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Celiac.com 09/29/2020 - Currently, the only medically accepted treatment for celiac disease is a completely gluten-free diet (GFD), which can be both expensive and challenging to maintain. One promising celiac treatment currently in development is larazotide acetate (AT-1001), an anti-zonulin, designed to regulate gut permeability in people with celiac disease. A team of researchers recently conducted a systematic review and meta-analysis of data from all randomized controlled trials (RCTs) assessing the effectiveness and safety of larazotide acetate in celiac patients. The research team included Ahmed Abu-Zaid, Noor Tariq Alhaddab, Razan Abdulkarim Alnujaidi, Hadeel Abdulaziz Alharbi, Fulwah Alangri, Naseem Alyahyawi, Aminah Kamal, Abdulaziz Khalaf Altowairqi, Habeeb Alhabeeb, Sami Almustanyir, and Reem Abdullah Alyoubi. They are variously affiliated with the College of Medicine at Alfaisal University in Riyadh, Saudi Arabia; the Department of Pediatrics at King Abdulaziz University Hospital, Jeddah, Saudi Arabia; the Department of Medicine at the Ministry of Health in Riyadh, Saudi Arabia; the Department of Medicine at the Alhada Armed Forces Hospital in Taif, Saudi Arabia; and the Research Center at King Fahad Medical City in Riyadh, Saudi Arabia. The team began by searching four databases from inception to 20-August-2020 using related keywords to isolate appropriate studies of larazotide acetate in people with celiac disease. The team identified all relevant RCTs and assessed bias risk. They then pooled continuous outcomes as mean difference and dichotomous outcomes as risk ratio with 95% confidence interval under fixed-effects meta-analysis model. They found four RCTs that met the study parameters, which included 465 celiac patients on larazotide acetate, and 161 on a placebo. Three and two studies included data on the results for patients on gluten challenge and GFD, respectively. The total effect estimates showed no substantial difference in lactulose-to-mannitol ratio between larazotide acetate and placebo groups. Analysis showed that larazotide acetate resulted in a significant improvement in symptoms in the gluten challenge, but not in the gluten-free subjects. The larazotide acetate group reported a favorable change in celiac-disease gastrointestinal symptom rating scale (celiac disease-GSRS) in the gluten challenge patients, compared with the gluten-free patients. Compared to the placebo, larazotide acetate reduced incidents of "adverse event" (AE) gluten-related diarrhea in gluten challenge patients, while other AEs remained similar among the treatment groups. From their data, the study team concludes that larazotide acetate is well-tolerated in patients, and better than a placebo at relieving celiac-related gastrointestinal symptoms. This article has not been peer reviewed. It reports new, un-evaluated, medical research, and should not be used to guide clinical practice. Read more about using larazotide acetate to treat celiac disease at Merxiv.org.

Celiac.com 09/04/2021 - I was recently chided by Melissa Jones. She is a reader who wrote to say that I had missed an important element of the topic when I discussed the discovery of zonulin and the therapeutic promise offered by this discovery. Melissa’s complaint was that I should have included a discussion of the connection with lung disease. I agree. After some reflection, I think that there is a good deal more that should be said about this recently discovered protein, including its connection with lung disease. Excessive amounts of zonulin are produced by those who have intestinal diseases. These particularly include celiac disease and type 1 diabetes. Zonulin is a likely factor in autoimmune thyroiditis, systemic lupus erythematosus, Sjogren’s syndrome, scleroderma, and at least sub-groups of multiple sclerosis patients and many rheumatoid arthritis patients. Zonulin may also be a major factor in the development and maintenance of many learning disorders and psychiatric illnesses. Current research has shown that zonulin weakens protective barriers throughout the body, in the intestines, lungs, blood vessels, skin, and perhaps, the brain. Research has also connected increased zonulin production to gluten consumption, but there may be additional factors that can trigger production and the resulting compromise to the various protective barriers this protein regulates. Lung disease is only one facet of this complex issue. The range and rate of lung diseases among celiac patients is broad and elevated, so Melissa’s concerns are well grounded. Some researchers report a greater frequency of many lung diseases including bird fancier’s lung, farmer’s lung, Idiopathic pulmonary hemosiderosis, lymphocytic bronchoalveolitis, pulmonary sarcoidosis, cavities in the lung walls, fibrosing alveolitis, and while there is some disagreement in the literature, there may also be higher rates and greater severity of asthma among celiac patients. Nonetheless, it should not be surprising that we experience an increased risk of lung disease since there is considerable similarity between the barrier functions of the mucosa of the lungs and that of the intestines. Thus, the search for a drug that can help us maintain the integrity of this barrier could protect against lung disease and provide important benefits for gluten sensitive individuals who are at greater risk of developing breathing problems along with the host of other ailments that involve compromised protective barrier function. For instance, investigations of zonulin have the potential to help people with