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Medical literature on the leaky gut provides useful information that may help unify the picture of how diets used in autism are addressing some issues that have been studied more carefully in celiac disease. This mini-paper will review these mechanisms that may not yet be familiar to many in the autism community.
Most people have heard of the term "leaky gut" but may not realize that this term refers to how larger molecules may get into the blood when structures called tight junctions that are there to seal the gaps between intestinal cells, have instead, opened up. This opening creates a passage that lacks the same type of regulation that happens when substances move through intestinal cells. Scientists like to call this movement of fluid and its solutes through this opening "paracellular transport". Other tissues can be leaky like this, too, like the bladder, kidney cells and even the blood brain barrier.
How does paracellular transport work?
Below you'll see a drawing of the epithelial cells that are the absorbing part of the gut. It is important to notice that these cells are very different on the food side versus the blood side where you are trying to shuttle the nutrients that come from digestion.
Think of your gut as a big hose. That hose has an outside and an inside. The picture below is a cross section, as if I cut through the hose with a knife, and we are looking at the open edge of the hose as it would be seen on the top side.
This is called the blood side or serosal side
or basolateral side.
This is the brush border or apical side or "lumen" where the food is.
INSIDE of the "hose"
The big rectangles are intestinal cells, and the goods from food travel from the bottom (or food side) to the top (or blood side).
The ]]]] represents the highly absorptive side that is touching the food that is going through the intestine, and it has transporters on it that help to absorb particular things across this membrane. The membrane also excludes some things from crossing into cells. You'll hear this side called the brush border, too, because of the villi that make this side look very different. Here is a photograph of the brush border: Brush Border Photograph
The dashed line on top is the membrane that helps deliver things that were absorbed into these cells to the circulation. Nutrients move across the cell to get to this membrane that is on the blood side. Transporters within this membrane will move only certain selected things across that membrane in order to deliver them to blood.
In my drawing above, the line of ====== represents tight junctions which keep things from crossing between cells to get to the space that has access to the circulation. When this junction is closed, the nutrients HAVE to go through the cells to get absorbed, and that is a process that is regulated by the transporters on the top and bottom side working together.
Immediately below, I've put a link to someone else's cartoon of this scene, but this time, we are viewing things from the bottom side of the "hose". The point of the drawing is to show how glucose gets transported into the cell, moves across the intestinal cell, and then crosses that last membrane en route to the blood: View cartoon
Another system of regulation exists that has to do with nutrients taking a different route. Instead of going through cells, this time, the nutrients are going around, cells using the gaps that exist between these cells that are usually closed off by structures called tight junctions.
The substances that travel this route (called the paracellular route as opposed to the transcellular route) can be peptides from foods (like gluten or casein peptides or peptides from other foods), or non-protein molecules like oxalate. Oxalate is a compound found mainly in plants which is highly reactive and binds to calcium and other molecules.
So, when your tight junctions open up, those cells will change like this:
Brush border or apical side or "lumen" where the food is.
When the gate is open, many molecules pass through those open junctions just as your dog might go through an open gate in your fence. Remember there is a flow of solute-loaded fluid moving through these open gates.
Perhaps we've had the impression that having a leaky gut means something is broken, but that is not necessarily the case. The opening of the gates is regulated, and that regulation can be called upon by systems like the immune system. Certain of the immune system's cytokines open up the "gates" in order to let cells of the immune system in the blood have access to antigens that have been in the gut. Some new work has shown that this opening and closing of the gate also has a lot to do with calcium which makes this system of gatekeeping have an unusual relationship to dietary oxalate.
I've put a study at the end of this article whose authors discovered that some of this process of opening and closing the tight junctions appeared to be mediated through an interaction with calcium. This did not involve the concentration of calcium that was inside the intestinal cells, but it only involved the calcium that was outside the cell. Removing the calcium from either side of that tight junction could really change things, but changing the level of calcium inside the rectangle (representing the inside of the cell) made no difference at all.
Right next to where that gate is located on the basolateral (or blood side) are some molecules and a "sensor" that picks up calcium that is travelling in the fluid on this basolateral or blood side. I've represented that sensor as an asterisk. If there is adequate calcium at that sensor, then the leaky gut closes, just as if it had been zipped up. In fact, calcium is actually a key ingredient used to close the zipper. When there is not enough calcium present to close the gate, the gate stays open so that calcium from the food side can come in through the gap until there is enough calcium to close the gate again. In fact, at times, there are oscillations that occur as this gate opens and closes in response to calcium.
If after the gate opens to let calcium in, there is not enough calcium on the food side to travel through and bind the sensor, then that means there won't be enough calcium to zip up the zipper and close the gate again. The gate will stay open, and until enough calcium comes around to close the gate again, you've got a "leaky gut" that will stay leaky . This means it is important to think about all the circumstances that might cause the supply of calcium to diminish that is travelling from the lumen of the gut or what might cause the calcium on the basolateral side to get low.
