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Cell stress inflames the gut: New insights into chronic bowel inflammation

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Posted 7/1/2014 2:45 PM (GMT 0)
Cell stress inflames the gut: New insights into chronic bowel inflammation:
medicalxpress.com/news/2014-06-cell-stress-inflames-gut-insights.html

Goes along with this.

Deficient protein GM-CSF production found to impair gut's immune tolerance:
medicalxpress.com/news/2014-03-deficient-protein-gm-csf-production-impair.html#inlRlv


The top one is important because of the way it effects DDS and Bacterial Colitis models. Personally I don't agree with the deregulated response to normal flora thing that many use as an opening when writing studies..... never have.
Posted 7/1/2014 3:54 PM (GMT 0)
For some reason,in the back of my mind I am starting to think that.
UC is neither autoimmune, nor an aberrant immune response to commensal bacteria.

Mucus breach,with a normal immune response,when if leucocytes fail to clear the bacteria,and mucus breach

or low viscosity mucus,or thin mucus layer is not repaired, then all hell breaks loose.
Old Mike

Post Edited (Old Mike) : 7/1/2014 12:37:23 PM (GMT-6)

Posted 7/1/2014 5:56 PM (GMT 0)
Unless Im missing something, I dont see how this connects to UC at all. The paper shows that CHOP is down-regulated in UC, but that its inhibitory effects occur when it is up-regulated...
Posted 7/2/2014 8:45 AM (GMT 0)
The article is actually a prime example off all that's wrong with reading just "acticles" and taking them word for word and well, just poorly written stuff. Though it is an interesting study really.

First, you would be correct at interpreting that from what you read as that's what is seems to imply, but in fact what they mean is that in bacterial colitis, and a T-cell mediated colitis it (CHOP) is reduced, yet in Ulcerative Colitis (For real in humans) it is actually increased.

Second - this is important bacause it comes back to barrier function - In this case they are showing increased levels of CHOP delay, or slow the healing of epithelial cells. One take on it could be that this is a "gene" or "genetic" issue where those of us that overexpress CHOP for one reason or another and experience a "stress" event - be it viral, bacterial, or even mechanical stress (injury, pregnacy, extreme exercise) - which all elecit UPR (Unfolded Protein Response) experience delayed healing of our barrier and therefore we become open to a chroic infection/food antigens etc etc. after the intial "high stress" triggering event. So because healing is delayed or significantly slowed we never recover - or have a very hard time for most. Whereas those with properly regulated unfloded protein response heal faster and clear the infection. But there's lot's of different takes you could have on this study actully.

In any case, what it does show is that proper barrier function is key. Fix the mucus and barrier/fix the problem as OM likes to say.

-----
On a side note a lot of these "articles" start off with "IBD is a disregulated response to normal bacterial flora" or some variation of that... this is of course completely unproven. Or they start off saying IBD in an autoimmune condtion - same thing. Unproven. They need to start putting the words "It is thought" into those statements.

----

@OM - I think if it was "Autoimmune" or "Disregulted response to normal bacteria" recovery (from those that had sucess) from fecal transplants would not make sense. Both would perhaps worsen the issue. And with Auto-immune why would FT even bring about complete remission? Doesn't add up....

For those that do experience worsening of symptoms via Fecal Transplant I'm thinking this might really be due to a severely messed up/or total loss of barrier function and possible donor food source antigens triggering an increase in symptoms. Just something to think about...
Posted 7/2/2014 1:50 PM (GMT 0)
I never actually read the article in the link; never do. I always go straight to the actual paper itself for obvious reasons.

But are you sure its up-regulated in UC? I havent had a chance to read the article itself (just the abstract), but either this is the worst piece of writing Ive ever seen or something is off: "Consistent with observations in patients with ulcerative colitis, we show that despite UPR activation in the epithelium, CHOP expression was reduced in mouse models of T-cell-mediated and bacteria-driven colitis."

If it is up-regulated in UC patients then yes, it obviously has huge implications, but if not, its really irrelevant.

