Susan Costen Owens

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  1. Celiac.com 07/29/2016 - Celiac is an autoimmune condition, and along with other autoimmune diseases, scientists are beginning to have a larger context for understanding what could be contributing to its immune dysregulation. In the last decades we've seen diseases becoming prevalent now that look very different from the diseases of our ancestors. The American Autoimmune and Related Diseases Association lists 159 autoimmune diseases on their website (1), but most of these diseases are very new. In recent years, scientists began to identify and explore a new complex that was identified within our cells and belongs to our immunological line of defense. This new player is part of innate immunity, which is also called cell-mediated immunity. This is our body's rapid responder, and its approach to immunity is more like hand to hand combat. Its role is surveillance, and it uses generalized markers to identify something as an enemy and something the immune system needs to defeat. It looks for evidence of infection from bacteria, fungi, viruses and parasites but it also analyzes cellular debris. It is looking for any sort of danger signal that conveys the message that life is not normal as it ought to be (2). This analysis can even include looking for changes in pH (3). The innate branch of the immune system is dependent on cells that are called phagocytes, and these cells like to engulf small pieces of things they encounter, in a process called phagocytosis. Often these cells will be breaking down those pieces it engulfs and then will returning the nutrition it contained back into the extracellular space. After fragments from outside are internalized, cells needed a way to decide if what was engulfed should lead to a stepped up immune response. That's why it is not surprising that scientists recently discovered a whole network of molecules internal to these cells that form a complex called an inflammasome. There are various types of inflammasome that cover different biological niches (4). What this means is that, in response to what is deemed an enemy, a phagocytic cell will gather together a distinctive list of parts to assemble into an inflammasome, and then that inflammasome will produce specific cytokines called IL-1 beta and IL-18. These chemical messengers can then go and recruit more help. In contrast, antibody mediated immunity is more like having an air defense. The antibodies made by this part of our immune system function more like missiles that are sent out to find a designated target. Vaccines are designed for the antibody side of the immune response. Future recognition of a previous invader involves selecting a piece of protein, called a peptide, that is large enough to recognize. This side of our immune response forms a memory of that peptide so that in the future, our cells will use that memory to recognize that we have seen that germ before. If the germ is recognized from a previous infection, then the immune system can respond very quickly and with more hands on deck. The piece of the intruder's identity that will be remembered is determined by our HLA type, and that is determined by a section of DNA on our sixth chromosome. The vulnerability to celiac disease is defined by the genes that are behind the formation of HLA-DQ2 and/or HLA-DQ8. Scientists have known for many years that these two branches of immunity compete with each other and need to stay in balance. The chemical immune messengers called cytokines will shift our immune response between a dominance of cell mediated or antibody-mediated immunity. Until very recently, all the attention in celiac was on the antibody mediated branch whose major decision-makers are T cells, but even T cells can form inflammasomes (5). Scientists are now studying the innate immune response to gluten. Our innate immunity relies on a specialized call type called a phagocyte. Cells of this type of include monocytes, macrophages, neutrophils, granuloctyes, mast cells, dendritic cells, osteoclasts and even migroglial cells in the brain. Phagocytic cells will incorporate debris that comes close to them into a vesicle, and that is a sort of bubble with liquid and other contents inside. This vesicle is taken into the cell through a process called endocytosis. After that, this type of cell will quickly process the contents of that vesicle probably much faster than other cell types. This competence is likely why this type of cell is given the job of surveillance for invaders. It is also is useful as a tool for recycling things from the outside that they take in. Scientists prefer to call this set of cells the professional phagocytic cells. Other cell types can be enlisted for the job of phagocytosis but they don't have that role as their main purpose. That is why this different set is called the non-professional phagocytic cells and they may also form inflammasomes but may need more stimulation. (6). Scientists in the last decade have done experiments to learn how inflammasomes work. These intracellular immune complexes are assembled often in response to exposures to a type of molecule called a lipopolysaccharide that can be detected after engulfing the cell membranes of invading organisms. There are many other triggers, all recognized by their ability to tell us when something inside us is not as it should be. ATP, our body's energy molecule, when it is identified as coming in from the outside, can be a trigger for the inflammasome. Engulfing this sort of molecule suggests to our phagocytes that cell death events may have occurred in the environment of that cell (7). Some of our cells have been found to extrude nucleotides in self-defense, because leftovers from that kind of event may tell the inflammasome machinery that the cell is encountering a dangerous situation (8). This system recognizes that certain pathogens create holes in cell walls, so when a phagocyte encounters evidence of damaged membranes with holes in them, that alone can trigger a cell danger response that enlists inflammasomes. That means two popularly used medicines that kill fungus by inserting holes in their cells, Nystatin and Amphotericin B, have by themselves been found to create this danger signal even when there is no infectious agent. Doctors and lay people need to know that many signs that are usually associated with an infection, including fever, can occur when there is nothing infectious involved (9). Another inflammasome trigger is excess alcohol which can be very damaging when it triggers inflammasomes in the nervous system. (10) Another concern is environmental contaminates like asbestos and silica which have been studied the most when they are inhaled. (11) Crystals of uric acid associated with gout or other cell debris can also trigger the inflammasome, as can crystals of oxalate, which may be important to celiac disease since scientists have found higher levels of oxalate in celiac sprue. These crystals must reach a critical concentration to generate this cell danger mechanism in phagocytic cells (12). In the past, nobody really was aware that oxalate could have a major effect on the immune system outside of what it does in the kidneys. Scientists for so many years thought the kidney alone contained cells that oxalate could influence. That's why other cell types were not studied. At least now, we realize this narrow focus had been based on some premature conclusions. We should have known to look more broadly because there was so much evidence from Primary Hyperoxaluria, a genetic disorder where a defective liver produces oxalate that travels to the whole body, creating a condition called oxalosis. That's how we know that oxalate goes all over the body. For the longest time, nobody was measuring oxalate outside of kidney disease, even though there were a few exceptions, like in people after bariatric surgery, and in celiac sprue and in cystic fibrosis, and eventually, in autism (13). Because there already was a literature about oxalate in celiac sprue, when our project began, we started informing the public about