AIEC colonization and pathogenicity: Influence of previous antibiotic treatment

[kiny]

This is really interesting, because they show that only in NOD2 knockout mice AIEC persists.

They used 2 types of mice, wild types and NOD2 knockout mice.

When they infect them with AIEC nothing happens.

BUT, when they give them 3 days of antibiotics (which would wipe out the gut flora I assume) and then infect them with AIEC, AIEC starts colonosing.

Persistent AIEC colonization for 5 days was ONLY seen in NOD2 KO mice (people with crohn are often genetically NOD2 compromised)

When they use dextran sodium sulfate (they use this all the time to induce colitis in mice) AIEC persists.

If you infect the mice with an E coli commensal, nothing happened.


AIEC colonization and pathogenicity: Influence of previous antibiotic treatment and preexisting inflammation.

 

[kiny]

Wasn't there a study that linked prior antibiotics use with crohn?

 

[kiny]

I think this could also explain why some of those studies trying non-macrophage penetrating antibiotics have failed (flagyl, rifaximin etc), it might temporarely help for crohn since you are limiting commensal penetration into inflamed tissue, but without proper probiotics and without the capacity to control AIEC proliferation (LF82?) (since the antibiotic isn't macrophage penetrating) the antibiotic would stop working after a while.

 

[Moe.]

Thus article kiny. Interesting find. I'm surei remeber igor passau ask qu biological about the ssi vaccine and they stated that they are using a strain of e.coli to put crohns in remission/cure. They have been doing the same thing for cancer etc.
I wonder is it MAP. Is it E.coli? Why does it affect some? NOD2 behind this. Why is marijuana oil so effective. Why is ldn effective. So many questions yet no answers. I think that a combination of therapies should be given.
Not one therapy can treat crohns and be successful. It seems there are too many links.
I do not think anyone here has tried anti-map + remixade + scd . I'm not a doctor but I think it's pure bs that with all this technology there really isn't a cure. Clearly there not looking in the right place.

 

[kiny]

nissle 1917, yes I remember his post, dunno if that was one and the same though

probiotics start to become more dangerous now that they're genetically engineering them though, idk how I feel about them, the parasites they use from pigs aren't that harmless as normal probiotics any longer, they are genetically altered to invoke certain immune responses, they are no longer commensals found in the gut flora

F. Prausnitzii is the most hopeful one for me atm, it is a commensal found in normal gut flora, but it tends to disappear in people with crohn and it's potentially very anti-inflammatory in the gut, only problem is that it is will take a while before it is approved, it is treated as a medicine. It can not withstand oxygen, it's anaerobic also, but that's not the real problem (they can package probiotics fine for anaerobic bacteria), problem is the studies to get it approved are costly.

LF82 is the AIEC one found in crohn all the time, although they found a few more in pediatric patients

genome sequence of it: http://www.plosone.org/article/info...RI=info:doi/10.1371/journal.pone.0012714.t001

 

[kiny]

this is it, LF82 AIEC, it stick to the small intestine ileum region

 

[kiny]

I wonder is it MAP. Is it E.coli? Why does it affect some? NOD2 behind this.

yah, failed autophagy through NOD2 mutation in CD, inability to clear AIEC will lead to inflammation

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

There is some kind of link between AIEC and MAP, it's an older study, but either of both allows the other to grow, was a whole article about it, hmmm, I will find it again sometimes.

 

[wild_one353]

this is a very interesting study.

i often wonder the significance of genetic contributions like nod2 to the development of crohn's, when the mutation is only found in 30% of crohns patient, suggesting it is not causative.

since nod2 is supposedly involved in sensing intracellular bacteria i wondered how that woudl ever play any significance if typically no pathogenic bacteria ever really come in contact with our cells, as all of our skin is covered in probiotic bacteria, which acts like our "first skin", so i imagined a serious disruption of this "first skin" is perhaps required before any pathogen ever gets into the actual cells of our body, this study seems to suggest that very concept, where antibiotics were necessary for aiec colonization, the prequisite being a breaking of the first skin barrier.

as for kiny's question about whether there was any studys linking antibiotics to crohns/ibd here are a few.