As for the other bit, the argument that its a dis-regulated response to commensal bacteria largely comes from the fact that KO mice dont develop UC in sterile conditions, so the commensal bacteria have to be involved in generating that response. Theres obviously other reasons as well, but this is the most obvious one. So, I think its an accurate description, its just not comprehensive.
Posted 7/2/2014 2:28 PM (GMT 0)
Marauder: Yes of course the commensal bacteria are involved.
One of the mainstream theories of UC is that it is an aberrant immune response to commensal bacteria.
What I am saying is that the immune response is normal/not aberrant,but the mucus/mucosal breach for some reason not repaired. After more and more bacteria get to the mucosa,the immune response becomes more intense,colaterial damage/tissue remodeling/dysbiosis then starts to take place.
Once the immune cascade takes palace it is hard to stop.
Why wont it stop,mucus/mucosal breach not repaired,thin mucus layer,low viscosity mucus,bacterial
protease,goblet cell depletion.
Old Mike
Posted 7/2/2014 2:39 PM (GMT 0)
"Fix the mucus and barrier/fix the problem."

If this was the case, wouldnt that German approach of retarded release phosphatidycholine (sp.), aka rPC, have panned out into a solid winner, since it was all about coating the degraded mucus barrier? Last I recall, pretty much no one on this forum had any success with it. I tried it but couldnt tolerate it-- it worsened pain and cramps in me-- so my experiment couldnt last long enough to know, but although the published studies for rPC sounded amazing, and there is a German forum by UC users of the stuff, there havent been any replicated studies nor has it seemed to go anywhere in onward studies.
Posted 7/2/2014 2:42 PM (GMT 0)
I see, so your hypothesizing that the initial injury is not due to an aberrant (or autoimmune) response to the commensal microbes, but some other factor, but that the damage is not being repaired properly and thus, the chronic inflammation?

Its an interesting idea. The probiotic/FMT successes both support and refute it (what else is new). At the very least, id say that an impaired mucosal healing is at least part of the issue.
Posted 7/2/2014 2:54 PM (GMT 0)
Pro: Yes I remember the whole thing quite well,even tried PC enema.
Anyhow,if the mucus layer is thin in depth,or of low viscosity,or denuded from the mucosa,or there
is a lot of phospholipase, PC wont do much good.  Once you get goblet cell depletion,your in big trouble.

Here is an example of dogma for the past 50 years being dead wrong,kidneys can regenerate.
Came out this am. What else are they dead wrong about.
http://medicalxpress.com/news/2014-07-adult-kidneys-constantly-remodel.html
Old Mike

Post Edited (Old Mike) : 7/2/2014 9:00:10 AM (GMT-6)

Posted 7/2/2014 3:36 PM (GMT 0)
@Maurader - it's up-regulated in IBD see the link below;

Even the studies you have to be mindful - this one uses the opening statement "Endoplasmic reticulum (ER) stress is a causative factor of inflammatory bowel diseases." - kind of in "iffy" statement by the author/researcher.

Endoplasmic reticulum stress-activated C/EBP homologous protein enhances nuclear factor-kappaB signals via repression of peroxisome proliferator-activated receptor gamma:
www.ncbi.nlm.nih.gov/pubmed/20829347

There's many more that show the same. So this is why it's very interesting - and that they just wrote that statement in a confusing manner. I only knew because I have a thread buried on here somewhere about mis-folded proteins from a while ago so caught onto it. Otherwise my take would have been the same as yours.

----
ALSO in regards to knock out mice in sterile environment - It doesn't matter if they are knock-out (missing an immune response gene or whatever) or good old fashioned normal perfectly healthy mice. Neither develop Colitis like symptoms (and many other diseases) in a germ-free (sterile) environment. Germ free animals outlive non-germ free. So this clearly demonstrates bacteria are required and strongly suggestive they are causal - BUT that does not necessarily mean they are commensal - commercial means we obtain some sort of benefit from them or visa versa. So it suggests that pathogenic bacteria might be the problem, except no one has yet to have been able to identify a specific species. Take for example cavities - In a germ free environment you can feed mice all the sugars and such you want and they will not develop cavities. Introduce various known pathogenic oral bacteria and wham - they develop cavities. These are non-commensal oral bacteria. So they may and may not be present in everyone. This is why they are trying to develop oral vaccines for cavities.