these links on our website, www.lowoxalate.info. More recently we have written a series of articles about oxalate in this journal, discussing the science, and also practical issues about how to reduce oxalate while on a gluten free diet. That was working with knowledge we had then, but now we know that this issue of inflammasomes has been a part of the story we didn't know, but it holds great promise of possibly addressing why there could be complications in celiac sprue that do not resolve by merely going gluten free. Another trigger for the inflammasome is homocysteine (14). The pathway to recycle homocysteine back to methionine is called remethylation, and this process requires both methylcobalamin and the folic acid cycle. Others on internet groups have brought attention to polymorphisms in one of the relevant enzymes, called MTHFR. This system is also tied to the process of making sulfate, taurine and glutathione, because homocysteine can be routed that direction when the body is trying to resolve oxidative stress. Many of these steps require B6, and heme is also needed to direct homocysteine towards transsulfuration. The issue of excess homocysteine may prove to be more important to our non-professional phagocytic cells that are found lining our blood vessels, because these same vessels can also take up oxalate, creating a condition of vascular swelling called livedo reticularis (15). Issues with both homocysteine and oxalate have been associated with atherosclerosis (16). Did your child's pediatrician recommend giving your child Tylenol before his immunizations to make him more comfortable about his body's reaction to his shots? Scientists have now found that Tylenol not only depletes our body's ability to deal with the oxidative stress from immunization, but it also turns on the inflammasome (17). The inflammasome will skew immune defense away from Th2 adaptive immunity, and that is unfortunate, in this case, because the process of developing a Th2 response was the whole point of giving a child a vaccine. Our vaccines are designed to contain adjuvants that skew the immune response in the Th2 direction (18) but some adjuvants may not be working as expected (19). Researchers sometimes look for the evidence that someone has developed antibodies before they will call an immunization a success. That test will ordinarily not be ordered by a pediatrician, but instead, a child will simply later be given, by default, a booster shot. Is there any chance the recommendation of Tylenol or other inflammasome activators could have impaired the antibody response in some children? Certainly, the new research on inflammasomes might suggest that in children who fail to make antibodies after a vaccine, a look at what is happening with innate immunity could be in order before assuming that these systems are working normally. Are doctors testing antibody titres or doing other immune testing in children with celiac sprue? This may be more important if such a child has developed another autoimmune condition. Has gluten had other ways of affecting the immune response? We have known that gluten and proteins from milk, soy, and even spinach will form opioid peptides as they are broken down. Like other opiates, these active peptides can be addictive and would be able to skew an immune response (20).Opioids can also paradoxically activate inflammasomes in the spinal column which then may provoke, amplify, and prolong pain. (21) Other work showed us that activation at the same opioid receptors that drugs use can limit our absorption of the amino acid cysteine. This amino acid is needed by our bodies in order to provide glutathione, the primary cellular antioxidant that protects us from oxidative stress, and this is especially important to save us from neurodgeneration (22). Why is that important? The formation of glutathione can calm down a mitochondrion that is upset enough for it to be generating reactive oxygen species (ROS). Unfortunately, scientists recently learned that the ROS produced by a mitochondrion under such stress will also trigger the inflammasome. Having adequate glutathione is especially important when our bodies are coping with the demands of immune activity, as during illness or after immunization. Unfortunately, oxalate at those times may compete with glutathione for entry into the mitochondrion at the mitochondrial dicarboxylate carrier (23). Until very recently, we did not know that partially digested pieces formed from gliadin could trigger the formation of the inflammasome. This occurred more in peripheral blood mononuclear cells (PBMCs) from people with celiac sprue compared to healthy donors (24). The people who did this research may not have known that people with celiac tend to be higher in oxalate than other people, and they also may not have known that oxalate by itself has been found to trigger the formation of the inflammasome. People with celiac may need to be careful about avoiding both triggers for inflammasome formation. In a different context, another group of scientists discovered that PBMC's exposed to titanium salts made from oxalate caused immunotoxicity when other salts of titanium did not produce that toxic effect. That experiment tells us that oxalate does enter the type of cell that was also found to respond in celiac disease to these digests of gliadin by formation of the inflammasome (25). The well-studied vulnerability of individuals with celiac to antibody mediated effects of gliadin came from the adaptive arm of our immunity. The HLA type is definitely known to be relevant there, but it would not be relevant to an issue of cell-mediated immunity. That is why it is a puzzle that the authors of this study did not control for oxalate by matching the control and celiac subjects for the oxalate content of their cells. The differences they saw in response to the gliadin digest may have required higher levels of oxalate in those cells. Do we know? If that could be the case, then it becomes possible that the response they recorded in celiac cells might also happen in those who are higher in oxalate for other reasons, but who lack the HLA risk genes that are definitional of celiac. We simply cannot tell if the risk of inflammasome activation in their experiment involved having the oxalate content of these cells also working in some kind of synergism with gluten. It is important to note that here we are talking about oxalate that this type of cell may have accumulated earlier in its life or during its time in the blood. Here we are not talking about oxalate that someone may have just eaten. It is possible that an inflammasome-mediated function could explain why there are so many people who don't have celiac disease discovering that removing gluten from the diet makes them feel better. The academic community and others are still having a hard time believing this story (26), and cannot understand the recent popularity of gluten free foods in the general population. A different reason for thinking about a possible synergism between a gluten free and a reduced oxalate diet came from a recent poll done by the Oxalate Project at www.lowoxalate.info. Those results revealed that the majority of those who reported positive effects in their autoimmune disease by reducing oxalate had been extremely high in oxalate before they reduced oxalate. Curiously, 58% of those responding to the poll said they were also gluten free, but only 16% had celiac sprue. Those who were both gluten free and low oxalate reported a 10% higher positive effect from reducing oxalate than those who were not also gluten free. That could be important. Many scientists still think a standard American diet will keep oxalate below 200 mgs a day, but 84% of the individuals answering that poll said that they started out with levels of oxalate over 300 mgs a day. Recent changes in eating habits for high oxalate foods may have been the result of powerful advertising that has been telling people that high oxalate foods are the healthiest foods available. Anonymous poll data has no way to be verified, and that fact keeps us from assuming that we can derive information from this poll about oxalate's role (if any) in contributing to their autoimmune condition. Even so, the poll told us that out of all respondents, 73% reported a positive effect in their autoimmune condition by reducing oxalate, but those with celiac sprue (some who had other autoimmune conditions) did much better. 88% of them reported a positive effect on their autoimmune condition. That was actually a higher percentage than what was recorded for any of the other autoimmune conditions. Does that mean that it might be important for autoinflammatory processes to be careful about both gluten and oxalate? (27) We may learn the answer to that question as more people with these issues try both dietary changes together. Some scientists now are generating data that they feel supports the idea that excessive activity of inflammasomes could be related to the etiology of autoimmune disease (28). The changes that the inflammasome makes to our bodies can be harsh, and in fact, some scientists studied sepsis in animals and found that just by blocking inflammasome activity by various inhibitors, they could save those animals from a certain death. The irony is that the animals were still infected, but survived anyway. That means that what had been killing them was their immunological response to infection instead of the infection itself. This type of research is still very new, but it may change some of our assumptions (29). What interventions have scientists found that will suppress inflammasome activity? The good news is that a lot of their research has involved supplements that anyone can buy in a health food store, and some people were already using them for different reasons. One of those items is resveratrol. When it was first studied, it seemed to have been made out of red wine, mostly, but our project has discovered that commercially, the usual product is made from an herb called Japanese knotwood, which is known to be high in oxalate (30). The Oxalate Project has not yet tested the oxalate content of commercially available brands of resveratrol to see how much oxalate ends up in a capsule, but that testing is on its agenda. The supplement quercitin is also an inflammasome inhibitor (31). CoQ10 is another supplement that has become widely available in drug stores and health food stores because it is needed to correct a mitochondrial problem created by statin drugs. Fortunately, CoQ10 also inhibits the inflammasome, mainly by keeping the mitochondrion happier and better protected from the need to generate reactive oxygen species (32). A popular source of sulfur called MSM (methylsulfonylmethane) also was found to inhibit inflammasomes (33). So has its close cousin DMSO, a solvent that was once used as a delivery system for secretin, when it was proposed as a treatment for autism (34, 35). Another exciting inhibitor is 3-hydroxybutyrate, which is one of the two ketones (along with acetoacetate) that our bodies make in ketosis (36). Ketosis occurs when the body is not getting enough energy from carbohydrate, and it switches into a mode of burning fat, and that produces these ketones. Some people will try to induce this switch in metabolism on purpose, like those dealing with seizures who find the seizures are controlled with a ketogenic diet. If the change that this ketogenic diet accomplished was due to down regulation of inflammasome activity, that might bring new hope or strategies to mind for individuals where this diet treatment by itself failed. Such individuals may have had a different environmental component that was still activating inflammasomes in spite of their use of the use of the ketogenic diet. This mechanism may point to yet another reason that obesity, which may have come from excess consumption of carbohydrate, has been linked with inflammasome activation (37). We can hope that more investigation of other activators and other inhibitors for those with seizures might yield better success. Also, the association with ketosis may explain a previously overlooked benefit experienced by people who were exercising the discipline of fasting…the age-old tradition that comes from many cultures. These traditions are more striking when realizing that obesity can activate inflammasomes and inflammasomes are thought to be behind the roots of metabolic syndrome and diabetes (38, 39). Pharma does have some drugs already in its cabinet which scientists have found will inhibit inflammasomes. There are probably more such drugs in the pipeline and we may soon hear advertisements for this new class of drugs. Our Oxalate project has already begun to hear of some doctors and hospitals using the over the counter inhibitors resveratrol or coQ10 to successfully protect patients who were at risk for developing sepsis. More research obviously needs to be done in this area and this new frontier has become very attractive to scientists. One of the first big questions they may need to ask is whether our health care protocols in Western medicine have led to over-stimulating this arm of immunity by emphasizing killing strategies with antimicrobial therapies or other drugs that may leave crystals or other debris behind. Why might that have been a problem? Phagocytes are upset about cellular debris and disrupted membranes. Some scientists have been finding that our bodies may stay healthier by tolerating some infections rather than experiencing the excessive immune activity that comes from activating inflammasomes. It will take a long time for some of these scientific ideas to trickle down and begin persuading doctors to make changes in their prescribing habits for antibiotics and other antimicrobials. Some doctors and other practitioners are already finding that inflammasome inhibitors could be an appropriate adjunct therapy during antibiotics. Of course, since this is such a new scientific area to study, it may take years before proper clinical studies can be done to address all these issues. In the meantime, it seems wise for anyone prone to autoimmune disease to avoid triggers for inflammasomes that are easy to avoid. This would include things like being overweight, eating foods that encourage uric acid formation (and the risks known for gout). It could include situations that encourage the body to make oxalate and that could include deficiencies of B6 or thiamine, or excess use of Vitamin C. It could come from excess dietary oxalate. We also need to consider the use of drugs or supplements that are known to form crystals in blood, or Tylenol, or antifungals that punch holes in cell membranes. We need to be vigilant about our status for homocysteine. We need to be careful about our level of consumption of alcoholand our exposureto other environmental contaminants. In time, we will learn of many other triggers. If there is a suspicion that inflammasomes are related to a disease process that we find in our bodies, then we should at least think about using one of the over the counter and safe and well-studied inflammasome suppressors. As the research continues, we can hope that scientists studying in this area will show us more ways to dial down the frequency and the unpleasant symptoms and other consequences of autoimmune disease and autoinflammation. References: 1. (http://www.aarda.org/autoimmune-information/list-of-diseases/) 2. Doria A, Zen M, Bettio S, Gatto M, Bassi N, Nalotto L, Ghirardello A, Iaccarino L, Punzi L. Autoinflammation and autoimmunity: bridging the divide. Autoimmun Rev. 2012 Nov;12(1):22-30. doi: 10.1016/j.autrev.2012.07.018. Epub 2012 Aug 2. Review. PubMed PMID: 22878274. 3. Rajamäki K, Nordström T, Nurmi K, Åkerman KE, Kovanen PT, Öörni K, Eklund KK. Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. 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  2. Celiac.com 07/17/2015 - This article originally appeared in the Spring 2015 edition of Journal of Gluten Sensitivity. Why is a researcher whose field for twenty years has been autism now writing an article about celiac disease and its possible relationship to oxalate? This takes a little explaining. My training in graduate school was all about looking into old literature to find pieces of research that had been lost, or were never incorporated into current models. I learned that new science could provide a different context for old findings. The importance of this process came home when more than a decade ago I was sitting at an enormous oval table at the National Institutes of Health where an important meeting was addressing how the heads of various National Institutes of Health and the CDC would handle a theory about a possible environmental trigger related to autism. One scientist rose to the floor, and began to explain his reason for discounting the new theory's importance. He proposed that this theory did not fit into previous models of autism, and began to say that the scientific process worked like the construction of a brick wall. Everything added to that wall should fit into the foundation and bricks that had already been laid. How often does this view of science as being a construction of human beings, rather than a discovery of nature, keep us from accepting new lines of research? Has scientific consensus ever ended up wrong after the appearance of new findings? Yes, many times. In this meeting at the NIH, at that moment, a senior scientist, Dr, Bernard Rimland, rose to the floor. Those who knew this man realized he had singularly changed the view about the science of autism twice, accomplishing these major shifts of thinking during different decades. I don't have a transcript from that meeting, but Dr. Rimland rose to say something like this: "My experience is very different. I find that science is more like a crossword puzzle, in that you may have been working at the puzzle from one end and filled in places that looked correct until you began working from another side and discovered that something you filled in before must have been wrong. That's when you erase the part that you thought had been right, and you find another answer that will make the parts fit from both directions." That speech has been a guiding light to my own research since then, helping me have the motivation to recover all the pieces that were lost or misunderstood or left out from the past whose absence left a model that only approximately provided a place for all the known pieces, but left many other pieces "loose" and unable find a proper fit. In 2005 after spending ten years studying the biological roles of sulfate in the body, I began to investigate another negatively charged ion that travels on the same transporters. I reviewed the published literature on oxalate in any condition, looking at basic science and clinical research over the last two centuries. I was looking for gaps and opportunities for improving the identification of oxalate-related diseases outside the kidney. My work for twenty years had focused most intensely on autism, and I had found that oxalate was high in autism, but this finding needed to be put in context and studied formally. It was mystifying to me why work from basic science about oxalate was only being applied to patients with kidney disease. How could we identify others with oxalate-related disorders? In the fall of 2005, along with several associates, we started our Oxalate Project. Using the same methodologies I had developed in the previous decade using the internet to interact with a broad range of patients, we began seeking those with any condition that was already related to oxalate in the literature, and patients with other conditions where the science took us. Included in this effort was setting up a project at the Autism Research Institute that we named the Autism Oxalate Project. In October of 2006, I attended the International Celiac Disease Symposium in New York City. I was hoping that the findings in oxalate research on malabsorption and intestinal disease, and specific findings on oxalate in celiac disease published since the 1970's were being discussed at this conference. I heard not a word about oxalate there. These scientists probably did not realize that when oxalate levels in the blood become high, it can get stored all over the body where it can produce effects in any potential organ…not just the kidney. I had learned that systemic effects from oxalate could change the course of a condition in patients over years of time. For patients with celiac disease, this storage might have occurred primarily during the years before diagnosis when problems with fat digestion would have increased the percent of oxalate absorption from the diet. In autism, I had learned that, as in celiac disease, some investigators had noticed oxalate's elevation in urine in isolated individuals, but they had been taught by articles in peer-reviewed literature to dismiss this finding as irrelevant when those individuals didn't have kidney stones. Basically, the literature kept saying that kidney stones would always be the first presentation of an oxalate problem—but was that true? Why would that be true? As I began to attend numerous world conferences on oxalate, I was very surprised to find that the only people there besides botanists, were those involved in kidney research. My previous studies in the literature had identified many articles describing oxalate producing effects all over the body and in multiple systems. New work on oxalate transport was finding regulation of oxalate's movement all over the body. Why wasn't this research being applied to patient care outside the kidney and why were certain laboratories insisting on a kidney diagnosis before they would even measure oxalate? Since my own work at that point included running a support group for people reducing oxalate and our doors were open for people with any condition, we had seen patients with more than twenty different conditions report an easing of their symptoms or even complete cures when they brought their oxalate levels down. Would the scientists be able to catch up with this wealth of experience that today has involved more than 17,000 families? Here is an example: I worked with a team of oxalate and autism researchers in Poland to establish the prevalence of oxalate's elevation in autism. The study that this work produced became available online in 2011, but officially went to print in September of 2012 in the European Journal of Paediatric Neurology. It was the first study to examine whether the levels of oxalate in blood plasma would correlate to the levels in 24 hour collections of urine in those who were not in kidney failure. We discovered that the levels in these two compartments did not correlate at all, especially in the controls. This meant that the oxalate field's dependence on urine tests as sufficient to identify those with oxalate problems was probably misplaced. It made sense that the two compartments would not "agree" because oxalate's movement between tissues, we now know, is regulated and its regulation would be different in different organ systems. How many other conditions were experiencing effects from elevated oxalate in blood that were not accurately reflected by only using urine tests? What did we know about variability from day to day, or even rhythms within the day, for oxalate secretion in other conditions? What did we know about how any variability should affect the interpretation of lab results, or our interpretation about the timing and presentation of symptoms in other conditions? A striking finding in our paper seemed to have been also referenced in a paper from Mayo Clinic, showing that urine oxalate in normal controls seemed to stay below the reference level of 0.46 mmol/1.73 m2 (24 hr.) Perhaps the point of the kidneys regulating that level so tightly was to protect the kidneys from risks of kidney stones or nephrocalcinosis, but that particular control of urinary secretion seemed lacking in autism. Scientists were beginning to discover secretion to other compartments, such as the intestines, the lungs, and the skin for example. Why would someone doing research even think to measure oxalate secretion and regulation in these other sites in clinical settings? In the past, everyone had assumed that measuring urine was sufficient. The graph of plasma versus urine looked completely different in those with autism compared to controls. What would a similar graph look like in celiac disease? Would the graph show different patterns at different ages, or before and after treatment with a gluten-free diet? Data from a study from Saccomani et al. may suggest that a limit to urinary secretion may be preserved in children with celiac disease, but would limiting secretion in the kidney sometimes lead to a greater accumulation of oxalate in tissues? Our autism study revealed that there are problems with assuming that a single urine test could be used to screen patients when oxalate could be elevated in blood and causing problems in the rest of the body. More than fifteen years ago (not published but presented at a think tank) I noticed problems in lab tests in autism with what looked like it could be caused by a variability in creatinine secretion. This would create a problem in interpretation for any urine test ratioed to creatinine, but the reason we would see this variability in autism made sense when a rat study recently found that oxalate in the kidney changes the movement of creatinine out of blood and into urine when oxalate was made to be high experimentally. This type of study urgently needs to be replicated in humans before anyone can have confidence that this affect on creatinine isn't compromising our data from spot urine tests. Suddenly it seems very sensible that in the oxalate field, it has become common practice to use 24 hour tests. Readers need to realize that this issue would affect anything measured in urine and ratioed to creatinine, not just oxalate! From data I've reviewed and analyzed statistically from more than a thousand organic acid tests, and from other literature, I also doubt that this single mechanism is solitary in contributing to problems in interpreting urine tests that use this ratio. Can we still legitimately think that physicians should not worry about oxalate levels unless their patients have developed kidney stones? Celiac disease is one of many conditions where high oxalate levels have frequently been found in patients. Some of the other conditions include bariatric surgery, cystic fibrosis, inflammatory bowel disease, short bowel syndrome, autism and more. Are doctors and nutritionists understanding that patients with these disorders will experience risks from oxalate to the rest of their body? Are they noticing when these patients develop issues outside the kidney that their symptoms might be related to oxalate? I've learned that the answers to these questions is most often, no. In our project's work with such patients we have reduced body oxalate levels through strategies of dietary modification, and by the use of specific vitamins, minerals and probiotics that have been shown to reduce oxalate. We've seen these changes alter the expression of their presenting disease in unforeseen but positive ways. It will take decades before all our findings from ten years of work in dozens of conditions can be confirmed by scientific studies. That does not mean these patients have to wait for academic studies to be published to see for themselves if reducing their exposure to this clearly recognized toxin will help improve their own health. Do physicians know that research on kidney stone patients have identified issues in their kidneys that lead to their increased risks of forming kidney stones from oxalate levels that would not produce stones in others? Could oxalate that was elevated in blood and tissues (and currently not being secreted at high levels in urine) cause problems to other parts of the body, contributing in unknown ways to comorbidities like those found in celiac disease? At the celiac symposium I attended, there were so many issues that were being discussed as being unresolved by the use of a gluten-free diet. That surprised me. Could those issues have been triggered by oxalate that was absorbed into the body before a gluten-free diet had resolved steatorrhea? Steatorrhea is the condition where excess fat stays in the feces, possibly causing the stool to float or have an oily appearance. Studies had shown that untreated celiac disease often was associated with steatorrhea. This condition elevates fat in the gut and that fat travels undigested all the way to the colon. Oxalate scientists had found that the fat left in the intestines during the journey to the colon would tie up calcium that ordinarily binds oxalate from the diet. About 80% of the calcium that travels through the gut stays in the gut. The purpose may involve the formation of a calcium oxalate salt in the feces that limits oxalate's absorption in the colon. Otherwise that oxalate could be transferred to blood if it is not first metabolized by the microbes in the gut. This is a bigger problem than the higher amount of oxalate in the diet. This might become a more serious problem when people with celiac disease use new grains that are gluten-free but which we know now are extremely high in oxalate. During the mid-nineteen thirties, prominent groups began recommending adding vitamin D to milk to prevent rickets, knowing that vitamin D enhances the absorption of calcium from the gut. Back then, oxalate research had not yet found a protective role for most of the calcium to remain in the gut to protect us from oxalate. Physicians had advised kidney stone patients to avoid calcium, but later determined that calcium in the diet was protecting patients from absorbing oxalate. Later studies showed that oxalate that remains in the intestines as a free anion (unbound to calcium) can and will be absorbed into the body once it reaches the colon. When this unbound oxalate is taken into the blood, there it was found to be able now to tie up free calcium that was needed to protect our bones and work in our metabolism. Free oxalate could a lso be taken into cells via oxalate transporters where it could disrupt calcium signaling inside cells and wreak havoc in the mitochondria and endoplasmic reticulum. Free oxalate can disrupt activity also in the nucleus where nature has supplied a specific oxalate binding protein. Is this protein sometimes overwhelmed when oxalate gets too high? Before I attended this celiac symposium, I had not heard that some of the autoimmune and cancer risks associated with celiac disease may still be there even with a gluten-free diet. Who was asking what else besides gluten could be contributing to these risks and were they being studied? Was oxalate one of those risks? People on our listserves that help people reduce dietary oxalate were telling us they experienced improvements in autoimmune conditions on a low oxalate diet. No one has had time to examine these reported changes formally yet, but could oxalate have a potential connection to the risks of autoimmunity or even transformed cells in celiac disease patients? I learned to ask these types of questions in graduate school and in the years that followed as I continued to find science that had been learned "out of order", and rejected as an important piece of the science because at the time there were missing pieces that were only discovered later. My intense study of medical literature's missing links brought to my attention so many valuable scientific discoveries that at the time they were published had been cast off as irrelevant. As I started to look intensively for more and more of these lost pieces, I made another astonishing discovery. I learned that we do not fund researchers to go digging through past scientific work to find links that may never be rediscovered after scientists with other priorities and agendas direct research efforts into other directions. Does science proceed linearly? Why should it? Are you personally one of the types of people that when doing a jigsaw puzzle, you first find all the outside pieces, and then start grouping colors and actually have a plan for which piece you will try to find next? My plan is to keep looking for pieces that didn't fit into models in the past to see if today's new findings will finally reveal how they now fit in well with today's insights. I don't think laboratory scientists or clinicians are the best equipped to do this sort of work, but organizations funding science expect that to be where this sort of integrative work will originate. I have found instead that most investigators who are up to their ears in current scientific projects or who are developing protocols for others to follow will not take very much time to dig deeply for lost pieces. There are rare exceptions to this observation. I have actually met a lot of this special breed of scientist, who loves to think outside the box and has respect for what might have been lost and loves to dig through old findings. Nevertheless, sociologists who study such things tell us that most scientific studies are never read outside of a small group of narrow interest and will only have influence for a few years. With this being the general expectations, who is left to do the work of recovering lost work from the past? Who also brings in work from other disciplines previously thought unrelated to a condition? In the oxalate field, molecular biologists have now discovered that oxalate shares transport with sulfate and bicarbonate, which means oxalate also gets into the regulation of pH. While these transporters regulate these ions, they also move a lot of water across cell membranes. In some places, oxalate shares transport with iodine, and of course, that makes us think of things related to the thyroid and all the histories of later onset thyroid disorders and autoimmune conditions. Pathologists found that the older you are, the more your thyroid gland will fill with oxalate, and this can be associated with a loss of thyroid activity. That makes sense now that we understand that these substrates are linked in the way the body handles them. But what about anemia that can develop in celiac disease? Scientists found that transferrin's carbonate ion can be replaced by oxalate if oxalate can gain access to this site at sufficient concentrations. When that happens, unlike the carbonate ion, the oxalate anion won't let go of the iron, so it sequesters iron irreversibly. This mechanism has never been thought to be related to the anemia in celiac disease. What about the tendency towards osteoporosis or osteopenia in celiac disease? Some remarkable studies conducted in the late 1930's (actually after Popeye made his appearance) fed groups of rats a basal diet deficient in a good calcium source, but they made up the rat "RDA" for calcium by using either turnip greens or spinach. Turnip greens are high medium in oxalate content, but spinach is extremely high. The rats fed the spinach, during their lifetime (and many died prematurely), had impaired growth (also seen with celiac disease). They had bones and teeth that wouldn't mineralize. The rats on spinach were unable to reproduce except for one litter of two pups that were quickly devoured by their mother at birth. In contrast, the rats fed turnip greens, which are roughly otherwise equivalently nutritious, completed the study in great health with shiny coats and all the perks of being a healthy rat. Did Popeye deceive us about the benefits of what has become a much more popular food, often called "the healthiest food there is?" By the way, one of these studies was conducted by Campbell Soup Company! Our oxalate project, which makes its home at www.lowoxalate.info with its associated support groups on Yahoo and Facebook, has now served more than 17,000 families in helping them discover for themselves how oxalate has been contributing to health issues…with problems that resolved as they brought down their body burden of oxalate. We've seen this one change fundamentally alter the course of more than twenty disorders, and these disorders are not very much alike. Some are genetic and some are probably not genetic, but are you wondering why they aren't alike if they are all associated somehow with oxalate? With new genetic tools and new basic science to help us, it is now a lot easier to figure that out. Members of the SLC26 family of oxalate transporters that move a special set of nutrients across cell membranes are expressed at different levels and in different combinations in different organs and cell types. Scientists are just now starting to ask the questions about how they may be regulated, or "turned on" or "turned off". When is the immune system involved in this regulation? When may we find genetic differences in the use or expression of these transporters? We already know a few observations related to their expression in the lungs and in the inner ear and in the mucosa, but at this stage in the game, there is much more science about their regulation that we don't know compared to what we already have discovered. We do know now that it was a mistake to think oxalate was only secreted in urine. How many studies in the past based their conclusions on urine being the only place to look? Oxalate is now known to be secreted in the lungs where scientists in Russia have been making much progress in understanding its roles in asthma and COPD, but I would just about guarantee that your immunologist or your pulmonologist doesn't know about that research yet, but it has been going on for years and years. Oxalate is also secreted to the skin and can cause terrible rashes. Is it related to dermatitis herpetiformis? Who has measured for oxalate in those lesions associated with gluten sensitivity? In primary hyperoxaluria, secretion of oxalate to the skin has led to serious lesions that can even turn into gangrene. People on our listserves have reported the swelling of blood vessels in the skin termed livedo reticularis, and others have described and pictured all sorts of skin lesions, including an odd appearance of glitter in the skin that appears imbedded, but glistens beautifully in the sun. No, these people were not vampires! Our bodies not only get oxalate from dietary sources. The body is also producing oxalate internally as a by-product of certain metabolic processes that normally keep oxalate levels low. In the genetic condition, Primary Hyperoxaluria Type I, still believed to be found in only one in a million individuals, these individuals lack a B6-dependent enzyme that ordinarily converts a normal byproduct of metabolism to a very safe amino acid. When this enzyme activity is lacking from this genetic defect or from B6 problems, oxalate builds up inside the cells where it is made and where it might produce local damage. The amount of oxalate produced with the genetic defect is so high that it spills out into the body, primarily from the liver, and produces a condition called oxalosis where oxalate damages tissues all over the body, and in the bones, and the heart, and often leads to death by kidney failure. Through the work of Marguerite Hatch and other scientists, we have learned that signals now being studied will instruct intestinal cells to take oxalate out of blood and secrete it into the stool. Even though a vast literature has associated inflammatory bowel diseases with producing an increased absorption of dietary oxalate through a leaky gut, that is apparently not the whole story. The body has mechanisms to rid itself of normal levels of excess oxalate, but in primary hyperoxaluria Type I, these efforts seem never enough to protect the body. In Mayo's database it was reported that 59% of those with this genetic disease experience abdominal pain. Oxalate is a known inflammatory molecule. Does oxalate secretion to the gut produce inflammation and pain? This certainly needs to be studied by gastroenterologists but does that discipline even know about this oxalate research? Who is showing them this science? Have you ever wondered if there is anyone who ensures that discoveries from basic science are applied by the physician to patient care when the finding isn't related to drug development? We humans do not have genes to degrade oxalate. That is why oxalate, once absorbed into blood can collect in our tissues and cause damage. Nature has provided a way for increased oxalate in our blood to join the contents of our intestines so that it can find and bind calcium in the gut and then can leave in the feces. That is not the only reason oxalate from blood is sent there. The gut is home to microbes that are capable of degrading oxalate. This purposeful removal of a substance toxic to humans happens only if the oxalate-loving microbes are there and healthy enough to perform this service for us. This wonderful system fails, however, in conditions like cystic fibrosis, where continuous use of antibiotics may have killed the microbes that perform this service for us. Unfortunately, even in those without cystic fibrosis, many commonly used antibiotics, like the Z-Pack, can kill our oxalate degrading microbial friends. Another problem is that widely used antibiotics can also kill back the biotin producing microbes in the gut. Why is that relevant to oxalate? An important class of enzymes called biotin-dependent carboxylases, were found to be invaded by oxalate when higher levels of oxalate travel to where these enzymes function. Since these enzymes function in critical roles in the mitochondrion (with only one enzyme of this type serving us in the cytosol) scientists learned that oxalate may seriously impair their enzyme activity, putting our mitochondria in great distress. Scientists also found this interference is fairly easily addressed by high doses of biotin. Many years ago, I realized that doses of biotin being recommended by physicians and others were in all likelihood too low to provide effective restoration of the function of biotin-dependent carboxylases whenever oxalate had become elevated in mitochondria . I read about doctors treating dystonia caused by a thiamine transport defect with high dose biotin at 5-10 mgs/kg/day. Children with this thiamine transport disorder were kept on this dose of biotin for years with no problems, but when the dose was lowered, the dystonia came back. Why are some physicians worrying about giving 5 to 20 mgs a day to grown adults? I can only guess that they were unaware of the literature on biotin's safety and were never able to witness how their patient's lives might change on higher doses. Competition at enzyme active sites will matter much more than blood or urine levels. Unfortunately, we have no way of measuring tissue or organelle levels of oxalate in routine patient care. Clearly, more work needs to be done in this area to see where and when higher doses are needed. Unfortunately, many doctors are in unfamiliar territory with higher doses of biotin, and may be unaware of biotin's track record of great safety even at very high doses. We must ask, if someone is dangerously high in oxalate, which choice will cause more harm to them, taking high dose biotin, or failing to take higher doses of biotin when that could lead to a loss of function of those important enzymes? Do scientists and doctors realize that anything which damages mitochondrial function might also lead to villous atrophy? Did elevations of oxalate happen before the changes that lead to a diagnosis of celiac disease? There are actually many other mitochondrial enzymes known to be inhibited by oxalate. If oxalate seriously affects mitochondrial function, what might that have to do with what else we know about celiac disease? Right now, the first two articles that come up in pubmed when searching on celiac disease and oxalate are articles that should get us thinking. The first is an article entitled, "Subclinical celiac disease and crystal­ induced kidney disease following kidney transplant". Its abstract says, "Subclinical celiac disease is commonly overlooked and hyperoxaluria is not usually investigated in kidney patients." This article described a patient with hyperoxaluria, but this patient was lacking overt diarrhea, fat malabsorption, or nephrocalcinosis. The article that comes up next on this search speaks of measuring children with celiac disease, and concludes, "In contrast to adults, increased urinary excretion of oxalate was not detectable in children with celiac disease." Was that happening because oxalate that was getting into the blood was being secreted at this age more appropriately to the gut, or the lungs, or the skin, instead? Or had their oxalate been collecting in tissues like the gut, where it might be starting to impair mitochondrial function, possibly leading in time to villous atrophy? It would be hard not to notice that currently in the US, it is becoming popular to try gluten-free eating even if someone does not have celiac disease. That situation also describes several members of my own family who do not have celiac disease, but found out about twenty years ago that being gluten-free turned around our health so significantly that we never were tempted to go back to eating gluten. I had actually gotten the idea to try life without gluten from autism research which had been looking at a different reason to be sensitive to gluten, termed "the opiate excess theory". When I was at the medical library doing research when I was in graduate school, I found this theory discussed in a decades old book talking about schizophrenia. Soon I was privileged to know two of the major scientists working in this area, Paul Shattock and Kalle Reichelt. They found a protein in wheat (gliadin) and in milk (casein) that as they were digested formed peptides that had opioid activity. These peptides were capable of producing signals at opiate receptors meaning they might produce reactions or side effects seen when taking opiate medications. Later work also discovered opioid peptides in soy. The reason that this research might be important to celiac disease is that part of the benefit seen by removing gluten may come from eliminating these opioid signals, but these signals may continue to be a problem if you are still consuming large amounts of milk or soy. Recently, some further implications have appeared in this research area. Another of my autism colleagues, Richard Deth, found at his laboratory that the peptides that form opiates also block the absorption of cysteine across cell membranes. This unexpected finding probably has its biggest implications in the gut (preventing sulfur absorption) and in the brain, where sulfur is regulated a little differently. I recommend his recent paper to tell you more details, but it simply means that some of the benefits people with celiac enjoyed on a gluten-free diet may have been related to this other characteristic of opioid peptides. These same individuals may find that their health will improve even more if they controlled milk and soy. In the second year of our project on oxalate, I spoke at a conference in Germany and was invited for lunch in the home of a family with a child with autism on a gluten-free diet, but I noticed that this child and the children with autism I met in Germany were not doing as well as I was used to seeing in the USA. As I sat at their table, I found out that most of their gluten-free bread was made with buckwheat as a major ingredient. Buckwheat is, a very high oxalate grain. Was this keeping their son from getting better? Because I knew so many children with autism who had done much better than before after they eliminated gluten and casein, this to me seemed a sufficient reason not to reintroduce these foods to children already off these foods as we looked into the role of oxalate in autism. That's why, as we began our research on oxalate, I purposefully set out to test the raw ingredients being used commercially and in households for individuals on gluten and dairy-free diets. Our project discovered that there was a problem with buckwheat, amaranth, quinoa, and two late arrivals, chia seeds and hemp. We already knew oxalate was high in seeds like sesame seeds and poppy seeds, and also high in nuts like almonds which were now being made into milks for those on dairy-free diets. Soy is also high in oxalate, meaning soy has two problems—its opioid peptides and its oxalate level. In grains, most of the oxalate is in the bran, so the more "whole grain" a product is, the higher it will be in oxalate. Our listserve was literally flooded with individuals who found they got "sick" soon after they adopted what they thought was a "healthy diet". Another issue was the high levels of oxalate in chocolate and carob, which are used extensively in gluten-free "comfort foods". Last year, I attended a gluten-free expo in my city and picked up a cookbook full of new exciting recipes that were put together for this expo, and I saw that most of the recipes contained grains, or nuts or seasonings that were extremely high in oxalate. I couldn't help but wonder: Is this going to backfire for people, and will they recognize what is happening if by using these recipes and foods that they will find their health does not improve and may even get worse? In helping so many thousands of people reduce oxalate, our oxalate project has learned one thing clearly, and that is that giving someone a one page list of foods to avoid rarely successfully reduces oxalate in anyone. We have been told this most often by kidney stone patients who were given these lists by their doctors. Patients have told us hundreds of times that health improvements were not realized until they made this diet more like calorie counting. This is what we do in our support groups where people also monitor the contribution to their total oxalate level that comes from medium oxalate foods. This is why I would ask those reading this article to please seek our help if you wish to reduce oxalate, and do not strike out into the unknown on your own or confine yourself to the use of lists you might find on the Internet or at your doctor's office. Hundreds of Listmates have told us these lists had serious inadequacies and misinformation and little overlap with what they actually had been eating. We have also learned something else that is critically important. People who have been on an extremely high oxalate diet and then have reduced their diet's oxalate content too quickly, have gotten themselves in trouble. Some have ended up in emergency rooms in metabolic crisis with the doctors there unable to help them, because the doctors had never had training about why someone in this situation would get so sick. Even before our project started, we knew from studying the literature on those with primary hyperoxaluria, that when oxalate supply is reduced quickly by removing the liver that was putting out so much oxalate into their bodies, after replacing it with a normal liver, the amount of oxalate that suddenly began to leave the tissues of their body could potentially damage the replacement organ. Doctors have reported a very high death rate with these patients, which is reported to be much higher than death rates from other reasons for liver transplants. But what about what happens when reducing dietary oxalate? The food industry's recommendation of multiple fruits and vegetables has happened at the same as they began promoting many foods as super-foods and nutrient rich. Unfortunately, many of these same foods are so high in oxalate that they can keep someone from being able to retain and utilize minerals that are coming from other foods in the same meal. This can promote hyperabsorption of oxalate and increase risks of mineral imbalances. Our support groups have been deluged with individuals coming to us now with diets containing thousands of milligrams of oxalate putting their urine oxalate levels in ranges formerly seen only in the genetic hyperoxalurias. A low oxalate diet tries to keep the total oxalate load to between 40-60 mgs per day in adults As we said before, people who have been eating extremely high levels of oxalate need to reduce oxalate very slowly while the body adapts to the change. We have amassed a lot of experience with helping such individuals. The need for caution and more gradual change should not surprise us, because scientists are now telling us how quickly dietary changes can alter the function and composition of our microbial community and can also quickly alter cellular regulation of whatever enters and exits cells. These are compelling reasons to change the oxalate level slowly. Our website is www.lowoxalate.info. Our Yahoo group and our Facebook group are both called Trying_Low_Oxalates. We are partnering with non-profits and scientists from many fields around the world to fill in the missing science for a long list of disorders. Our work has gone far beyond autism, and we have been monitoring labwork on many conditions. We want to help make this dietary alteration as easy and safe as possible. We hope some of you readers will begin to get educated in this area. If you begin to reduce your oxalate, please let us know what reducing oxalate accomplishes for you. Since my early years in autism research, I have been convinced of one main principle. People with a condition will know their own bodies well. They are more likely to make important observations of change compared to a professional who comes in with too many preconceived expectations and has only a limited acquaintance with their subject's previous life. The first step in the scientific process really happens before scientific steps are put into use. The first "pre-step" is observation of something that does not fit old models. Frankly, after twenty years in research on autism, I don't believe the first step is best done by scientists and/or physicians. Why? Often someone new seeing a problem for the first time will notice aspects of that problem that people relying on old models will think is irrelevant and leave alone. That is why, to me, careful observations of hundreds and thousands of patients interacting can become the opportunity for forming new hypotheses that a scientist can later be recruited to test. This coordination of this volume of patient input was impossible before the internet allowed patients to find each other. But now, I think this is the most fertile field there is for making new scientific discoveries. Please, let's not confuse those two processes. First, we need to observe changes without layering expectations on what we see that comes from experience with only one type of patient. By looking at a broader diversity of patients, and discovering the overlap of their observations, we have a much better chance at noticing unexpected patterns that are significant. When people with no expectations of what ought to be ignored end up making the same observation time and again when they don't know each other, THEN you have something to legitimately research. At that point, the scientist can get involved with the second step, which is verifying the observations and seeing how widely they apply in one disorder or even more broadly. Using both steps, and both sets of eyes, and the marvelous ability to combine observations from thousands of individuals using the internet, we are now likely to begin to understand the complex role of oxalate in celiac disease and in many other disorders. From the author: If you have ever been diagnosed with an autoimmune disease and have been trying to lower oxalate, will you participate in the development of this science by filling out a survey? We would also like to find out whether reducing oxalate has affected your autoimmune condition. The link to our survey is here: https://www.surveymonkey.com/r/CMN5KK7 References: Baker PW, Bais, R, Rofe, AM Formation of the L-cysteine-glyoxylate adduct is the mechanism by which L-cysteine decreases oxalate production from glycollate in rat hepatocytes. Biochem. J. (1994) 302, 753-757 Capolongo G, Abul -Ezz S, Moe OW, Sakhaee K . Subclinical celiac disease and crystal-induced kidney disease following kidney transplant . Arn J Kidney Dis . 2012 Oct ;60(4) :662-7 . Halbrooks PJ, Mason AB , Adams TE, Briggs SK, Everse SJ . The oxalate effect on release of iron from human serum transferrin explained . J Mol Biol. 2004 May 21;339 (1):217-26. Kohman, E.F. Oxalic acid in foods and its behavior and fate in the diet. The Journal of Nutrition, 1940 18(3): 233-246. Konstantynowicz J, Porowski T, Zoch-Zwierz W, Wasilewska J, Kadziela -Olech H, Kulak W, Owens SC, Piotrowska-Jastrzebska J, Kaczmarski M. A potential pathogenic role of oxalate in autism . 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