autoimmune diseases. This research may even offer a new, proactive therapy for workers in the baking and milling industries, for severe burn victims who will predictably develop intestinal distress, and for cancer patients who are undergoing radiation treatments. Even patients with skin diseases may be helped. The therapeutic promise of the gluten-free diet for improving various psychiatric diseases, learning disabilities, and behavior problems might also be realized, at long last. The potential therapeutic implications of zonulin research, for a wide range of patients, are startlingly broad. I attended Blake Patterson’s presentation at the 12th International Celiac Disease Symposium on Saturday, November 11th in New York City. Alba Therapeutics, with Blake Patterson at the helm, is currently developing a drug that is aimed at delivering AT-1001 with meals. This substance blocks zonulin action by cloning the receptors which bind to zonulin but do not relax the tight junctions and are subsequently wasted in feces. This would decrease the compromising impact of zonulin by reducing permeability at tight junctions between cells of the protective tissues of the intestine, lungs, blood vessels, and perhaps, the blood barrier. This blockage, if it is achieved, may provide a means of regulating the tight epithelial junctions that create the various protective barriers mentioned earlier. Although he was extremely conservative when discussing the potential benefits of the drug Alba is developing, there can be little doubt that he has considered many more potential applications than I can think to list. The short-range objective, and the intended market of this drug, is to provide a more rapid and complete disease remission. Although it may ultimately allow a celiac patient to eat a normal diet, this is not the only objective of their development work. I have little personal interest in eating gluten again, but it would be nice not to have to worry about accidental and trace sources of gluten if that is part of what the drug offers. Research has already shown that a gluten-free diet can prevent type I diabetes from developing in two genetically susceptible people. One was at high risk of developing diabetes while the other already had it. This confirms the many animal studies that have shown, among the genetically susceptible, a dose-dependent relationship between gluten ingestion and the development of type 1 diabetes. It is a small leap to infer that if AT-1001 restores the barrier function in the intestinal wall of diabetic patients, as a gluten-free diet does, it should also stop the autoimmune attack on islet cells which make insulin in the pancreas. The current belief is that when gluten is leaking into the bloodstream and genetically susceptible people mount an immune response against that gluten, the antibodies identify certain sequences of amino acids in the protein structure. These sequences are similar to those found in islet cells, so the antibodies will also attack and destroy these insulin producing cells of the pancreas. By tightening the junctions of the protective barrier in the intestinal wall, thus stopping the leakage of gluten into the bloodstream of genetically susceptible individuals, AT-1001 should also stop the autoimmune result of this process frequently referred to as molecular mimicry. AT-1001 could be used not only to protect surviving islet cells in the type 1 diabetic who still has some production capacity, it can also aid the long-term survival of transplanted islet cells. These transplants are somewhat limited, in current circumstances, because the transplanted cells are destined to be destroyed by the same autoimmune process that destroyed the individual’s original islet cells. Thus, the therapeutic implications for this drug go far beyond Alba’s short term objectives. Many celiac patients, myself included, experience significant lung disease. I am well aware that my history of smoking cigarettes, now fifteen years in the past, contributed to my lung disease. On the other hand, I’m also aware that when I visit rural locations where there is little air pollution, my lung function improves dramatically. My own lung problem results, in part, from extensive scarring on the walls of my lungs. This scar tissue impedes the normal exchange of oxygen and carbon-dioxide across the lung wall, to and from the blood. This component of the problem probably won’t get much better. There is also an allergy-driven asthma component to my difficulties. This facet of my lung problems, as shown by my improved lung function, when away from urban air pollution, could be helped dramatically by a drug that tightens the barriers in the lining of my lungs and protects me from the absorption of these airborne particles of pollution. Zonulin research is so new that it is difficult to predict where it might go, or the medicinal purposes it might serve. Those of us who have been frustrated by watching the medical community overlook the scope and severity of gluten-induced illness may well be vindicated by this work. I had the privilege of speaking to a support group at the University of Arizona Medical School in Tucson last year. At that time I stated that the discovery of zonulin should lead to the Nobel Prize for Fasano et. al. because of the enormous implications of their discovery. The more important outgrowth of this research is that many millions of sick and/or vulnerable people may benefit enormously from AT-1001 if it can be formulated to successfully and effectively regulate the impact of zonulin in humans. It will save and enhance the quality of many lives.