Antibiotic use and the development of Crohn's disease. 2004
http://www.ncbi.nlm.nih.gov/pubmed/14724158

Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease -dec 2010
http://www.ncbi.nlm.nih.gov/pubmed/20940708

Potential Association Between Tetracycline Antibiotics and Inflammatory Bowel Disease- SEPT 2010
http://dermatology.jwatch.org/cgi/content/full/2010/917/4

Association between the use of antibiotics and new diagnoses of Crohn's disease and ulcerative colitis-DEC 2011
http://www.ncbi.nlm.nih.gov/pubmed/21912437


also here is a more precise study on the effects of antibiotics on human flora

The Pervasive Effects of an Antibiotic on the Human Gut Microbiota, as Revealed by Deep 16S rRNA Sequencing
http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060280

 

[kiny]

thank you links

since nod2 is supposedly involved in sensing intracellular bacteria i wondered how that woudl ever play any significance if typically no bacteria ever really come in contact with our cells, as all of our skin is covered in bacteria, which acts like our "first skin", so i imagined a serious disruption of this "first skin" is perhaps required before any pathogen ever gets into the actual cells of our body, this study seems to suggest that very concept, where antibiotics were necessary for aiec colonization, the prequisite being a breaking of the first skin barrier.

yah NOD2 recognises bacteria, this study confirmed http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3424850/?tool=pubmed

if AIEC is involved defective NOD2 signaling would never be able to control AIEC, you would keep getting infliltration

AIEC is also a trojan horse like MAP, it takes advantage of TNF-alpha and macrophages, it's exploiting them, especially in NOD2 compromised people, since you lack signaling to detect it

 

[kiny]

some probiotic need NOD2, gut flora is constantly communication with the nervous system, the "good" bacteria don't just sit there, they talk with us all day long, day and night, the immune system is constantly telling them what's going on and what they have to do next

SO, if you have your own bacteria that need to respond to NOD2 signaling, but NOD2 is compromised in a CD person, then you get defective gut flora control.

That's why researchers who want to make probiotic for crohn want to know if a bacteria depends on NOD2 to work well, otherwise it will not work well in CD patients with compromised NOD2 signaling.

Good bacteria in our gut talk to us 24/7, that's the gut-brain barrier through the nervous system. That's why stress affecting crohn is not that far fetched, stress can cause dysbiosis in ruminants. Dysbiosis happens all the time in crohn.

 

[wild_one353]

as for a link between antibiotics and ibd, i have taken multiple extended courses of doxycycline for acne, easily 3 course ranging from as little as one month two six months, do not recall all the details at the moment, but not until i took a course of amoxicillin, did i start to have serious problems with my digestion, eventually leading to crohsn diagnosis. coincidentally, both these antibiotics have been linked to crohns disease, but now i dont think it was just a coincidence, they were involved in the process somehow.

 

[kiny]

yah, I believe in the perfect storm theory too

it takes a number of elements to eventually get crohn (which could be more than one disease btw)

not all of the people who have crohn have defective NOD2

all the elements add up, prior antibiotics, NOD2/ ATG16L1 gene mutation (many others), maybe stress causing dysbiosis, exposed to MAP or other pathogens, etc

perfect storm theory would not lead to one single disease, crohn is multiple diseases with clinical symptoms that are similar

(more reason that the perfect storm is needed is that exact twins don't always both get crohn, happens only in 50% of the cases, genetic predisposition is involved, but the fact that in only 50% of the cases genetically similar twins both get crohn means something else happened)

 

[wild_one353]

some probiotic need NOD2, gut flora is constantly communication with the nervous system, the "good" bacteria don't just sit there, they talk with us all day long, day and night, the immune system is constantly telling them what's going on and what they have to do next

SO, if you have your own bacteria that need to respond to NOD2 signaling, but NOD2 is compromised in a CD person, then you get defective gut flora control.

i do recall one study suggesting that the entire healthy inflammatory response is initiated by signals from the bacteria itself in helping to instruct our own cells in knowing how to behave appropriately. the concept of chronic/dis regulated inflammation could theoretically involve a serious dysruption in these bacterial communitys.

it is interesting how you report the need for nod2 by some probiotic bacteria, do you have any more details of this relationship?

