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Celiac.com 05/09/2022 - Data from gene expression, lipidomic and growth impairment indicate that celiac disease begins long before the body starts to have an immune response to gluten. The influence of gluten intake in the first years of life as a potential risk factor for celiac disease is currently debated among researchers. A team of researchers recently set out to estimate the risk of developing celiac disease based on the amount of gluten intake and the serum inflammatory profile in genetically predisposed infants. The research team included Auricchio Renata, Calabrese Ilaria, Galatola Martina, Cielo Donatella, Carbone Fortunata, Mancuso Marianna, Matarese Giuseppe, Troncone Riccardo, Auricchio Salvatore & Greco Luigi They are variously affiliated with the Department of Translational Medical Science, University Federico II, Via S. Pansini 5, 80131, Naples, Italy; the European Laboratory for Food Induced Diseases, University Federico II, Via S. Pansini 5, 80131, Naples, Italy; the Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy; the Laboratory of Immunology, Institute for Experimental Endocrinology and Oncology, National Research Council (IEOS-CNR), Naples, Italy; the Neuroimmunology Unit, IRCCS Fondazione Santa Lucia, Rome, Italy; and the the Department of Molecular Medicine and Medical Biotechnology, University Federico II, Naples, Italy. The team evaluated an Italian cohort of children at risk for celiac disease, and enrolled twenty-seven children who developed celiac disease, along with fifty-six control subjects, matched by sex and age. The team also conducted a dietary interview at 9, 12, 18, 24 and 36 month intervals. They assessed serum levels of cytokines INFγ, IL1β, IL2, IL4, IL6, IL10 IL12p70, IL17, and TNFα, at four and thirty-six months. They found that infants who went on to develop celiac disease by six years of age showed increased serum cytokine levels at four months of age before gluten introduction. Elevated cytokines included INFγ, IL1β, IL2, IL6, IL10, IL12p70 and TNFα. Children who later developed celiac disease consumed substantially more gluten in their second year of life than the controls. For those children, gluten intake in the second year of life was strongly correlated with serum cytokines INFγ, IL2, IL4, IL12p70, IL17 at thirty-six months. The dietary pattern of infants who developed celiac disease was marked by high consumption of biscuits and fruit juices and low intake of milk products, legumes, vegetables and fruits, which may invite questions about pre-celiac gut microbiota health in these subjects. The researchers found that genetically predisposed infants who developed celiac disease showed a unique serum cytokine profile at 4 months before gluten consumption. In these children, gluten intake was strongly correlated with an inflammatory profile in serum cytokines at thirty-six months. This is one of the first studies to demonstrate such a clear relationship between cytokine profiles and infant gluten intake in advance of the development of celiac disease. Further study could help to develop preventative screening that Read more in Scientific Reports volume 12, Article number: 5396 (2022)

Celiac.com 03/15/2021 - COVID-19 is mainly a respiratory illness, but there is mounting evidence to indicate that the gut and gut microbiota may play a role in the disease. A team of researchers recently set out to determine if the gut microbiome is linked to disease severity in patients with COVID-19, and whether variations in microbiome composition might resolve with the passing of the SARS-CoV-2 virus. The research team included Yun Kit Yeoh, Tao Zuo; Grace Chung-Yan Lui; Fen Zhang; Qin Liu; Amy YL Li; Arthur CK Chung; Chun Pan Cheung; Eugene YK Tso; Kitty SC Fung; Veronica Chan; Lowell Ling; Gavin Joynt; David Shu-Cheong Hui; Kai Ming Chow; Susanna So Shan Ng; Timothy Chun-Man Li; Rita WY Ng; Terry CF Yip; Grace Lai-Hung Wong; Francis KL Chan; Chun Kwok Wong; Paul KS Chan; and Siew C Ng. To get the answers, the team reviewed blood, stool and patient records from 100 patients with laboratory-confirmed SARS-CoV-2 infection, from two different hospitals. They collected serial stool samples from 27 of the 100 patients up to 30 days after the resolution of SARS-CoV-2. They assessed gut microbiome composition by shotgun sequencing total DNA from stool extraction. They then measured plasma concentrations of inflammatory cytokines and blood markers. Compared with non-COVID-19 patients, those with COVID-19 showed a substantially changed gut microbiome, whether or not they received medication. In COVID-19 patients, a number of gut microbiota with known immunomodulatory potential, such as Faecalibacterium prausnitzii, Eubacterium rectale and bifidobacteria were low, and remained low up to 30 days after Covid-19 abated. In these cases, Covid-19 severity reflected elevated concentrations of inflammatory cytokines and blood markers such as C reactive protein, lactate dehydrogenase, aspartate aminotransferase and gamma-glutamyl transferase. The connections between gut microbiota composition, levels of cytokines and inflammatory markers in patients with COVID-19 suggest that gut microbiota composition reflects disease severity and weakened immune responses. Moreover, because gut microbiota imbalance after Covid-19 resolution may lead to persistent symptoms, it is important to understand how gut microorganisms are involved in inflammation and COVID-19. Read more in Gut The researchers are variously affiliated with the Department of Microbiology, The Chinese University of Hong Kong, Shatin, Hong Kong; the Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong; the Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong; the State Key Laboratory for digestive disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Shatin, Hong Kong; the Stanley Ho Centre for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong Department of Medicine and Geriatrics, United Christian Hospital, Kwun Tong, Hong Kong; the Department of Pathology, United Christian Hospital, Kwun Tong, Hong Kong; the Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong; the Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong; the Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.