Celiac.com 06/16/2021 - Weeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called Multisystem Inflammatory Syndrome in Children (MIS-C). A new study offers hope for diagnosis, treatment and prevention of MIS-C. Gastrointestinal symptoms are common in MIS-C patients and severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not previously been identified. A team of researchers recently set out to learn more about diagnosing, treating, and preventing MIS-C. The research team analyzed specimens from 19 children with MIS-C, 26 with acute COVID-19, and 55 control subjects and assessed stool samples for SARS-CoV-2 by RT-PCR, and plasma samples for markers of breakdown of mucosal barrier integrity, including zonulin. They used ultra-sensitive antigen detection to probe for SARS-CoV-2 antigenemia in plasma, and then characterized the resulting immune responses. As proof of concept, we treated a MIS-C patient with larazotide, a zonulin antagonist, and monitored impact on antigenemia and clinical response. The team demonstrated that, in MIS-C patients, prolonged presence of SARS-CoV-2 in the GI tract leads to the release of zonulin, an intestinal permeability biomarker, which causes SARS-CoV-2 antigens to flow into the bloodstream, and triggers hyperinflammation. The one MIS-C patient treated with larazotide, a drug which is currently in clinical trials as a possible treatment for celiac disease, showed a coinciding decrease in plasma SARS-CoV-2 Spike antigen levels, inflammatory markers, along with clinical improvement above that resulted from presently available treatments. The team's data detailing the pathogenesis of MIS-C offers insight into targets for diagnosing, treating, and preventing MIS-C, which are crucial to addressing this increasingly common severe COVID-19-related disease in children. Read more at The Journal of Clinical Investigation. The research team included Lael M. Yonker, Tal Gilboa, Alana F. Ogata, Yasmeen Senussi, Roey Lazarovits, Brittany P. Boribong, Yannic C. Bartsch, Maggie Loiselle, Magali Noval Rivas,4 Rebecca A. Porritt,4 Rosiane Lima,1 Jameson P. Davis, Eva J. Farkas, Madeleine D. Burns, Nicola Young, Vinay S. Mahajan, Soroush Hajizadeh, Xcanda I. Herrera Lopez,5 Johannes Kreuzer, Robert Morris, Enid E. Martinez, Isaac Han, Kettner Griswold Jr., Nicholas C. Barry, David B. Thompson, George Church, Andrea G. Edlow, Wilhelm Haas, Shiv Pillai, Moshe Arditi, Galit Alter, David R. Walt, and Alessio Fasano. They are variously affiliated with the Department of Pediatrics, Massachusetts General Hospital, Boston, United States of America; the Department of Pathology, Brigham and Women’s Hospital, Boston, United States of America; the Department of Medicine, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States of America; the Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, United States of America; the Department of Medicine, Massachusetts General Hospital, Boston, United States of America; the Department of Immunology, Wyss Institute for Biologically Inspired Engineering, Boston, United States of America; the Department of Genetics, Harvard Medical School, Boston, United States of America; the Department of Obstetrics, Gynecology, and Reproductive Biology, Massachusetts General Hospital, Boston, United States of America; the Massachusetts General Hospital, Boston, United States of America; the Department of Immunology, Massachusetts General Hospital, Boston, United States of America; and the Department of Pathology, Harvard Medical School, Boston, United States of America.

