Zonulin, Leaky Gut, And Gluten Sensitivity

[Lizz7711]

The last few days i've been doing a lot of research into leaky gut issues (thanks to Rachel-24!). I came across some really interesting information about a protein called Zonulin that is really helping me to put all the pieces together. One question I was having was that, ok, I know I have a leaky gut, but when I react to perfume smells or dryer sheets and get a migraine, that's not due to my intestines, it must be due to a "leaky brain", so there is more to the story than just healing the leaky gut.

Here's a summary of what I believe is going on based on the research:

1) When celiacs AND non-celiacs ingest gluten, the zonulin protein level in our gut and in our brains increases, but at a higher level for celiacs.

2) Zonulin is called a "gatekeeper" of the tight junctures in our intestine...when the levels of zonulin go up, it OPENS the junctures and keeps them open until the levels go down again.

3) So, when we ingest gluten, the junctures open and let all kinds of molecules into the blood stream that shouldn't be there, causing all kinds of problems for people...celiac and non-celiac alike.

4) Furthermore, zonulin opens the junctures in the brain, (lungs also?) so it is hypothesized that the blood-brain barrier is also compromised, which makes sense when you consider how many people have neurological/behavioral reactions to gluten and other substances.

5) The question not answered here is: WHY is zonulin increasing so much and how do you get it to stop doing that, besides stopping ingesting the gluten?

6) My theory, based on many conversations here and elsewhere, is that one factor in causing zonulin to react in a maladaptive way, could be due to high levels of heavy metals, especially mercury and lead, which are known to affect zonulin and all kinds of other systems/enzymes in our bodies. Systemic candida is probably also a factor.

7) I think that the best hope for true healing is to get rid of these heavy metals by getting fillings safely replaced and then undergoing chelation. Additionally, we have to add probiotics, enzymes, antioxidants, etc, get rid of yeast as well, to continue to heal the intestines and help the body regulate itself better.

8) Celiacs will always have to avoid gluten, and i think most people should, but I do beleive for those with gluten sensitivity but without celiac genes, there is hope to eventually be able to eat gluten if the above steps are followed.

9) They are doing trials with drugs to block zonulin I think...but i'd prefer to do the above stuff myself, to actually get rid of the underlying causes.

In my next post i'll post some of the website links where I got this information.

[Lizz7711]

In my next post i'll post some of the website links where I got this information.

Ok, here are a few of the studies/sites on zonulin (you can find more if you google zonulin and celiac):

Scand J Gastroenterol. 2006 Apr;41(4):408-19. Drago S, El Asmar R, Di Pierro M, Grazia Clemente M, Tripathi A, Sapone A, Thakar M, Iacono G, Carroccio A, D'Agate C, Not T, Zampini L, Catassi C, Fasano A.

Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines.

Mucosal Biology Research Center, Center for Celiac Research and Division of Pediatric Gastroenterology and Nutrition, University of Maryland, School of Medicine, Baltimore, MD 21201, USA.

OBJECTIVE: Little is known about the interaction of gliadin with intestinal epithelial cells and the mechanism(s) through which gliadin crosses the intestinal epithelial barrier. We investigated whether gliadin has any immediate effect on zonulin release and signaling. MATERIAL AND METHODS: Both ex vivo human small intestines and intestinal cell monolayers were exposed to gliadin, and zonulin release and changes in paracellular permeability were monitored in the presence and absence of zonulin antagonism. Zonulin binding, cytoskeletal rearrangement, and zonula occludens-1 (ZO-1) redistribution were evaluated by immunofluorescence microscopy. Tight junction occludin and ZO-1 gene expression was evaluated by real-time polymerase chain reaction (PCR). RESULTS: When exposed to gliadin, zonulin receptor-positive IEC6 and Caco2 cells released zonulin in the cell medium with subsequent zonulin binding to the cell surface, rearrangement of the cell cytoskeleton, loss of occludin-ZO1 protein-protein interaction, and increased monolayer permeability. Pretreatment with the zonulin antagonist FZI/0 blocked these changes without affecting zonulin release. When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability that was blocked by FZI/0 pretreatment. Conversely, biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability that never reached the level of permeability seen in celiac disease (celiac disease) tissues. Chronic gliadin exposure caused down-regulation of both ZO-1 and occludin gene expression. CONCLUSIONS: Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.

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"Our current platform is based upon the discovery of zonulin, a paracrine signaling protein that regulates the paracellular permeability of cell barriers throughout the body. Epithelial and endothelial cell layers serve as barriers between body compartments and the environment, maintaining gradients and regulating substance and cellular exchange between these spaces. Physical barrier function is provided by the cells themselves and by a key "gate" that exists between the cells, the tight junction. Found in humans and other mammals, zonulin serves the function of transiently, physiologically and reversibly opening these tight junctions, which are present in barriers as diverse as the intestinal mucosa and the blood-brain barrier."

Alba Therapeutics - Zonulin Technology

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"Zinc L-carnosine appears to block the initiation of leaky gut syndrome.