Scientists have figured out that calcium in the lumen can be tied up in fat when one has fat maldigestion and malabsorption. The fat left undigested in the gut binds calcium and makes something of a soap, but this doesn't provide that either the fat or the calcium will get absorbed. This also means that the calcium would fail to make it to the basolateral side when the gate was open, and that would mean the calcium wouldn't be there to interact with the molecules that govern the tight junctions by sensing that there is adequate calcium there. Scientists have done experiments to quantify how this fat effects oxalate absorption, and they also have noted that very often people with celiac disease have this very same maldigestion of fat. This offers one reason people with celiac sprue have a predictable problem with this leaky gut and a condition of excess oxalate absorption that is reflected by high levels of oxalate excretion in the urine called hyperoxaluria.
Undigested fat is not the only way to tie up that needed calcium. Calcium could also be tied up by soluble oxalate that comes from food high in oxalates that were eaten and are present on the inside of the gut.
Food is not the only source of oxalate in the gut. Nature has provided a system to help the body get rid of excess oxalate. Intestinal cells become loaded with oxalic acid when this acid is transferred into them from circulation from the basolateral or blood side, and from there, this acid is actually secreted into the gut. Why does this happen? It is nature's way of ridding the body of a compound that is highly reactive and can be damaging to organs in the body, especially after those organs have already suffered some sort of injury. Oxalates seek injured tissue because they bind to molecules that ordinarily may be hidden from them in healthy tissue.
The secretion of oxalate into the gut happens regardless of the source of those oxalates. That oxalate may have come from the diet, or from chemical or environmental exposure to precursors to oxalate (such as to glycolic acids), or from excess production of oxalates by our own cells due to vitamin deficiency, genetic defect, or some other reason. Scientists have found our bodies make excess oxalate when deficient in vitamin B6, which is a vitamin that has been under a lot of study in autism. Some people may make excess oxalate from an excess of glycine. There are also genetic defects that produce excess oxalate. If there are times when our bodies produce extra oxalates for a good purpose, it has not been discovered yet, but we will be looking for this good purpose in our oxalate project.
One factor that may determine the level of secretion of oxalate into the intestine is its concentration gradient. Oxalate will try and move from places where it is in a higher concentration to places where it is in lower concentration. An excess level of oxalate on the food side of enteric cells may hamper the secretion of oxalates from the blood side. The body may use signals like angiotensin II to step up oxalate secretion from intestinal cells, but sometimes, even though the level in blood might be higher, the secretion may be disrupted by a biochemical signal. This happened experimentally when the signal from angiotensin II was disrupted....something that might happen with an ACE inhibitor or possibly with a chelating agent. More work needs to be done here.
It makes good sense that the body sends excess oxalate to the gut, because the gut is where calcium from the diet could bind the oxalate and that would keep it from being reabsorbed. The oxalate can just stay in the stool in the form of calcium oxalate because it is only the unbound form that is readily absorbed. There are many studies about this.
A different method of reducing oxalate absorption is provided by microbes inside the gut whose role is to eat oxalates and turn them into something else. Unfortunately, these same microbes are easily killed off by antibiotics. Quite a number of studies have found a lack of these specialized bacteria in people who develop oxalate-related health problems. Trying to address this problem, a biotech company is currently working on a probiotic/enzyme formula to "recolonize" the most capable oxalate-eating bacteria, which is oxalobacter formigenes.
The intestines might feel better when the secretion into the gut of oxalic acid is reduced, because research has shown that oxalic acid is by nature corrosive and burning to tissues. Even so, whenever the intestines lose the ability to get rid of "waste" oxalate (using this secretion coupled with binding calcium or being metabolized by oxalate-eating bacteria), then the oxalate remaining in circulation can cause someone to suffer the consequences of having higher levels of oxalic acid reaching other tissues.
A study a number of years ago found that the proteins from wheat and corn could induce a leaky gut in rats which had first been made niacin deficient. Since then, other work has found that there is a relationship between exposure to the wheat protein gliadin and the excess production of a talented disrupter of the tight junction called zonulin.
Zonulin is a physiological molecule which was discovered in 2000. Before that discovery scientists had been studying a mimic of this molecule: a toxin produced by a phage that infected a bacteria that could be infecting a human. This toxin was called Zot, and all its talents at disruption of the tight junction came from its being a mimic of zonulin. By watching what Zot did, scientists learned a whole new set of interactions that were governing paracellular transport in the gut.
Zonulin's presence (similar to lack of calcium) opens up the tight junctions between cells. Scientists found that zonulin was elevated both in serum and in the lumen of the gut in celiac disease. They also learned by monitoring people with skin reactions to gluten called dermatitis herpetiformis, that this leaky gut/zonulin phenomenon was a part of the disease process that occurred before the flattening of the villi. They learned that the disruption caused by zonulin could be set in motion by a simple exposure to gliadin.
Apparently, zonulin keeps the gate open. I don't think they've figured out exactly why or how it does that, but this may have to do with the fact that the piece of gluten called gliadin mimics part of a molecule called calreticulin that carries a huge load of calcium. Calreticulin is known to be involved in the regulation of oxalate in plants, but any role for calreticulin at this location at the tight junction has not been characterized in animals. There also seems to be one other molecular mimic of gluten at this site in intestinal cells.
Unfortunately, we are stuck with the order in which scientific discovery is taking place because this work on zonulin and the leaky gut is brand new. Antibodies to calreticulin have been found in celiac disease, and also in a lot of other autoimmune diseases associated with a leaky gut that tend to develop alongside celiac disease. This raises several questions:
These new-found mechanisms confirm why hyperoxaluria is a well known component of celiac disease. In fact, celiac disease is the main disease emphasis circling around the study of zonulin. I've put abstracts from three studies below that talk about this connection between zonulin and celiac disease, but there are only thirteen articles on zonulin in the whole of Medline so far.
Certainly, we need to consider that one of the benefits of gf/cf diet might have been an improvement in the barrier function in the gut which would not only reduce the opioid peptide absorption, but would also limit the absorption of oxalates and allergy-provoking food peptides of all sorts. We also need to consider that the introduction of very high oxalate foods as a substitute for gluten and dairy may compromise some of the benefits of removing gluten.
Disaccharidase deficiency apparently appears before villous atrophy shows up in celiac disease. The order to this decline may suggest that something related to the changes at the tight junction that come from exposure to gliadin may furnish the reason that disaccharidase activity falls off so early in celiac disease. Is there a parallel order of things in autism that explains why disaccharidase activity would get low when it does? The lack of disaccharidase activity is the reason for restricting disaccharides in the SCD diet and that restriction does seem to quell the fire in the gut for a significant set of people.
I find myself wishing that the SCD diet as it became used in autism hadn't evolved with such an emphasis on high oxalate foods. There is nothing about restricting disaccharides that means you HAVE to eat high oxalate foods. What might have happened is that parents were seeking more calories for their children, and wanted to make foods that were more like familiar bread products because they couldn't use those complex carbohydrates in cooking on SCD. Perhaps they found that their children really went after these high oxalate foods once the high foods were introduced. The body does accommodate somewhat to high oxalate foods, but the eagerness of these children for these foods may have also been tied to a somewhat "addictive" quality of oxalates that some parents have reported on our website....addictions which seemed to diminish as the children's exposure to oxalate was lowered.
Because these high oxalate foods were likely included in the SCD in an attempt to enhance nutrition and the calorie count, including them in the diet seemed the right thing to do. Most of the research showing the damage that oxalates can do outside the kidney was and still is not widely known. For this reason the originators of the SCD could not have anticipated what oxalates were capable of doing when a leaky gut allowed these oxalates to be absorbed in a higher than usual quantity.
When we began the oxalate project, we certainly didn't anticipate this issue either, but we've learned this negative side of oxalates together as we saw children improve in very surprising ways after getting off high oxalate foods. Gastrointestinal issues were improving in these children going lower oxalate. Yeast issues were getting better. Dysbiosis seemed to be improving. Some of the children were getting rid of problems with chronic diarrhea or constipation, in addition to having some relief from urinary problems, if those had already developed. These changes were amazing enough, but what really surprised us is when we started hearing about changes in cognition and speech, fine motor and gross motor improvement, and even catch-up growth in children who had not been growing. Is there a chance these absorbed oxalates were also getting past the blood brain barrier, a type of tissue whose barrier regulation is similar to the gut?
Some moms and dads figured out the problem with high oxalate foods on their own because they watched their children's reactions and took them off the nuts and certain vegetables long before anyone started talking about oxalates. These parents are the true scientists who were so very observant! Our oxalate project gave them a vocabulary to describe what they observed, but it also linked them to other parents who were finding that their children were also affected by oxalates.
We have found that some of the children who previously had horrible reactions to rice and corn and even wheat and dairy are tolerating some of these foods and other starches when sticking to a lower oxalate diet. The increased tolerance to these foods may have come from getting the tight junctions closed which would eliminate the overexposure of the immune system to these food antigens. If this is truly the case, the change might diminish allergic reactions to food and might possibly help restore the disaccharidase activity. All this will have to be studied formally, because right now these improvements are only the reports of parents. Through this project we are getting closer to understanding what it is that should be studied scientifically and what should be measured.
In summary, I hope all this will mean that we are getting closer to understanding something important in the mechanisms that can set into motion, or that will keep in motion, the gut disruption and gastrointestinal pain in children with autism. Maybe a lot of the problem circles around calcium regulation and tight junctions losing their grip, but there may be other players and other places of disruption for these molecules that scientists have not yet identified.
I find it fascinating how much we have been able to learn from celiac disease research. Maybe we should think hard about how and why gastroenterologists tell us that osteoporosis is often the first presenting symptom of celiac disease, for that, of course, is another issue that has a lot to do with calcium.
Our future goals of this project will go beyond the initial management of diet issues or addressing related issues of tissue permeability. We are currently recruiting scientists to specifically study oxalate issues in autism. A further goal will be characterizing the functions of oxalates in animals in areas that go beyond crystal formation, calcifications, or kidney disease. Obviously, we are still at the very beginning of this project.
Please read the abstracts below. I hope they will help fill in the gaps in this information, especially if you are comfortable with their technical nature.
Susan Costen Owens
Research Associate, Husson Science Research Institute
A member of the DAN! Thinktank of the Autism Research Institute
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