Celiac.com 04/20/2021 - Non-celiac gluten sensitivity (NCGS) is marked by intestinal and extraintestinal symptoms triggered by gluten-containing foods, but with no celiac disease or wheat allergy. There are currently no known biomarkers to diagnose non-celiac gluten sensitivity, and the gold standard double-blind placebo-controlled gluten challenge is clinically impractical. A team of researchers recently set out to investigate the role of serum zonulin as a diagnostic biomarker of NCGS and to develop a diagnostic algorithm. The research team included Maria Raffaella Barbaro, Cesare Cremon, Antonio Maria Morselli-Labate, Antonio Di Sabatino, Paolo Giuffrida, Gino Roberto Corazza, Michele Di Stefano, Giacomo Caio, Giovanni Latella, Carolina Ciacci, Daniele Fuschi, Marianna Mastroroberto, Lara Bellacosa, Vincenzo Stanghellini, Umberto Volta, and Giovanni Barbara. They are variously affiliated with the Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy, the First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Italy; the Department of Clinical Medicine Public Health Life Sciences and Environment, University of L'Aquila, Italy; the Department of Medicine, Surgery, and Dentistry Scuola Medica Salernitana, University of Salerno, Salerno, Italy, and the Department of Medical and Surgical Sciences, University of Bologna, Italy. For their multi-center study, the team enrolled 86 patients with either self-reported or double-blind confirmed non-celiac gluten sensitivity, 59 patients with diarrhea-predominant IBS (IBS-D), 15 patients with celiac disease, and 25 asymptomatic control subjects. The team assessed Zonulin serum levels, and calculated the associated diagnostic power. They recorded any clinical and symptomatic data. They also assessed the effect of diet on zonulin levels in a subgroup of patients with non-celiac gluten sensitivity. Compared with asymptomatic control subjects, the non-celiac gluten sensitivity patients, regardless of diagnosis modality, and celiac patients showed substantially increased levels of zonulin, as did both non-celiac gluten sensitivity and celiac patients, compared with IBS-D patients. Self-reported non-celiac gluten sensitivity showed increased zonulin levels compared with double-blind confirmed and not-confirmed non-celiac gluten sensitivity. There's been a lot of talk about gluten-free diets benefiting non-celiac gluten sensitivity patients, but this study found that six-month wheat avoidance significantly reduced zonulin levels only in non-celiac gluten sensitivity patients with positive HLA-DQ2/8. Wheat withdrawal was associated with reduced zonulin levels only in non-celiac gluten sensitivity with the HLA genotype. Zonulin levels were 81% accurate in distinguishing non-celiac gluten sensitivity from IBS-D. By excluding celiac disease, a diagnostic algorithm combining zonulin levels, symptoms and gender increased that accuracy to 89%. Certainly finding a reliable new biomarker for non-celiac gluten sensitivity would be a big deal. This study shows that zonulin can be an accurate diagnostic biomarker for non-celiac gluten sensitivity. When combined with demographic and clinical data, Zonulin levels can differentiate non-celiac gluten sensitivity from IBS-D with high accuracy. Expect more investigation into the use of zonulin levels as an accurate diagnostic biomarker for non-celiac gluten sensitivity. If it pans out, expect to see it developed for clinical practice, though that may take some time. Source: Gut, 2020 Nov;69(11):1966-1974.

Celiac.com 01/23/2020 - Researchers at the University of Maryland, under Alessio Fasano, have, once more, expanded the boundaries of human knowledge. The implications of their most recent discovery may soon unlock the mysteries of several autoimmune conditions including celiac disease, inflammatory bowel disease, type 1 diabetes, multiple sclerosis, and some types of cancers. Their discovery and subsequent report of zonulin, in 2000, was an enormous step forward. It provided insight into one, perhaps the only, common mechanism that causes leaky gut. Until then, many theories about leaky gut were proffered but none could be substantiated. We only knew that some autoimmune diseases, bowel diseases, and food allergies (or delayed sensitivities as some call them) seemed to trigger a leaky gut. Many of those with food allergies seemed to get some relief from eliminating foods to which their immune systems reacted, but we really did not understand the process by which these allergenic substances and various diseases induced a leaky gut. However, with the discovery and subsequent characterization of zonulin, it quickly became clear that a leaky gut was an important precursor to the development of at least some forms of autoimmunity. Although many medical practitioners continue to express skepticism about the importance of a leaky gut, emerging research findings should soon quell their concerns. Subsequent pharmacological research by Alba Therapeutics suggests that we may soon be able to abolish the permeable intestine that underlies so many autoimmune and other debilitating conditions. Currently in clinical trials, Alba Therapeutics is finding that Larazotide Acetate (formerly AT 1001) is abolishing the inflammatory sequelae when individuals with celiac disease consume gluten. Healthy digestion involves absorption of tiny, digested particles into the epithelial cells that line the intestine. These particles are then passed out the other side of the cell and into the bloodstream. These cells line the gut and maintain tight junctions to provide a protective barrier, except when zonulin attaches at cellular receptors. That is when the cells move further apart, allowing larger, undigested molecules to bypass the epithelial cells. Larazotide is designed to capture excess zonulin, which is over-produced by genetically susceptible individuals in response to ingested gluten. This drug is designed to capture the excess zonulin proteins and waste them in fecal matter, rather than allowing them to attach at receptors on epithelial cells. It is by this means that Larazodide is designed to prevent the development of a leaky gut, regardless of the cause of excessive zonulin production. Readers familiar with my work will not be surprised to learn that I’m not planning on eating gluten anytime soon. But I’d sure like to be able to take a pill containing an otherwise harmless substance, when dining out, whether at restaurants or at friends’ homes. I’d also like a tool that will help me to identify any other foods against which I may be mounting an inflammatory immune response. I imagine getting up in the morning and eating a couple of pancakes made from bean flours that I’m currently not able to tolerate. If I take some Larazotide first, and I get through the morning without my typical reactions–bloated stomach and heartburn–then I’ll know both what the culprit is and what I can do if I really want to have a couple of bean flour pancakes one morning. Similarly (and much more importantly) it will provide people with a tool for helping them to determine whether they are experiencing symptoms of food allergies or if their discomfort is caused by something else. For instance, if someone is unsure whether their foggy thinking really is the result of eating gluten, they can try Larazotide for a couple of meals. If their foggy brain clears up, but returns when they stop Larazotide and eat a meal containing gluten, then they will know that food (probably gluten) is likely the culprit. They may wish to pursue further self-testing or laboratory testing to identify specific problematic foods. This drug may also provide a tool for investigating children with attention deficit disorders (ADHD). If food sensitivities are the underlying culprit, these children should behave and pay attention fairly normally after a period of taking Larazotide before they consume any foods. We currently have no idea just how long such an intervention might take, but I’m hoping that researchers will soon answer such questions. I recently attended a conference on Crohn’s and colitis. When talking about treatments, the primary issues under discussion were the impact of various drugs on individuals present. The patients present shared a wealth of pharmaceutical knowledge. There was also considerable discussion of research aimed at a cure. In fact, the hosting organization seems quite fixated on finding a cure in the very near future. What a boon it would be, for everyone concerned, if Larazotide turns out to be that cure! But we knew all of this before. In fact, I’ve detailed most of this information in previous issues. What is new, and intensely exciting, is that the research group at U. Maryland has now determined that zonulin not only functions to increase intestinal permeability and inflammation, it is also a precursor to haptoglobin 2, a marker of inflammation that is exclusive to human beings. No other primates produce this protein, and only 80% of humans produce it. Considerable research has connected sub-groups of this marker to a variety of cardiovascular diseases, a range of autoimmune conditions, and many cancers. Thus, the production of zonulin, which will ultimately mature into haptoglobin 2, is a feature of many more ailments than was previously imagined. Since Larazotide is designed to capture and waste zonulin in fecal matter, we will soon be able to see what impact this drug can have on a variety of autoimmune diseases–and it promises to offer a tremendous benefit by halting the leakage of undigested proteins into the bloodstream that may be triggering autoimmune reactions by a process known as molecular mimicry. But that isn’t all Larazotide might offer. It could also offer insight into what has been characterized as the plague of the Twentieth Century, cancer. These inflammatory markers, haptaglobin 2, are elevated in association with many cancers. If the inflammation proves to be a significant factor in the survival of tumors, we will be able to block its production and deny this substance to the cancerous tissues. If, on the other hand, these inflammatory markers help the immune system to destroy tumors, we know how to trigger its production (in 80% of humans) and autoimmunity can be deterred by intravenous feeding during treatment. Either way, there is genuine cause for hope. My money is on the former possibility. I suspect removal of excess zonulin will reduce malignancies, but that is because diet can play an enormous role in cancer. There is already considerable anecdotal evidence suggesting a ketogenic diet is a viable therapy for insulin sensitive cancers. Time magazine ran a feature article titled “Can a High Fat Diet Beat Cancer?” in their September 17, 2007 issue. (The greatest difficulty these researchers are encountering with these trials is dietary compliance. Another serious problem is that their ethical approval required that all conventional treatments be exhausted before beginning the dietary trial. Thus, many of their research subjects are very sick before they begin the diet. For these reasons, one of the universities has stopped running these trials despite some promising preliminary results.) Whichever way it goes, Larazotide may well lead to some dramatic advances in cancer research in the very near future. Larazotide may also help some type 1 diabetics turn back the clock. Those who undergo islet cell transplants can usually only expect a year or two of reduced insulin requirements before they return to their former status. Larazotide may be able to halt the autoimmune destruction of the islet cells which produce insulin, allowing individuals who undergo transplants to experience relatively normal lives, without worrying about balancing the size of their insulin injections with their carbohydrate intake. They may well be able to forego injections entirely for the rest of their lives. Individuals with various autoimmune diseases may be able to halt the progression of their illness and return to more normal lives. Those with multiple sclerosis, Crohn’s disease, some forms of arthritis, lupus, and a host of other ailments may be stopped in their tracks. There may even be hope that people like me, with chronic lung disease, will be able to begin rebuilding healthy lung tissues. Reduced haptoglobin 2 may result in reductions in inflammatory reactions to airborne allergens. This, in turn, may permit us to breathe well enough that we can exercise and build healthy lung tissues without scar tissues. I’m not suggesting that we will be able to return to our 25 year-old activities, but I believe we may be able to live more normal, more productive lives for whatever time we have left. Finally, Larazotide may even bring about reductions in the excess mortality found in the celiac disease and gluten sensitive community. We have a lot to be grateful for. The research group directed by Alessio Fasano is making enormous contributions to broadening medical understanding of celiac disease, expanding medical knowledge of autoimmunity and cancer, and increasing celiac awareness (see: Scientific American, August 2008, “Surprises from Celiac Disease” by Alessio Fasano). As I said at the beginning, “They’ve done it again!”