Celiac.com 02/05/2021 - Recently, a team of doctors in the Czech Republic conducted a study of the inflammatory action of wheat gluten, and its relation to chronic diseases. Even with all of the research that has been conducted, many of the causes and mechanisms behind inflammatory and autoimmune diseases remain shrouded in mystery. Doctors just don't know what causes most autoimmune diseases or how they actually work. It is assumed that some sort of a breakdown occurs in the innate and adaptive immune system that regulates the body's mucous. On one level this makes a great deal of sense. Epithelial cells make up our skin and the linings of our respiratory, digestive and uro-genital tracts. From the moment we're born, our epithelial cells are coming into contact with the substances from the outside world. Our skin is regularly bombarded by germs, bacteria, and other foreign substances. Just the simple act of breathing brings dirt, germs, bacteria and other foreign substances into contact with the epithelial cells that line our lungs. Eating and drinking brings dirt, germs and bacteria into contact with the epithelial cells that line the digestive and uro-genital tracts. It is the job of our mucous layers, and the mucous they generate, to protect our epithelial cells that line our respiratory, digestive and uro-genital tracts. When the mucous layer fails, the immune system can be stressed. When the immune system breaks down or over-reacts, autoimmune ailments can result. Unlike the multiple layers of epithelial cells that form the protective layers of our skin, just a single layer of epithelial cells protects our uro-genital, respiratory and digestive tracts. Many people are surprised to learn that the surface area of human skin averages just two square meters in size, while of the lining of the respiratory, digestive and uro-genital tracts average about 300 square meters. Again, these surfaces are mostly covered with just a single layer of epithelial cells, yet to fend off the millions of micro-organisms that regularly bombard them they must be able to tell the bad from the good microorganisms and to keep the bad ones from crossing the epithelial barrier. Unlike other food proteins, the group of proteins in wheat, known as gliadin, has the ability to cause immune cells to produce cytokines. Cytokines are proteins and peptides that function as signaling compounds. Simply put, they tell other cells what to do. Inflammatory Activity of Gluten in Chronic Disease In the case of celiac disease, the presence of wheat protein activates immune cells to produce cytokines that tell the cells lining the intestine to become inflamed as a means of protecting the body against what it sees as a foreign invader. In the skin, mucosa, and lymphoid tissues there is a highly specialized kind of white blood cell called a dendritic cell. The role of dendritic cells is to initiate a primary immune response by activating lymphocytes and secreting cytokines. Research has shown that when these dendritic cells are exposed to wheat gliadin, they cause the body to increase the production of cytokines, which in turn triggers inflammation of the mucosal layer. This pattern of activity seems to play an important part in celiac disease. As stated earlier, this thin epithelial layer is all that protects the body from invasion by harmful intruders. It is also a place where nutrient exchange occurs. In the respiratory tract, oxygen is exchanged. In the digestive tract, nutrients are absorbed. In fact, for nutrients to be absorbed, it is necessary for there to be a degree of permeability in these cell linings. If they kept everything out, we'd die of malnutrition, or maybe thirst. If they let everything in, we'd likely die of one disease or another. So, the body keeps up a delicate balancing act here. In fact, the body has developed a highly sophisticated system of mechanical and chemical mechanisms whose job it is to protect this single layer of epithelial cells by identifying, degrading and removing intruders, while identifying and permitting beneficial items like nutrients to pass freely into the body for processing. In healthy folks, this process works very smoothly. The bad stuff is broken down and cleaned out, while the good stuff is permitted to cross the barrier and to carry the proper nutrients to our bodies. Once we leave the sterile environment of the womb, billions of different bacteria begin to colonize most of our mucosal and skin surfaces. Whether a person is healthy or not, the number of foreign bacterial cells living on and in our bodies far outnumber the cells we have when we are born. Most of these bacteria are beneficial, with the most beneficial bacteria residing in the gut. In fact, there are so many different kinds, with such high levels of specificity, that scientists haven't yet been able to cultivate