTH a deficient response and overactive. so why is that?


I feel it makes the most sense if you categorize it as innate immunodeficiency, which is what most studies are doing now.

Macrophages are part of the innate immune system. They are everywhere in the intestines, they are your first line of defense against bacteria in the intestine, they encapsulate and phagocytose bacteria. The chronic inflammation does involve the adaptive immune system, antigen presenting cells and T cells, but the major focus is the immunodeficient macrophages.

Study after study have shown macrophages of crohn's disease patients are very different from healthy controls. Cytokine release is also not abnormally high in response, some studies suggest it is actually lower than it should be to clear those bacteria.


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## rollinstone (Apr 22, 2015)

kiny said:


> I feel it makes the most sense if you categorize it as innate immunodeficiency, which is what most studies are doing now.
> 
> Macrophages are part of the innate immune system. They are everywhere in the intestines, they are your first line of defense against bacteria in the intestine, they encapsulate and phagocytose bacteria. The chronic inflammation does involve the adaptive immune system, antigen presenting cells and T cells, but the major focus is the immunodeficient macrophages.
> 
> Study after study have shown macrophages of crohn's disease patients are very different from healthy controls.


Any more news on macrophage penetrating antibiotics?


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## rollinstone (Apr 22, 2015)

Ps. Thanks for all your info kiny


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## kiny (Apr 22, 2015)

rollinstone said:


> Any more news on macrophage penetrating antibiotics?


Don't know any, cipro is very effective against E Coli, including AIEC, but within a few weeks, AIEC becomes resistant. Cipro is still a viable treatment for crohn's disease, I've had crohn's disease as a kid, and after a decade, I still see it being used if all else has failed.

But it only work for a short while, before people get sick again, once bacteria become resistant to it, it stops being useful in the short term.

You also can't give it long term, people don't tolerate it well, and it can cause serious side effects if you would give it long term, but if all else has failed, I see it used still.

http://www.ncbi.nlm.nih.gov/pubmed/22508665


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## mf15 (Apr 23, 2015)

This ties in with my research on taurine, which will protect macrophages from ROS but it will also protect the intercellular bacteria from being killed.
Arginine will make more NO from inos, is that what crohns people need.
I have UC arginine supplements make me worse.
A question might be, protect the macrophages in both diseases with taurine, to lower
inflammation, or not.  In other words is the overwhelming inflammation
causing a problem with the macrophage clearance of bacteria, in crohns.
Vegetarians get little dietary taurine, would love to know if vegetarians get less crohns and more UC,when compared to just vegetarians,not the omnivore
population.  See semi vegetarian diet and crohns.
So for UC take taurine for crohns arginine, or not.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128366/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC303164/

semi vegetarian diet crohns
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877178/

old thread on this diet, hard to tell
http://www.crohnsforum.com/showthread.php?t=13170

arginine h pylori
http://iai.asm.org/content/75/9/4305.full

Here is my whole thread from healingwell, lots of important info.
Actually need to read both threads to know what is really going on.
First thread may apply more to crohns.
Old Mike
http://www.healingwell.com/community/default.aspx?f=38&m=2540341

http://www.healingwell.com/community/default.aspx?f=38&m=3322927


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## xeridea (Apr 23, 2015)

This paper delves a little deeper into subsets of macrophages and identifies those that drive the increase in pro-inflammatory cytokines. It's a little off-topic vis-a-vis AIEC, but nonetheless interesting on learning more about the role macrophages play in CD.


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## rollinstone (Apr 23, 2015)

xeridea said:


> This paper delves a little deeper into subsets of macrophages and identifies those that drive the increase in pro-inflammatory cytokines. It's a little off-topic vis-a-vis AIEC, but nonetheless interesting on learning more about the role macrophages play in CD.


Interesting they suggest presence of an auto antibody? Unless I missread it. Would be very grateful if someone could break it down in less scientific terms.


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## InstantCoffee (May 3, 2015)

kiny said:


> Don't know any, cipro is very effective against E Coli, including AIEC, but within a few weeks, AIEC becomes resistant. Cipro is still a viable treatment for crohn's disease, I've had crohn's disease as a kid, and after a decade, I still see it being used if all else has failed.
> 
> But it only work for a short while, before people get sick again, once bacteria become resistant to it, it stops being useful in the short term.
> 
> ...


Well I guess I'm screwed. I've been on flagyl, bactrim and cipro on and off for my chronic abscesses. They never worked either.


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## mf15 (May 3, 2015)

Some might find this of interest if you have crohns.
Where as arginine makes my UC worse, as they note in the paper.
Old Mike
http://jn.nutrition.org/content/138/12/2481.full


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## JMC (May 6, 2015)

*Monocyte-derived Macrophages from Crohn's Disease Patients Are Impaired in the Ability to Control Intracellular Adherent-Invasive Escherichia coli and Exhibit Disordered Cytokine Secretion Profile.
*

http://www.ncbi.nlm.nih.gov/pubmed/25805890

*CONCLUSIONS:*
MDM from CD patients are unable to restrict intracellular AIEC replication, leading to disordered inflammatory response influenced by disease activity.


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## wildbill_52280 (May 6, 2015)

JMC said:


> *Monocyte-derived Macrophages from Crohn's Disease Patients Are Impaired in the Ability to Control Intracellular Adherent-Invasive Escherichia coli and Exhibit Disordered Cytokine Secretion Profile.
> *
> 
> http://www.ncbi.nlm.nih.gov/pubmed/25805890
> ...


unexpected finding. How would one explain this.


> AIEC-infected MDM from patients with quiescent CD released significantly higher amounts of IL-6 and TNF-alpha than those with active disease or those from HC.


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## xeridea (May 12, 2015)

This study published today describes the biochemical mechanism by which commensal E. Coli can proliferate during a flare, contributing to the disease state. 

These findings define a fundamental mechanism by which E. coli surpasses the host innate immune responses during inflammatory gut diseases and gains a distinct survival advantage.


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