 

[kiny]

it is interesting how you report the need for nod2 by some probiotic bacteria, do you have any more details of this relationship?

yes, person I talk to talks to study group all time

"We observed that some lactobacilli (e.g., Lactobacillus salivarius Ls33) induced regulatory DCs in vitro able to protect mice from 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis after adoptive transfer in a NOD2-dependent manner."

knock yourself out: http://www.landesbioscience.com/journals/gutmicrobes/article/18255/?show_full_text=true

 

[kiny]

sometimes I wish I had an easier disease, I remember they did mantoux test, and I wished I had TB, cause it would be easier to deal with *sniff*

at least it's interesting, although I hope progress is soon

 

[kiny]

that the entire healthy inflammatory response is initiated by signals from the bacteria itself in helping to instruct our own cells in knowing how to behave appropriately. the concept of chronic/dis regulated inflammation could theoretically involve a serious dysruption in these bacterial communitys

yah, that's the dysbiosis they see in crohn, the bacteria work together with the immune system, they learn all the time, those bugs communicate all the time with us, non-stop, constantly talking over the nervous system wavelength, they are WAY more important that most people think, they are living creature with their own genetic code, their own receptors and their own function


they should screen people for NOD2, and tailor make probiotics

 

[kiny]

linking for reference and wiki tags from before, I keep wikipedia microbe section updated too, last year it had no info at all, now it has decent info, many parts of the puzzle I think are there

(will be kind of upset if cornell uni is right, uncontrolled T cell response to commensal would be hard to control, but if it's simply AIEC it would be way easier to treat)


Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response.
Lapaquette P, Bringer MA, Darfeuille-Michaud A.
Source

Clermont Université, Université d'Auvergne, UMR-Inserm/Université d'Auvergne U1071, USC-INRA 2018, Clermont-Ferrand, France.

 

[Moe.]

I Used to get tonsillitis. Doctor used to throw antibiotics at me all the time.
Got c diff. Then got cured. Two years later and 4x a year of antibiotics got dx. All because he wouldn't let me remove them. Imagine that is the cause.

The ssi vaccine that clears e.coli. Do you believe it gets rid of this Aiec?

 

[kiny]

don't know what ssi vaccine is, thought it was about nissle 1917

macrophage-penetrating antibiotics can kill AIEC, but AIEC become resistant too if you discontinue

rifaximin and some other antibiotics have low bioavailability, AIEC can interact with peyer's patches and it can invade deep mucosa, those antibiotic are not macrophage penetrating and have low bioavailability, I do not think they can be effective against AIEC very much, I assume

hmm, they don't know if AIEC is causative either, since AIEC doesn't rule out T cell response to gut flora at all, so if you could clear out all the AIEC from someone, what would happen....I dunno

 

[Moe.]

No not nissel.

Ssi vaccine. Qu biologics . Read about it. Clears a certain strain of e coli

 

[kiny]

LF82 AIEC sticking to ileal enterocyte cell of a crohn's patient, 1000x magnification:

other 4 AIEC strains they could show adherence by using CD isolated epithelial cells (enterocyte) were strains: LF31, LF71, LF73, and LF100

commensal E Coli doesn't do this, in controls AIEC doesn't manage to adhere to epithelial cells either, only in CD

AIEC are trojan horses, they reproduce inside a macrophage inside the phagolysosomal compartment, avoiding apoptosis, the macrophage releases TNF-alpha, which upregulates "CEACAM6" which from what I understand gives them the ability to bind to ileal enterocyte, so they are tricking the immune system into releasing TNF-alpha and are exploiting it for their own growth

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1868786/?tool=pubmed