all of them. These beneficial bacteria in the gut play an important role in immunity, metabolism, and other activities. Gluten's Connection to Various Chronic Diseases A wide range of inflammatory and autoimmune diseases are associated with celiac disease and untreated celiac patients, including a higher risk of complications from anemia, infertility, osteoporosis, and gastrointestinal cancer. Many other disorders are associated with celiac disease, including endocrine diseases like type 1 diabetes, thyroiditis, connective tissue diseases, liver diseases, and Down syndrome, along with nervous system disorders like epilepsy, ataxia, and peripheral neuropathy. One of the strongest associations with celiac disease is autoimmune diabetes. We now know that 5-10% of diabetic patients have celiac disease, a rate more than 5 to 10 times that of the general population. Almost all of these patients improve on a gluten-free diet. It's unclear why a gluten-free diet might produce improvement in some of these people with these conditions, but one prominent hypothesis is that a percentage of folks with those conditions have compromised gut barriers that somehow permit undigested gluten that provokes an immune response. An interesting side-note here is that mainstream researchers have recently begun to admit that diabetes, which was previously thought to be "exclusively" endocrine in nature, and heart disease, which was thought to be "purely" circulatory in nature, are both characterized by an inflammation component. In other words, inflammation of tissue, and therefore, of cells, plays an important part in both diseases. Similarly, celiac disease, which was thought to be largely gastrointestinal in nature, is increasingly showing connections to a wide range of disorders that affect nearly every major organ in the body. Strangely, or perhaps not so strangely in light of this recent evidence, a gluten-free diet seems to have a beneficial effect on a number of chronic diseases in people who are entirely free of celiac disease. Some patients with psoriasis and urticaria, for example, have shown improvement with a gluten-free diet, as have some patients with cryptogenic ataxia and peripheral neuropathy. A number of schizophrenics have shown a reduction of symptoms on a gluten-free diet. Also, a number of people with rheumatoid arthritis who observe a vegan, gluten-free diet have reported improvement in their condition. Animal models have proven to be helpful in better understanding many different diseases and to help create new and more effective treatments. There's a whole specialized area of biology called "Gnotobiology." These people specialize in working in germ-free conditions. Gnotobiologists have developed strains of animals that are reared in germ-free environments. Imagine if you had never been exposed to any of the harmful or beneficial bacteria that colonize the human body once it leaves the sterile environment of the womb. You would make a great guinea pig for better understanding how disease might work. Like people, once rats are born, they undergo a profound change. Intestinal microflora have a major effect on their mucosal immune system. One of the benefits of using gnotobiotic animal models is that researchers can separate the effects of microflora and dietary antigens. Since scientists know that applying wheat-gliadin to the gastro-intestinal tracts of conventionally raised rats of the AVN strain beginning shortly after birth results in pronounced jejunal changes, that is, celiac-associated lesions, it's beneficial if they can have a "clean" group of rats to test and compare against the conventionally raised rat group to see if there's some kinds of microflora that might provide some protection against celiac disease. One of the things that the research team discovered is that breastfeeding seemed to be profoundly protective against the adverse effects of wheat gluten. The research team actually looked at rat pups in which they had induced enteropathy to compare those given breast milk to those handfed on formula. Among other things, they found that rats that were suckled never showed flat mucosa so characteristic of celiac damage when exposed to wheat-gliadin. Its unclear exactly why this is, though breast milk has so many beneficial elements to it, that it's hard to imagine it not being responsible for a great deal of immune-related development in general. Rat breast milk in particular imparts epidermal growth factor (EGF), which seems to play an important part in of the rat's jejunal cells. The research team also studied the effects of gliadin in a model system. In fact, the team was able to take a close look at the effects of gluten on cells within the stomach cavities of mice. In one test, a group of rats received epidermal growth factor via breast milk, while another group received