Celiac.com 01/25/2020 - Depending on what source you read, there may be as many as 6.5 million celiac patients in the U.S. With these numbers, I have long believed that we really need to either find a cure or an effective way to manage this disease. I, like many others, have been wondering if a "magic pill" would ever be produced so I could escape from the dry, terrible tasting, overpriced gluten-free food. Thus, when I read an article about some research being done on celiac disease, I contacted the company conducting the clinical trials so I could be placed on their mailing list and hear about the results as soon as possible. At the time, I was not eligible to participate. To my surprise, a few months later, I was contacted by the agency conducting these trials. They asked if I would like to participate in the next testing phase of a medication called Larazotide which was being produced by Alba Pharmaceuticals. Prior to this opportunity, my only contribution to the celiac community was my list of foods that were actually palatable, and which I sent to newly diagnosed celiac sufferers on request. I also talked to my local specialty stores to ask them to order certain brands of foods and discontinue a certain brand of baked good that tastes like sand. With the invitation to be involved in this research, I now felt that I had an opportunity to really weigh in on a potential cure for this disease and really make a difference. At the appointed time, I went in for my physical and briefing. After learning about the drug, the study, and what would be expected, I signed on. I took my meds as instructed and kept my bowel movement data on what was affectionately named my "Brown Berry". This device was supplied by the agency as well as follow up visits and what I considered the most important benefit, both a pre and post-study duodenal biopsy. I entered the program with some apprehension, but to my surprise, it went quite smoothly. Appointments were made at my convenience and the contract allowed participants to leave the study at any time. The physical examination and subsequent follow ups were thorough and I was made to feel like a valuable part of the study. This article is not a promotional piece for Alba Pharmaceuticals. I had not even heard of them until I got involved in the study. It is however, a promotional piece is for all of you reading this is to become or stay active in the celiac community. I know from experience that involvement in such activities encourages you to take an active interest in your health. Whether it’s speaking to store managers about carrying quality products to make your life a little easier or getting involved in a study, it is time to be proactive. Don’t wait for someone else to step up. When this study is published sometime around the first of the year, I will be very proud of my small contribution. Let’s hope Larazotide is our "magic pill" and we can start enjoying real food again. Until then, please step up to the plate and become proactive in our health. We all benefit from each others’ contributions.

Celiac.com 11/21/2019 - Researchers know that zonulin increases gut permeability after exposure to gliadin in children with celiac disease. It's also known that kids with Nephrotic Syndrome have elevated plasma zonulin levels. That knowledge, along with the fact that protease activated receptor-2, which mediates zonulin effect in enterocytes, is present on podocytes, has led some researchers to wonder if gluten-induced elevations in zonulin might affect glomerular permeability and mediate proteinuria in children with Nephrotic Syndrome. A team of researchers recently set out to see if a gluten-free diet was helpful in controlling cases of difficult-to-manage Nephrotic Syndrome in children. The research team included Howard Trachtman, Laura Jane Pehrson, Suzanne M Vento, Laura Malaga-Dieguez, Debbie S Gipson, Katherine MacRae Dell, Tarak Srivastava, Kevin V Lemley, Frederick J Kaskel, Kevin EC Meyers, and Christian Faul. For their multi-center, open-label trial, the team tested the effectiveness of a gluten-free diet in children with steroid-responsive, difficult-to-manage Nephrotic Syndrome over a 6 month period. They defined a positive response as any reduction of 50% or greater in relapse rate, compared with the prior 6 months, or discontinuation of at least one immunosuppressive drug from the treatment regimen. They gathered data that included age, gender, race/ethnicity, serum creatinine, proteinuria, histopathology, and treatment method. Serum was collected prior to and at completion of the Treatment Period. They conducted blood tests both before and after the six month period to determine the effect on the glomerular cytoskeleton in vitro. Data are provided as mean±SD. The team evaluated eight girls and six boys, for a total of 14 children, under 12.4 years of age, with baseline serum creatinine levels of 0.46±0.12 mg/dl, and Up/c 0.45±0.49 (mg:mg). The group included 11 Whites, 2 Hispanics/Latinos, 1 Black, and 3 other racial groups. The team found 10 cases of MCD, and four cases FSGS in 4 cases. After six months of treatment, four participants had a positive response (two had a reduced relapse rate and two had a reduced medication burden), 5 showed no benefit, of whom 2 withdrew before 6 months, while 3 patients had not yet completed the 6-month Treatment Period, and 1 child was lost to follow-up. One child had no change in relapse rate, but showed a quicker response to corticosteroids while following a gluten-free diet. Overall, baseline plasma zonulin levels were 19.4±1.7 vs 13.4±0.9 pg/mL in four non-responders vs two gluten-free diet responders. Up to 33% of patients with difficult-to-manage NS show a positive response to a gluten-free diet. Elevated levels of plasma zonulin may predict a poor dietary response. This study shows that a gluten-free diet can help some children with frequently relapsing or steroid dependent Nephrotic Syndrome to reduce the need for immunosuppressive drugs. Doctors will do well to consider a gluten-free diet for such patients. Presented at the American Society of Nephrology The researchers are variously affiliated with NYU Langone Health, New York, New York, United States; NYU School of Medicine, New York, New York, United States; University of Michigan Mott Children's Hospital, Ann Arbor, Michigan, United States; Childrens Hospital Los Angeles, Pasadena, California, United States; Cleveland Clinic Children's, Cleveland, Ohio, United States; Childrens's Mercy Hospital, Kansas City, Missouri, United States; Children’s Hospital at Montefiore, Bronx, New York, United States; The Children Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania, United States and the University of Alabama at Birmingham, Birmingham, Alabama, United States.

Celiac.com 07/30/2019 - Studies have shown increased intestinal permeability in irritable bowel syndrome. Validating serum biomarkers for altered intestinal permeability in irritable bowel syndrome will facilitate research and pathophysiology-based therapy. A team of researchers recently set out to measure serum zonulin and intestinal fatty acid binding protein levels in diarrhea-predominant irritable bowel syndrome and constipation-predominant irritable bowel syndrome, and to compare the results with healthy control and celiac disease subjects. The research team included Prashant Singh, Jocelyn Silvester, Xinhua Chen, Hua Xu, Veer Sawhney, Vikram Rangan, Johanna Iturrino, Judy Nee, Donald R. Duerksen, and Anthony Lembo. They are variously affiliated with the Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America; the Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States of America; and the Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada. The team used enzyme-linked immunosorbent assays to measure serum zonulin and intestinal fatty acid binding protein levels in fifty patients with constipation-predominant irritable bowel syndrome, fifty with diarrhea-predominant irritable bowel syndrome, fifty-three with celiac disease, and forty-two healthy control subjects. Using the irritable bowel syndrome-symptom severity scale as a gauge, they found that patients with constipation-predominant irritable bowel syndrome and diarrhea-predominant irritable bowel syndrome had higher zonulin levels compared with healthy controls. They also found that zonulin levels in patients with constipation-predominant irritable bowel syndrome and diarrhea-predominant irritable bowel syndrome are comparable to levels in patients with active celiac disease. The results showed no correlation between zonulin levels and overall irritable bowel syndrome symptom severity. They did, however, show a positive correlation with weekly stool frequency, and unsatisfactory bowel habits in diarrhea-predominant irritable bowel syndrome. Patients with diarrhea-predominant and constipation-predominant irritable bowel syndrome both had lower intestinal fatty acid binding protein levels compared with celiac patients. In patients with irritable bowel syndrome, serum zonulin is upregulated at levels comparable to those for celiac patients, and match the severity of unsatisfactory bowel habits in diarrhea-predominant irritable bowel syndrome. Irritable bowel syndrome patients show no increase in intestinal fatty acid binding protein levels, which likely means no significant increase in enterocyte death. This is an interesting finding regarding serum zonulin levels in some patients with irritable bowel syndrome, as is the positive correlation with weekly stool frequency, and unsatisfactory bowel habits in diarrhea-predominant irritable bowel syndrome. Read more at the United European Gastroenterology Journal; 2019 Jun; 7(5): 709–715. doi: 10.1177/2050640619826419

Celiac.com 06/23/2017 - Dr. Alessio Fasano from the University of Maryland's Celiac Research Center published a paper in Clinical and Developmental Immunology last month. It focused on a new drug developed by Dr. Fasano that has shown promising results in both animal and human trials. But is this the 'magic pill' that will cure celiac disease and gluten sensitivity? Let's take a look. The new drug, formerly called AT1001 but now renamed Larazotide Acetate, is a zonulin inhibitor. For those who have never heard the word 'zonulin', you might think it's a term from a science fiction movie. But zonulin is the protein that causes the 'gates' or openings between the cells making up the lining of the small intestine to open and close. These openings are called tight junctions and when zonulin gets excessive, a leaky gut ensues. Dr. Fasano has made great inroads to prove that a leaky gut is a problem that must be handled with gluten intolerance. The leaky gut perpetuates gluten's negative impact on other parts of the body. It can also initiate autoimmune disease. One key point to keep in mind is that 'leaky gut' occurs because molecules can pass between cells when they shouldn't. In addition, molecules can pass through cells which they also shouldn't. Unfortunately this new drug only impacts the former, not the latter. So, the drug Larazotide Acetate is a zonulin inhibitor. Now that we've reviewed what zonulin does as regards opening the gates, the purpose of inhibiting its action should make sense. How well does it work? In the recent human trials that were double-blind, randomized placebo-controlled (the best type of study, but I would expect no less from the stellar Dr. Fasano), a gluten exposure created a 70% increase in intestinal permeability (leaky gut) in 57% of the placebo group but only 28.6% of the patients receiving the drug (4 out of 14 patients) experienced such increased permeability. Further, gastrointestinal symptoms were significantly more frequent among patients of the placebo group as compared to the group that received the Larazotide. A pro-inflammatory substance known as interferon gamma was also evaluated. This is manufactured by the body when a specific foreign/toxic agent is recognized by the body's immune system. As expected, levels of interferon gamma increased in 4 out of 7 of the placebo patients (57%) but only 4 out of 14 larazotide patients (28.6%) saw any increase. The good news is that this drug seems well tolerated and it does reduce the leaky gut response that gluten ingestion normally creates. Further, it also reduces the percentage, by about half, of the production of interferon gamma. These are all excellent results. But, and it's unfortunately a very big 'but', we have a very long way to go before such a drug would be useful for your typical celiac or gluten sensitive patient. Will Dr. Fasano and his team be able to tweak this drug such that it functions at a higher level of efficacy? I certainly hope so, but let's analyze exactly what this drug does in its present state: The drug still resulted in almost 30% of the patients experiencing a 70% increase in permeability (leaky gut) – Not good. A highly pro-inflammatory (this means that it creates degenerative disease) substance known as interferon gamma was also produced in nearly 30% of the drug-consuming patients tested – Not good. Leakiness, or the passage of negative substances through cells is not affected by this drug – Not good. Of course on the plus side, over 70% of those tested DID have a very good result with apparently no untoward side effects – Very good. At what point is the efficacy high enough that you'd be willing to subject yourself to a possible reaction? Do realize that any gluten ingested increases your chance of disease, chief amongst them cancer and autoimmune disease. Is there a level of function of the drug that you would chance taking it? Is it 90%, 99%? Does any drug ever get that good? Well, as a big fan of Dr. Fasano's, I would say that if anyone can do it, he and his team can. But at the same time, I cannot help but think of all the other drugs I have encountered. As 'wonderful' as they sometimes seem initially, they almost always fall from grace when some horrible side effect is realized. Would I guinea pig my own health that I've fought so hard to regain? Would I recommend taking such a chance to my children just so that they could consume some white flour product? I don't think so. How about you? What do you think? If the drug were available right now at its efficacy of 71%, would you take it and hope you weren't in the 29% for whom it didn't work? I'd love to hear your thoughts. If you are wondering if you're gluten intolerant or know that you are but still aren't enjoying good health, consider calling us for a free health analysis: 408-733-0400. We are here to help! Our destination clinic sees patients from across the country and internationally so you do not need to live locally to receive assistance. To your good health! Reference: Alessio Fasano, Clinical and Developmental Immunology, Published online 2012 October 10. "Novel Therapeutic/Integrative Approaches for Celiac Disease and Dermatitis Herpetiformis."