I suspect this effect centers around betaine/carnitine/histidine

metabolic pathways. Ergothioneine is the betaine of a sulfur-containing

derivative of histidine (aka thiolhistidylbetaine or

2-thiol-L-histidine-betaine or thioneine/thionein). Ergothioneine is

the apoprotein of metallothionein (an apoprotein is a polypeptide chain

that has not yet formed a complex with the prosthetic group - a

non-amino acid compound attached to a protein required to form the

active holoprotein). So, ergothioneine depends on adequate amounts of

histidine (which is contained in carnosine) and betaine. Mercury and

lead poisoning induce leaky gut syndrome. Mercury can deplete the

natural chelator metallothionein, thus depleting carnitine, histidine,

betaine, ergothioneine and related compounds - in addition to

molybdenum, which is also found in metallothionein. (Mercury and an

opioid ligand in wheat both stimulate prolactin which then stimulates

B-cell production and can lead to autoimmunity.)

Why is this important?

Carnitine is built on a betaine. Inflammatory bowel injuries knock out

carnitine transport in the gut. Carnitine appears to play a role in

preventing PKC activation, which is required for zonulin signaling in

leaky gut. With inadequate carnitine levels, leaky gut may be easier to

induce. Curiously, zinc L-carnosine also seems to inhibit a leaky gut

pathway - PLC - at least in some other tissue types. PKC is important

to the function of mu opioid and thus cannabinoid receptors in the gut,

which seem adversely affected by inflammatory bowel injuries. Low-dose

naltrexone, which upregulates mu opioid receptors, is effective for such

conditions. In previous postings I've sketched these arguments out,

including how the loss of local cannabinoid receptor expression might

lead to B-cell overproduction and autoimmunity. There are also

important connections with local gut flora, which stimulate mu opioid

and cannabinoid receptors.

I'm as yet unclear how zinc L-carnosine figures into this network. I

suspect a direct effect on zonulin but I don't know if anyone's ever

looked at this. It contains histidine and that is necessary for

ergothioneine formation and vital to an important metabolic

detoxification pathway".

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Any thoughts or further insights on this? I know i've just scratched the surface, but i'm so excited to begin to see how this disease and it's reactions on the body are starting to make sense, because that means i'm closer to healing! (if only I had the money to get rid of all these fillings right now )

[Lizz7711]

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This is a link to a yahoo group about trying a low oxalate diet (found to be connected with autism and also with celiac issues). If you scroll down this files link, you'll see a Word document called "Mechanisms behind the Leaky Gut" and it's a very interesting article. It does mention the whole zonulin factor. It also talks about the role of calcium in opening the tight junctures, and how having a diet high in oxalates (found in many great healthy foods like leafy greens and nuts ) without enough calcium can also cause those junctures to remain open too long, allowing toxins/undigested food particles into the blood stream.

[Rachel--24]

If you scroll down this files link, you'll see a Word document called "Mechanisms behind the Leaky Gut" and it's a very interesting article. It does mention the whole zonulin factor. It also talks about the role of calcium in opening the tight junctures, and how having a diet high in oxalates (found in many great healthy foods like leafy greens and nuts ) without enough calcium can also cause those junctures to remain open too long, allowing toxins/undigested food particles into the blood stream.

I was actually going to mention this article to you with regards to your question about *why* the gates would remain open....but I see that you found it already.

Yes, I agree that there are some imbalances caused by metals or other factors which are playing a role in this. Mineral transport is affected by mercury and other metals (but mercury especially). Under normal circumstances cells can "pull" minerals in and pump them out as needed. Mercury is known to interfere with this process.

Mercury has the ability to get into the cell and take the place of the mineral which *should* be there. Those essential minerals become displaced and even though we may be getting enough through diet and supplementation....the body may not be able to utilize it. This is one way that mercury in particular can cause all sorts of imbalances in the body. It can lead to a cascade of problems involving enzyme systems, detox pathways, digestion, etc. etc.

Calcium is one mineral which tends to be easily displaced...and I would have to assume that if lack of calcium is involved (as suggested in the article) there would have to be a chronic underlying situation for that problem to not resolve and for those gates to remain open.

Mercury competes with calcium for cellular binding sites and, through this mechanism, can decrease cellular calcium or increase extracellular calcium.

This is why people with mercury toxicity may have elevated calcium in a hair analysis (and also low mercury)...because there is too much displaced calcium (extracellular) in the body....the mercury is intacellular and is not coming out in the hair.

Calcium is used as a treatment for people having problems with oxalates building up... and in my opinion something has to be wrong somewhere in the body for a person to have these kinds of issues. A healthy body should be able to break down food components such as oxalates, salicylates, amines, sulfur, etc.

Sulfate is another important factor (not discussed in that article). Sulfate is essential for maintaining a healthy intestinal lining. If something interferes with sulfur metabolism and prevents the body from converting sulfur to sulfate....there becomes a deficiency of sulfate. Sulfate is *needed* for intestinal health as well as detoxification (sulfation pathway).

Sulfur metabolism can be damaged by mercury. If the body is lacking sulfate this can result in leaky gut.

In addition to nourishing the brain and the nervous system with sulphur, it is also important to nourish the gastrointestinal system. The mucins, which line the epithelial lining of the gastrointestinal tract, are actually sulphated glycoproteins, which need sulphur to maintain their structure and function appropriately. If sulphation is low, then the gastrointestinal system will incur inflammation with gut dysbiosis and increased permeability leading to leaky gut syndrome.

Personally, I think alot of different things can play a role in the development of leaky gut. It can become multifactorial and I dont think it would be just one single cause (such as calcium deficiency) contributing...but rather several things going on at the same time. It can become quite complicated...unfortunately.

I think the biggest players would be heavy metals, toxins (of all kinds) and the gut infections that usually go hand-in-hand with these issues (yeast in particular).