straight formula with no EGF. Both were treated with wheat-gliadin. Rats without EGF showed villous atrophy, while those receiving breast milk, and thus, EGF, were protected against pathological mucosal changes and also against celiac-associated damage. Basically, it all boils down to several things: First, it looks very much like the way is paved for the development of celiac disease by the innate immune system when the presence of gliadin promotes functional and phenotypic maturing in dendritic white blood cells, which then leads to the gliadin peptides being presented to certain T lymphocytes, which then trigger the associated inflammation and resulting damage. The research team concluded that it does, indeed, seem to be the unique structure of gluten and its fragments that provokes the response from the mechanisms of innate immunity. In predisposed individuals, gluten seems to more readily activate an immune response than other proteins like soy protein and egg protein. Breastfeeding seems to offer some protection against gluten intolerance and associated damage. In many cases, a gluten-free diet brings about improvement in chronic inflammatory and autoimmune diseases. Celiac disease is just one of many inflammatory and autoimmune diseases to be associated with the intestinal damage arising from chronic exposure to gluten in gluten-intolerant individuals. Also, many inflammatory and autoimmune diseases show improvement once gluten is excluded from the diet. Reference: Published In "Inflammation and Infection. The Golden Triangle: Food—Microflora—Host Defense". P.J. Heidt, Z. Midtvedt., V. Rusch, D. van der Waaij (Eds.) Old Herborn University Seminar Monography, 2007

08/03/2020 - New research shows that cytokines, particularly IL-8 and IL-15, could be used as markers to distinguish celiac disease from non-celiac gluten sensitivity (NCGS) and healthy people. Researchers have noted that levels of some inflammatory cytokines rise in people with celiac disease and NCGS, in contrast with healthy subjects. A team of researchers recently set out to create an accurate tool for using cytokines to distinguish healthy patients from those with celiac disease and NCGS. The research team included Fatemeh Masaebi, Mehdi Azizmohammad Looha, Mohammad Rostami-Nejad, Mohamad Amin Pourhoseingholi, Navid Mohseni, Gabriel Samasca, Iulia Lupan, Mostafa Rezaei-Tavirani, and Mohammad Reza Zali. They are variously affiliated with the Department of Biostatistics, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; the Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; the Department of Immunology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania; the Department of Molecular Biology and Biotechnology, BabesBolyai University, Cluj-Napoca, Romania; and the Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. The team assessed serum samples from 171 participants, including 110 celiac patients, 46 healthy subjects, and 15 with NCGS. They used commercial ELISA kits to detect levels for cytokines IL-1, IL-6, IL-8, IL-15, and IFN-γ. They applied the ROC curve analysis to establish the best levels for high sensitivity, specificity, positive and negative predictive values of cytokines, as the indicators of celiac disease, non-celiac gluten sensitivity, and healthy controls. In the NCGS group, the AUC values for IL-1, IL-8, and IFN-γ were 71%, 78% and 70%, respectively. IL-15 distinguished the celiac and NCGS groups from control group nearly 83% of the time, the highest overall. Additionally, IL-15 showed nearly 57% specificity, 82% positive predictive value, and 58% negative predictive value. IL-8 had nearly 75% sensitivity, the highest overall, with nearly 74% specificity, nearly 96% positive predictive value, and just over 30% negative predictive value. The team's results show that IL-8 and IL-15 could potentially act as markers for distinguishing celiac disease from the NCGS and healthy controls. The team suggests that the assessment of cytokine levels can be a useful tool for diagnosing celiac disease and NCGS and spotting the difference between the two conditions and healthy control subjects. Read more at: Iran Biomed J. 2020 Jun 1