It's a mild wording thing - but most research seem to point to a non-commensal organism at play.
Posted 7/2/2014 3:42 PM (GMT 0)
@OM

I think part of the problem is it's not known exactly what the problem with mucus is... Other than there seems to be a lack of sulfurmucins. So what (bacterial, viral or immune) is causing the disappearance of sulfurmucins in UC and Colon Cancer.

The mere presence of bacteria seems to induce sulfurmucin production over sialomucin - and specifically in the distal colon.
Posted 7/2/2014 4:06 PM (GMT 0)
Mark: Also notice at the end they mention several tases. Once our antiprotease enzymes are depleted
big trouble,or after we get dysbiotic,big trouble.

The initial event whether D from virus or bacteria,antibiotic thinning of mucus,mechanical abrasion/tear.

Mucus breached,bacteria get through leukocytes to mucosa,immune cascade starts,goblet cell loss,less good

quality mucus produced.

Why cant we repair the breach,yet others can. Big question.

Modern diet,cooking methods, excessive glycoalkaloid consumption, xenobiotic elimination differences.

Bad luck.
It could be something as stupid as how many times you wash your hands and with what.

Still looking.
As of yesterday went to all castile hand soap,in the soap dispensers in the house.
No detergents in them.

Old Mike

http://www.ncbi.nlm.nih.gov/pubmed/24969297
Posted 7/2/2014 4:36 PM (GMT 0)
OM,
Not eating soap really matters, rinse your dishes and your produce very well. Many organic farming methods rely heavily on soap. Wash wash and wash some more.

There are genes that also regulate mucus. Of interest to me are the SLC gene family
www.ncbi.nlm.nih.gov/gene/6566


Impaired butyrate oxidation in ulcerative colitis is due to decreased butyrate uptake and a defect in the oxidation pathway.
www.ncbi.nlm.nih.gov/pubmed/21987487


Hence why some people respond so amazingly to butyrate. But, we also have to make sure any pathogens that were there get unseated and the nutrients that are depleted get tanked up and the toxicness that has been hitting the liver has to get cleaned out... and supplement butyrate until we can get butyrate producting species established.

There are also the MHC genes... but that gets a bit more complicated.
en.wikipedia.org/wiki/Major_histocompatibility_complex
Posted 7/2/2014 4:59 PM (GMT 0)
Path: Thanks for the info.
It is not soap that is the problem,it is synthetic detergents/emulsifiers/surfactants.
Plain old castile soap is just sodium or potassium oleate,or some other fatty acid.
Old Mike
Posted 7/2/2014 5:53 PM (GMT 0)
1) I looked into it a bit more. Neither of the two papers that the paper you cited even mentioned the CHOP protein; let alone it being up-regulated. I only did the most brief of searches/read throughs, but Im almost certain it wasnt in any of their results. Additionally, those papers had very low sample sizes, so the results arent exactly conclusive, even if they were there. Ill look into this more when I get home.

2) Claims made in the intro dont really affect the validity of the paper though; its the methods and discussion you have to be concerned with : p And in this case, ER stress is a causative factor in IBD forsure. I dont think its necessary or sufficient, but it does lead to IBD.

3) I have a friend who studies ER stress for a living, so Ill get his take on this as well. He does respiratory work, but Im sure there is a lot of overlap.

4) Your absolutly correct, I only mentioned the fact that they were KO mice because we normally dont care about wt mice developing colitis, where as KO mice should :p
Posted 7/2/2014 6:14 PM (GMT 0)
@Maurader - CHOP is in fact short for "C/EBP homologous protein" dude.... so yes it is in fact up-regulated. The discussion is worse at times....

EDIT: It's also downstream from NFkB - so this has implications on inflammation - which is pointed out in the first - not just apoptosis.

Post Edited (Canada Mark) : 7/2/2014 12:19:32 PM (GMT-6)

Posted 7/2/2014 7:20 PM (GMT 0)
@Path - Many thing effect Butryrate uptake to epithelial cells - Number 1 is actually proper molecular structure of Mucus.

MHC 1&2 are proteins - and quite simple to an extent. MHC 1 displays "normal" proteins in cytoplasm and MHC2 displays external sources of "foreign" proteins, carbs and nucleic acids - It's they way the body tells if a cell is infected internally by virus etc etc. or if the body is infected with external pathogens. Spent a month on this in school this past year. MHC1 is actually quite ingenious - as long as the cells in our body are displaying the all is well and normal healthy functioning proteins, the immune system leaves them along - Viruses etc effect proteins in the cytoplasm and when these "abnormal" proteins are then exported to the cell surface via MHC class one molecules this is the kill signal.... The immune system will attack and destroy the cell. So it;s the body's way of looking inside a cell - just like we can't look inside out arm and see our insides - the immune system cannot see inside out cells. This is the method that allows the immune system to keep a check on what's going on inside our cells.

MHC 1 and 2 can be thought of more like ummm flag poles - And the flags they display are specific proteins/carbs and nucleic acids.


@Path
Avoiding soap isn't going help a darn bit. A good example/experiment: Grab some mucus on a plate, apply a drop of soap and leave sit there... you'll quickly find out it has no effect - and this method is HUGE quantity and concentration compared to what we may incidentally ingest. This has to do again with the actual structure of mucus.

@OM - synthetic detergents/emulsifiers/surfactants - It's darn tempting to think about and of course we can clearly see what it's suggested in the 10,000 biopsy paper etc etc. But in reality many people (98% of the population perhaps) go about their lives using these and washing dishes, clothes, ingesting and on and on and live just fine and never develop IBD. That's the part I struggle with in this aspect of the 10,000 biopsy paper. Maybe they make healing harder though.... Or a tougher process. It's one of those iffy, maybe there is something to it type topics. Again the structure of the mucus seems to be what dictates the effects of these and other chemicals/organic molecules have on us - be it useful or harmful - Eg: www.ncbi.nlm.nih.gov/pubmed/2221076 Butryrate/Acetate and so on being Short chain fatty acids, but many other things effect what can diffuse through mucus.

Really I laugh cause I went from being all about bacteria before school, then all about the immune system during because it was just down right amazing - and then after school I was like wow - This mucus stuff - like actual mucus is like the most crazy and intensely awesome stuff around.... and obscenely complex!

EDIT: I guess my question would be why don't synthetic detergents/emulsifiers/surfactants have a negative effect on everyone? You're wife or my mom or the lady bellow me that cleans and uses this stuff on a daily basis and had zero health problems. Frustrating stuff this IBD is, haha. I guess it could leave us open or more susceptible to a bacterial infection of some sort?

Post Edited (Canada Mark) : 7/2/2014 1:26:08 PM (GMT-6)

Posted 7/2/2014 9:54 PM (GMT 0)
Mark: Well of course you ask the age old question.

If we are all exposed to this stuff,why is not everyone sick with UC.

Don't know.

But I will venture to guess that everyone exposed to Western life is having some sort of perhaps subclinical

gut issue,they just don't know it.

We have IBD,but there are other millions and millions with IBS,something is going on.

Old Mike

here is a good paper

http://onlinelibrary.wiley.com/doi/10.1111/apt.12500/full

 

Post Edited (Old Mike) : 7/2/2014 5:26:12 PM (GMT-6)

Posted 7/2/2014 10:57 PM (GMT 0)
Hey guys great discussion!
I was wondering though: if mucous barrier is the main issue then how come FTs work? Because wouldn't introducing bacteria into a colon with defective mucous layer going to set off an even stronger immune response?
Posted 7/2/2014 11:18 PM (GMT 0)
Some get worse on FT,others no effect,some do get better. Banana girl had a big problem.
Ft may displace dysbiotic bacteria,which might express more protease.
Might depend on the level of dysbiosis.
Early onset UC,indicates that these people were not dysbiotic.
Early onset,meaning they took stool and mucosa samples for bacteria types,quickly after onset,and
before meds.
Dysbiosois comes later,5 years or so.
I suspect from immune damage,and or meds.

For me at this stage of my disease,extra bacteria from probiotics makes me worse,especially
really live ones from lacto fermented pickles.

Anyhow,concerning my other comments how can FT work at all if this disease is autoimmune,or an aberrant immune response to commensal bacteria.
Big big puzzle.
Old Mike
Posted 7/2/2014 11:20 PM (GMT 0)

Canada Mark said...
@Maurader - CHOP is in fact short for "C/EBP homologous protein" dude.... so yes it is in fact up-regulated. The discussion is worse at times....

EDIT: It's also downstream from NFkB - so this has implications on inflammation - which is pointed out in the first - not just apoptosis.

Yes I know what CHOP is short for. What Im saying is that the 2 papers that the paper you posted cited didnt even mention CHOP at all; let alone it being up-regulated. Look at references 14 and 15, maybe I just missed it, but I could find no mention of CHOP at all. Just because the abstract/intro says something, doesnt make it true.
Posted 7/2/2014 11:34 PM (GMT 0)
That's true OM... Air pollution get's us as well - increased incidences of diseases.

Mucus:
(Lowest Degradability) sulfomucins > neutral mucins >>> sialomucins (Highest Degradability)

Takes about an hour for bacteria to degrade through sialomicins and in 4 hours time they can degrade about 40% of sulfomicins. It's some pretty tough stuff.

On Concuors question - This is exactly why I was wondering about the food antigens making FT worse perhaps for some. Especially to those with UC and in rough shape. To answer that one might look at germ free mice.

"In Germ Free Mice, the firm inner layer of mucus is very thin compared to conventional raised mice. Adding bacterial products LPS and PGN to conventional mice causes no change in the firm layer of mucus, yet adding them to the Germ Free Mice restores the thin Inner Mucus to that of Conventional Mucus within 40 Minutes."

Perhaps contact, again with specific bacteria spur the re-establishment of specific mucus types (Mucins) as there's quite a few... Or the body is trying to rid bacteria maybe and producing thin fast shedding mucus and FT crowds out or even directly kills the bad guys (Bacterial/fungal antibiotics) type thing ? Lot's of different takes and ideas perhaps.

Sorry I don't have the link to the source of the above at the moment, but it's referenced a lot in the mucus papers like:

Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis: gut.bmj.com/content/63/2/281.full.pdf+html
Posted 7/2/2014 11:41 PM (GMT 0)
@Maurader - It's mentioned pretty much every second word through.... Not sure what you're reading. Maybe I posted a wrong link. Not sure.

Post Edited (Canada Mark) : 7/2/2014 6:00:02 PM (GMT-6)

Posted 7/3/2014 12:05 AM (GMT 0)

This is the right thread.

I pulled this out of one of my zillion mucus threads.

Chicken or the egg,worth another read by everyone.

Might explain why everyone does not get UC.

We still have the question why the defective sugar.

Old Mike

http://omrf.org/2011/04/11/omrf-finds-defective-sugar-root-colitis/

Posted 7/3/2014 12:05 AM (GMT 0)

Canada Mark said...
@Maurader - It's mentioned pretty much every second word through.... Not sure what you're reading.

Not sure how else I can say this to make it clear....

1) The data from your paper only showed the CHOP was up-regulated as a result of ER stress, not that it is up-regulated in IBD. Just because ER stress may be up-regulated in IBD doesnt mean CHOP is.

2) In the paper you posted, there is this sentence: "ER stress indicators, including CHOP, are elevated in intestinal epithelia from IBD patients (14, 15)." This is the only connection between CHOP and IBD I found in my quick skimming of the article. I looked into the two papers they cited for this statement, and neither paper mentioned CHOP expression at all; only the other markers of ER stress.

Unless I am wrong about the point two, what Ive been saying all along still holds


@ OM - Line from the article you posted: "For patients suffering from ulcerative colitis, days are marked by discomfort and pain." Can this be a candidate for biggest understatement of the year please?

Post Edited (Marauder93) : 7/2/2014 6:09:28 PM (GMT-6)

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