Celiac.com 12/04/2019 - There still is no easy and accurate way to monitor and diagnose celiac disease in patients who've been on a gluten-free diet for a while. Celiac disease patients on a gluten-free diet experience reactions to gluten, but researchers really don't understanding those reactions in any meaningful way. Systemic cytokine release was recently linked to reactivation of gluten immunity in celiac disease. A team of researchers recently set out to define the nature and time-course of symptoms and interleukin-2 changes specific for celiac disease patients. Their study shows that interleukin-2 assessment could help doctors monitor and diagnose celiac disease in patients already following a gluten-free diet. The research team included Jason A. Tye-Din, A. James M. Daveson, Hooi C. E, Gautam Goel, James MacDougall, Sarah Acaster, Kaela E. Goldstein, John L. Dzuris, Kristin M. Neff, Kenneth E. Truitt and Robert P. Anderson. They are variously affiliated with the Immunology Division, Department of Medical Biology, The Walter and Eliza Hall Institute, University of Melbourne, Parkville, Vic., Australia; Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Vic., Australia; University of Queensland, Brisbane, Qld, Australia; Sir Charles Gairdner Hospital, Perth, WA, Australia; ImmusanT, Inc., Cambridge, MA, USA; Prometrika, LLC, Cambridge, MA, USA; and Acaster Lloyd Consulting Ltd., London, UK. The team presented a gluten challenge to 25 celiac disease patients following a gluten-free diet, and to 25 healthy control subjects. Each group consumed a standardized 6 gram gluten challenge. The team compiled a Celiac Disease Patient-Reported Outcome survey and global digestive symptom assessment each hour for up to 6 hours after gluten challenge. They also recorded adverse events over a 48 hour period, and assessed serum interleukin-2 levels at baseline, and at 2, 4 and 6 hours. Healthy control subjects showed no detectable levels of serum interleukin-2, while 92% of celiac patients showed no detectable levels at baseline, but levels >0.5 pg/ml at 4 hours. Patient-reported outcome severity scores remained steady for all control subjects, while scores for celiac patients rose sharply after gluten in celiac disease patients. Symptoms of gluten exposure started at the 1 hour mark, and topped out after three hours. Patients with serious reactions typically suffered from nausea and vomiting, while those with milder reactions experienced headache and fatigue. The highest interleukin-2 levels were associated with more severe symptoms, especially nausea and vomiting. The timing and severity of gluten ingestion symptoms in people with celiac disease are strongly connected to elevated levels of serum interleukin-2. A gluten food challenge combined with interleukin-2 assessment could be valuable clinical tool for monitoring and diagnosing celiac disease in patients established on a gluten-free diet. Alimentary Pharmacology & Therapeutics

Celiac.com 08/19/2019 - Most gluten-free celiac patients will experience gastrointestinal symptoms within hours of gluten exposure. A number of studies have shown a connection between cytokines and adverse gluten-reactions. A team of researchers recently set out to examine systemic cytokine profiles and their connection to acute symptoms in celiac disease patients after reactivation of gluten immunity. To do this, the team carried out a series of multiplex cytokine measurements in celiac disease patients after a gluten challenge, both orally, and by injection. The research team included Gautam Goel, Jason A. Tye-Din, Shuo-Wang Qiao, Amy K. Russell, Toufic Mayassi, Cezary Ciszewski, Vikas K. Sarna, Suyue Wang, Kaela E. Goldstein, John L. Dzuris, Leslie J. Williams, Ramnik J. Xavier, Knut E. A. Lundin, Bana Jabri, Ludvig M. Sollid, and Robert P. Anderson. Patients receiving gluten by injection showed at least 15 elevated plasma cytokines, with IL-2, IL-8, and IL-10 being most common, with changes 272-fold, 11-fold, and 1.2-fold, respectively. IL-2 and IL-8 were the only cytokines elevated at 2 hours, prior to symptom onset. After gluten ingestion, IL-2 was the earliest and most prominent cytokine, with a 15-fold change after 4 hours. Supported by studies of patient-derived gluten-specific T cell clones and primary lymphocytes, the team's observations indicate that celiac-associated gastrointestinal symptoms are likely caused by rapid reactivation of gluten-specific CD4+ T cells by gluten. This research may lead to new ways to diagnose and treat those with celiac disease. Stay tuned for more on this and related stories. Read more at: Science Advances 07 Aug 2019:Vol. 5, no. 8. DOI: 10.1126/sciadv.aaw7756 The researchers in this study are variously affiliated with the Division of Gastroenterology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA; Immunology Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia; the Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia; the Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, VIC, Australia; the Centre for Food and Allergy Research, Murdoch Children’s Research Institute, Parkville, VIC, Australia; the Department of Immunology and KG Jebsen Coeliac Disease Research Centre, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway; the Department of Pediatrics, Department of Medicine, University of Chicago, Chicago, IL, USA; ImmusanT Inc., Cambridge, MA, USA; and the Department of Gastroenterology and KG Jebsen Coeliac Disease Research Centre, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway.