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    Can Fasting Help Regenerate a Damaged Celiac Disease Intestine?


    Roy Jamron
    • Journal of Gluten Sensitivity Autumn 2018 Issue

    Can Fasting Help Regenerate a Damaged Celiac Disease Intestine?
    Image Caption: Image: CC--Imad HADDAD

    Celiac.com 09/28/2018 - MIT researchers have found that intestinal stem cells removed from mice after fasting for 24 hours and grown in culture have twice the regenerative capacity of stem cells grown in culture from non-fasting mice. The study provides evidence that fasting induces a metabolic switch in the intestinal stem cells, switching from utilizing carbohydrates to burning fat. Switching these cells to fatty acid oxidation enhances their function significantly. The study also found that the beneficial effects of fasting can be reproduced by treating mice with a molecule that mimics the effects. Stem cell regeneration is dramatically improved by fasting in both young and older mice.

    Intestinal stem cells in humans lose their ability to regenerate as humans age, making it more difficult for older people to recover from gastrointestinal disease and disorders. Fasting and/or the use of drugs to mimic the regenerative effects of fasting on intestinal stem cells may, therefore, be useful to improve recovery from intestinal injury in older patients if the mice study findings are shown applicable to humans.

    This study brings to mind past research on the protein R-spondin1 which showed great potential in completely regenerating and restoring the intestinal lining. R-spondin1 was being developed as a drug by Nuvelo, Inc. of San Carlos, CA designated as NU206 in 2005. Despite early successful human safety clinical trials in 2008, research was shelved and the promising drug has continued to sit idle on the shelf for years. The patent for NU206 is now owned by ARCA Biopharma http://arcabio.com/ of Westminster, CO after a merger with Nuvelo, Inc. in 2009.

    Fasting to regenerate the intestinal lining is free and requires no FDA approvals (though physician supervision may be advised.)

    Fasting may provide other potential health benefits. A Yale study found that during dieting or fasting the compound beta-hydroxybutyrate is produced which inhibits the inflammatory response in several disorders including autoimmune diseases, type 2 diabetes, Alzheimer's disease, atherosclerosis, and autoinflammatory disorders.

    Fasting can also affect the activation of T cells. T cells are leukocytes, white blood cells. T cells are activated by antigens from pathogens presented to T cell receptors which initiates an immune response against the pathogens. In autoimmune disease, antigen presented to T cell receptors initiates an immune response which results in damage to the body itself. A Luxembourg Institute of Health study found that glutathione, important for metabolic waste disposal and detoxification, also acts as a switch which stimulates T cell energy metabolism while keeping T cells clear of metabolic wastes. Without glutathione, T cells remain inactive and sit in a hibernation state. T cell inactivity is undesirable for fighting off an infection, but, otherwise, keeping T cells inactive may ward off harmful effects of autoimmune disease.

    Fasting lowers the body's glutathione level as the body constantly consumes glutathione. In one 7-day fasting study involving healthy humans, a progressive decline in total glutathione concentration in leukocytes was found during seven days of starvation due to a decrease in free glutathione content. This study provides proof that fasting lowers glutathione levels in T cells. Hence, based on the Luxembourg study, fasting can reduce or stop the activity of T cells. Thus, fasting can be used to relieve the symptoms of autoimmune disease resulting from a T cell immune response, providing that the subject is otherwise infection free and has no condition requiring an active T cell response.

    Finally, as shown in a University of Southern California study, multiple fasting cycles lasting 2 to 4 days over a period of 6 months in both mice and humans work to rid the body of older and damaged white blood cells and trigger white blood stem cells to self-regenerate and fully repopulate the immune system with new white blood cells. Besides having applications to recovery from immune system damage caused by cancer chemotherapy toxicity, these immune system rejuvenation effects from fasting may have potential benefit applicable to treatment of autoimmune disorders.

    Sources:

    Fasting boosts stem cells' regenerative capacity.
    A drug treatment that mimics fasting can also provide the same benefit, study finds.

    Anne Trafton - MIT News Office
    May 3, 2018
    http://news.mit.edu/2018/fasting-boosts-stem-cells-regenerative-capacity-0503

    Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging.
    Mihaylova MM, Cheng CW, Cao AQ, Tripathi S, Mana MD, Bauer-Rowe KE, Abu-Remaileh M, Clavain L, Erdemir A, Lewis CA, Freinkman E, Dickey AS, La Spada AR, Huang Y, Bell GW, Deshpande V, Carmeliet P, Katajisto P, Sabatini DM, Yilmaz ÖH.
    Cell Stem Cell. 2018 May 3;22(5):769-778.e4. doi: 10.1016/j.stem.2018.04.001.
    https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(18)30163-2

    Mitogenic influence of human R-spondin1 on the intestinal epithelium.
    Kim KA, Kakitani M, Zhao J, Oshima T, Tang T, Binnerts M, Liu Y, Boyle B, Park E, Emtage P, Funk WD, Tomizuka K.
    Science. 2005 Aug 19;309(5738):1256-9.
    https://www.ncbi.nlm.nih.gov/pubmed/16109882

    Nuvelo, Inc. Announces Positive Results from Phase 1 Clinical Trial of NU206 in Healthy Volunteers.
    Published: Dec 10, 2008
    https://www.biospace.com/article/releases/nuvelo-inc-announces-positive-results-from-phase-1-clinical-trial-of-nu206-in-healthy-volunteers-/?keywords=nu206

    Anti-inflammatory mechanism of dieting and fasting revealed.
    By Karen N. Peart
    February 16, 2015
    https://news.yale.edu/2015/02/16/anti-inflammatory-mechanism-dieting-and-fasting-revealed

    Master detox molecule boosts immune defenses.
    Scientists discover an unknown immune mechanism.

    April 18, 2017
    https://www.sciencedaily.com/releases/2017/04/170418120923.htm

    Glutathione Primes T Cell Metabolism for Inflammation.
    Mak TW, Grusdat M, Duncan GS, Dostert C, Nonnenmacher Y, Cox M, Binsfeld C, Hao Z, Brüstle A, Itsumi M, Jager C, Chen Y, Pinkenburg O, Camara B, Ollert M, Bindslev-Jensen C, Vasiliou V, Gorrini C, Lang PA, Lohoff M, Harris IS, Hiller K, Brenner D.
    Immunity. 2017 Apr 18;46(4):675-689. doi: 10.1016/j.immuni.2017.03.019.
    https://www.cell.com/immunity/fulltext/S1074-7613(17)30129-2

    The effect of fasting on leukocyte and plasma glutathione and sulfur amino acid concentrations.
    Martensson J.
    Metabolism. 1986 Feb;35(2):118-21.
    https://www.ncbi.nlm.nih.gov/pubmed/3945186

    Fasting triggers stem cell regeneration of damaged, old immune system
    BY Suzanne Wu - USC News
    June 5, 2014
    https://news.usc.edu/63669/fasting-triggers-stem-cell-regeneration-of-damaged-old-immune-system/

    Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression
    Chia-Wei Cheng, Gregor B. Adams, Laura Perin, Min Wei, Xiaoying Zhou, Ben S. Lam, Stefano Da Sacco, Mario Mirisola, David I. Quinn, Tanya B. Dorff, John J. Kopchick, Valter D. Longo
    Cell Stem Cell. 2014 Jun 5; 14(6): 810-823.
    https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(14)00151-9
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102383/

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    Posted

    This is very interesting! I keep thinking of all the times I've been glutened and how long it took me to recover. Fasting would have helped with the recovery?

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    Not sure I could go two days without eating.  Does fasting mean water only?

     

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    I have been fasting for a while now, 16/8 schedule. I wonder if I'd have the same effects on my fasting versus the 2 days to 7 days fasting. I'd love to find out more. 

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    Guest Laura

    Posted

    That sounds interesting if I could make it a whole day without getting light-headed.

    I have reduced my meals to two per day & the amount to 1/2 due to early satiety.

    Eating food is revolting.  Varying from plain meat/veg/fruit causes GI problems.

    Got celiac in my late 50's after the introduction of modern wheat with it's massive increase in gluten content to 17 x the 1960's wheat, & its been downhill since then. No gluten cross-reactors are permitted : yeast, egg, dairy & coffee. No oils due to the toxic residue of hexane, bleach, defoaming agents, deodorizers. Cannot tolerate preservatives (nitrates/sulfites/celery powder)      I pay dearly when I ingest any of these additives & residues & preservatives.

    The geneticists thought they were so smart in hybridization of wheat to make it insect & drought resistant. Instead they made it "people resistant". If I had ONLY been warned this was coming, the harm could have been avoided.  It makes me feel like the entire US population were the test subjects of this harmful cross-breeding experiment.  

    Thanks for this article, I'll start my own experimentation with fasting.

    I hope that one day scientists find a way by which humans can swallow a pill in exchange for eating food.

    Celiac disease when at its worse is a living hell.

     

     

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    Not surprised. My gi naturally after my gluten challenge could not handle food. My digestion was impaired amongst many other symptoms. I would blend and purée foods anti inflammatory food combos for weeks.  I remember my celiac cousin asked one day what did you eat today ? early in recovery, I replied a peach and tons of water.

    I still remember months later when my gallbladder "turned back on" before then any attempt to eat meat had me awake all night in tears as my body struggled to digest with sub par performance of bile, gastric juices and enzymes apparent from my organs. I'd say to myself ok can't handle meat yet . Tcm helped tremendously to aid the healing process and no joke I slept for 2 years trying to repair 4 decades of damage.

    As many know some cultures do a periodic fast at certain times of year and often times researchers report how their group reveals better health overall. 

    So the researchers findings doesn't surprise me at all (science background), but a great conformation read.  

    For those who can't fast perhaps as many veterans on celiac .com suggest bone broth /clear liquids you make at home may be a good start. I use crock pot to make them and freeze batch excess. It maybe a way to experience relief and jump start health if a full fast cant be done, A quasi fast. As always lots of water!

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    This article is fascinating but I wish it would have included the actual fasting schedule and what exactly is meant by "fasting".  Is this water only?  Liquids only?  What is the 2 to 4 day cycle over 6 months?  Two days fasting, 4 days regular for 6 months?  That seems extreme.

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    Guest Laura

    Posted

    To AWOL: Thanks for your message.  So sorry to hear about your struggles with health. I never thought about TCM. My mother always told me that as bad as I think my life is; "look around & see what others are experiencing and you'll see what bad really is".  Due to my aging joints I began supplementing my Wellesse joint supplement with: 1/3 cup bone broth followed by 1/3 c cherry juice. I haven't bought the collagen II pills yet.  Just adding the broth & juice has made me feel better.  Joint pain has mostly subsided.

    To George: Agreed, not enough information supplied. Humans should no be more than 3 days without fluids or the kidneys begin to shut-down.

     

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  • About Me

    Roy S. Jamron holds a B.S. in Physics from the University of Michigan and an M.S. in Engineering Applied Science from the University of California at Davis, and independently investigates the latest research on celiac disease and related disorders.

  • Related Articles

    Roy Jamron
    This article originally appeared in the Spring 2004 edition of Celiac.com's Scott-Free Newsletter.
    Celiac.com 05/10/2004 - Identical twins enter life from the same womb sharing the same genetic code, the same family, the same home, largely experiencing the same environment as they develop from infancy through childhood and mature into adults. When celiac disease strikes one identical twin, the odds are the other twin also has celiac disease. Twin studies lead to the conclusion that celiac disease is strongly linked to genetic factors. Yet one identical twin may develop celiac disease while the other twin may remain completely free of celiac disease for decades if not for a lifetime.
    One study looked at 20 pairs of identical twins and 27 pairs of fraternal twins where at least one twin of the pair was known to have celiac disease. In 75% of the pairs of identical twins, both twins had celiac disease. In contrast, in only 11% of the pairs of fraternal twins did both twins have celiac disease. However, in 25% of the 20 identical twin pairs studied, one twin of the pair did not have celiac disease1. In another study which followed 5 pairs of female identical twins for 11-23 years (at least one twin of the pair having celiac disease or dermatitis herpetiformis), it was found that two of the twins who began the study with neither celiac disease or dermatitis herpetiformis remained free of the disease throughout the study2. In other words, something beyond genetics, some environmental factor, seems to be responsible for the onset of celiac disease. Exactly what is it that makes one twin intolerant to gluten and not the other?
    Looking for Answers
    To find an answer, one might start by asking when do signs of an intolerance to gluten first begin to emerge? A recent study in the UK looked at a screened sample of 5,470 children aged 7 years old and found 54 who tested positive for both tTG antibodies and IgA-EMA (tissue transglutaminase and antiendomysial antibodies) indicating celiac disease is likely present. This 1% prevalence in children is comparable to the 1% prevalence of celiac disease in adults in the UK. Since the prevalence of celiac disease is not greater in adults, this suggests that the onset of celiac disease begins in early childhood, even in cases where celiac disease is not diagnosed until later in adulthood. The authors of this study concluded, “The search for the trigger resulting in the breakdown of immune tolerance to gluten therefore needs to focus on infancy and intrauterine life3.”
    Breast-Feeding
    Breast-feeding has long been thought to delay or reduce the risk of developing celiac disease in children. This effect has been attributed to a number of potentially protective milk components and antibodies passed from the mother. Studies relying on questionnaires have found that the onset of celiac disease in children is significantly delayed if gluten is introduced into the diet while the child is still being breast-fed4-7. The effect of epidermal growth factor (EGF), a component of breast milk, was studied in newborn rats. Interferon-gamma and gliadin, a gluten protein, were administered to rat pups to induce gluten enteropathy. Celiac disease-like villus atrophy was found in rat pups fed an artificial milk diet without EGF but not in breast-fed pups or pups supplemented with EGF8. Recent research shows that breast milk also passes bacterial flora from mother to newborn9. Growth factors found in human milk have been shown to aid in establishing predominant species of commensal bacteria in the gut of breast-fed infants10. The makeup of microflora which colonize the gut in early infancy is dependant on many factors, including whether babies are bottle-fed or exclusively breast-fed, whether or not delivered by caesarean section, on treatment in neonatal intensive care units, hygienic conditions, and antimicrobial procedures. Initially, it is the maternal microflora that is the source of bacteria for the newborn gut. A diet of breast milk induces the development of a flora rich in Bifidobacterium in full-term infants11. The possibility that these microflora play critical symbiotic roles in the development of the intestine and its immunological functions has not yet been considered as a factor in the onset of celiac disease.
    The Beneficial Roles of Gut Bacteria
    Over 500 species of bacteria may be present in the human gut in concentrations of between 100 billion to 1 trillion microbes per gram adding up to about 95% of the total number of cells in the human body12,13. For many years it has been known that gut bacteria play an important and beneficial role in one’s health. Extraordinary new findings on how commensal microflora participate in early gut development and in the development of the immune system have been uncovered by recent research. Here is sampling of some of these discoveries:
    A study of 64 healthy formula and breast-fed infants, aged 0-6 months, examined fecal samples for intestinal colonization of Bacteriodes fragilis, Bifidobacterium-like, and Lactobacillus-like bacteria, and compared these results with counts of IgA, IgM, and IgG antibody-secreting cells in blood fluids drawn from the infants. The result was that infants colonized with B. fragilis at one month of age had significantly higher counts of IgA- and IgM-secreting cells at the age of two months than infants not colonized with B. fragilis. It was concluded that colonization timing and the type of bacteria colonizing the gut of newborns may influence the maturation of the naive immune system14.
    Bacteriodes thetaiotaomicron, a species abundant in the guts of humans and mice, has been the focus of much research, chosen because of its predominance in the microflora and ability to be genetically manipulated. Studies of this microbe introduced into the developing guts of gnotobiotic (germ-free) laboratory mice have found B. thetaiotaomicron seems to communicate with host cells in the intestine, altering and influencing gut development and function.
    One study has shown gene activity in the host is affected by B. thetaiotaomicron colonization. Using sophisticated DNA microarray devices, a comparison of gene expression of some 25,000 mouse genes was made between germ-free and B. thetaiotaomicron colonized mice. The activity of 118 genes was found to be increased or reduced by colonization. These genes are involved in several important intestinal functions, including nutrient absorption, intestinal permeability, toxin neutralization, intestinal blood vessel development, and postnatal gut maturation suggesting that these functions should be examined further in future studies15.
    An influence on fructose production in the gut by B. thetaiotaomicron was the first finding uncovered by researchers. Pre-weaned mice produce fructose sugar on the surface of cells lining the intestine providing a food source helping to establish commensal bacteria. B. thetaiotaomicron colonizing the gut of germ-free mice causes intestinal cells to continue fructose production after weaning. If B. thetaiotaomicron is not present after weaning, fructose synthesis stops. B. thetaiotaomicron actually senses when its supply of fructose is low and instructs the host to produce more fructose in response16.
    Gene activity findings led researchers to look at the development of the intricate network of intestinal blood vessels in mice raised germ-free and in mice raised colonized with B. thetaiotaomicron or normal gut flora. When the mice reached adulthood, capillary development in the intestines was examined. Capillary development in mice colonized with B. thetaiotaomicron or normal flora was normal and complex, but capillary development in the germ-free mice was immature and arrested. Further, it was, found for blood vessel development to occur, these microbes must interact with Paneth cells (epithelial cells located at the base of the “crypts” in the small intestine)17.
    The relationship of B. thetaiotaomicron with Paneth cells was further studied. It was discovered that Paneth cells produce a protein called angiogenin 4 or Ang4 and that Paneth cells are induced to express Ang4 by B. thetaiotaomicron. Ang4 and other angiogenins were found to exhibit bactericidal and fungicidal activities against certain known pathogens. It appears that B. thetaiotaomicron and other commensal microbes, which are themselves resistant to Ang4, take part in shaping the microbial ecology of the gut and innate immunity18.
    Another study found a relationship between commensal bacteria and the development of gut-associated lymphoid tissue (GALT) in rabbits. GALT consists of lymphocytes and organized tissues called Peyer’s patches and mesenteric lymph nodes (MLNs) located within the intestinal mucosa, which are involved in the induction of immunity and tolerance. During the first few months after birth, newborn animals and humans rely on antibodies passed maternally to fend off infections until the immune system can mature. After those first few months, a diversification of antibody repertoire normally takes place within the GALT. When, shortly after birth, the appendices of rabbits are tied-off and isolated to prevent colonization by microflora, GALT development within the appendices is arrested. Rabbit pups delivered sterilely, isolated and hand-reared on a sterile diet exhibited underdeveloped GALT and antibody repertoires. In further experimentation, a number of different bacteria species were introduced into surgically-rendered, germ-free appendices of rabbits. No bacteria species alone promoted GALT development. However, the combination of Bacteroides fragilis and Bacillus subtilis consistently resulted in the development of GALT and antibody repertoire. The conclusion is that specific combinations of microflora are required for GALT development19,20.
    In other research, the composition of commensal flora in rats was shown to alter intestinal permeability. Colonization with Escherichia coli, Klebsiella pneumoniae, and Streptococcus viridans significantly increased colonic wall permeability while colonization with the common probiotic strain, Lactobacillus brevis, significantly reduced permeability of the colon wall. Bacteroides fragilis induced only a slight permeability reduction21.
    Gut pathogens in combination with stimulation by cytokines such as TNF-alpha (tumor necrosis factor) can cause cells of the intestinal epithelium to respond by releasing proinflammatory cytokines like interleukin-8 (IL-8). A study found that probiotic strains, Bifidobacterium longum and Lactobacillus bulgaricus, can suppress IL-8 secretion in intestinal epithelia when stimulated by proinflammatory cytokines. Hence, some probiotic strains of bacteria may be able to down-regulate inflammation in the gut22.
    Other beneficial functions of microflora include the fermentation and removal of non-digestible dietary residue and the mucus residue produced by the epithelia; the derivation of energy as short-chain fatty acids by fermentation of carbohydrates in the colon; the production of vitamins, particularly those of the B group and vitamin K; the absorption of minerals and ions including calcium, magnesium and iron; and the formation of a protective functional barrier against pathogens23,24.
    A Role for Bacteria in Celiac Disease?
    As can been seen, commensal microflora play a myriad of complex, diverse and important roles in normal health and development. Much remains to be investigated, and new roles and functions microflora play are waiting to be discovered. The possibility that commensal bacteria are involved in the pathogenesis of celiac disease cannot be overlooked. Certainly, differences in the mix of microflora could account for why one identical twin may develop celiac disease while the other does not. Could the mix of commensal bacteria in newborn infants set the stage for the development of celiac disease? Could the onset of celiac disease be triggered by an event such as illness, use of antibiotics, stress, or pregnancy which alters the mix of microflora opening the door to a pathogenic interaction with gluten? One recent study has already found an association between antibiotic use and the development of Crohn’s disease25.
    Over the course of the last few years, much new understanding of the pathogenesis of celiac disease has come to light, but a fundamental question remains unanswered: Why does the immune system fail to tolerate gluten in some people? A possible mechanism involving one or more unidentified species of commensal bacteria possibly explaining why tolerance to gluten fails will be proposed and discussed here.
    Tolerance and Immunity
    The subject of tolerance and immunity is involved and complex, and science remains far from fully comprehending its workings. At heart, is how the immune system decides to react when an antigen is first presented to a naive T cell. The response of the immune system to an antigen is mediated and regulated by cell secretions of numerous proteins called “cytokines” sensed by a multitude of receptors on the various specialized cells of the immune system. Structural components of pathogens are also sensed by immune cell receptors called “Toll-like receptors”. Antigens may be any substance foreign to the body and may or may not actually be harmful. They could be components of food, or could be components of either friendly or pathogenic organisms.
    In celiac disease, the antigens are those gluten peptides which survive the process of digestion. In the current understanding of celiac disease, these peptides are transported across the mucosal epithelium as polypeptides. In mainly the subepithelial region, gluten peptides undergo a process called deamidation by an enzyme called tissue transglutaminase (tTG). A peptide is a chain of amino acids. Deamidation is a process that converts glutamine amino acid components of a gluten peptide into glutamic acid components. In the lamina propria region of the intestines, deamidated gluten peptides are taken up by antigen presenting cells called dendritic cells and presented by HLA-DQ2 or -DQ8 molecules on the surface of dendritic cells to receptors of gluten-sensitive naive CD4+ T cells (Note celiac disease here refers to a “cluster of differentiation” number, a numbering system for the cell-surface molecules which identify T cell type). Activated CD4+ T cells then differentiate and proliferate. Some T cells interact with B cells which, in turn, then differentiate into plasma cells producing antigliadin, antiendomysial and anti-tTG antibodies. Other T cells become natural killer or cytotoxic T cells, secreting cytokines which cause inflammation and damage to the enterocytes in the epithelium. Connective tissue cells called “fibroblasts” increase their output of matrix metalloproteinase enzymes which may play an active role in villus atrophy. Intraepithelial lymphocytes also increase, but their role is not clear26-29.
    Human leukocyte antigen (HLA) genes encode the class II molecules DQ2 and DQ8, the key genetic risk factors in celiac disease. The HLA system is the human version of the major histocompatibility complex (MHC). HLA class II molecules are expressed on the surface of antigen presenting cells such as dendritic cells. Virtually all celiac disease patients carry DQ2 or DQ8, but carrying DQ2 or DQ8 alone does not confer celiac disease. DQ2 and DQ8 molecules may be encoded by several different haplotypes. Haplotypes are combinations of alternative genes for the same trait (alleles) occupying different locations on a chromosome which tend to be inherited as a group. These DQ2 and DQ8 molecules play a central role in the pathogenesis of celiac disease. The function of HLA class II molecules is to bind peptide antigens and present them to CD4+ T-cell receptors. The pattern of amino acids in the makeup of the chain that forms the peptide antigen is called an epitope, and that pattern is crucial to the binding between HLA molecule and peptide. It is the misfortune of celiac disease patients that epitopes of deamidated gluten peptides just happen to match up and firmly anchor into the binding grooves of DQ2 and DQ8 molecules. This strong binding results in the activation of CD4+ T cells and the subsequent processes which damage the intestinal epithelia. But why is it that CD4+ T cells are not activated in everyone who possesses the appropriate HLA-DQ2 and -DQ8 haplotypes? The question arises again. Why is one identical twin tolerant to gluten and not the other?26-30
    Dendritic Cells
    Whether an outcome of tolerance or intolerance results when a dendritic cell presents an antigen to a naive T cell depends on many factors. A dendritic cell is a special type of white blood cell (leukocyte) which circulates throughout the body looking to acquire antigens. Dendritic cells engulf and internalize antigens through a process called endocytosis. In receptor-mediated endocytosis, dendritic cells express a variety of surface receptors to capture protein antigens. In macropinocytosis, dendritic cells surround and “drink up” soluble antigens. In phagocytosis, dendritic cells engulf pathogenic bacteria, viruses, fungi, dead or infected cells, or their products. After digestion and processing, the antigens are bound to HLA (or MHC) molecules and expressed on the surface of dendritic cells for presentation to T cells. Antigen presentation occurs after dendritic cells migrate to the lymph nodes which are rich with T cells. T cell activation also requires secondary stimulation by costimulatory molecules expressed on the dendritic cell surface. Dendritic cells have three stages in their life cycle: Precursor, immature and mature. Precursor dendritic cells arise from the bone marrow. Subsets of precursor dendritic cells have been identified that grow and differ with regard to observable characteristics (phenotype), function and anatomical location. Studies have linked dendritic cell subsets with particular functions such as T cell differentiation or tolerance induction. Immature dendritic cells spread throughout tissues seeking antigens. Dendritic cells enter the mature stage when they reach the lymph nodes after antigen capture and having become primed and ready to activate T cells with antigens and costimulatory molecules. The processing of antigens produces roughly 100,000 to 300,000 peptide-laden HLA molecules on the dendritic cell surface, most peptides represented by about 100 copies. A single mature dendritic cell is capable of stimulating 100–3,000 T cells31-34.
    Immature dendritic cells are capable of phagocytosis of bacteria. Dendritic cell phagocytosis of Salmonella and Borrelia burgdorferi has been observed and studied. Immature dendritic cells roaming the lamina propria below the epithelial cells of the intestine not only capture bacteria which invade and cross the epithelial barrier, but have been observed reaching through the tight junctions between epithelial cells with their dendrite arms to directly sample non-invasive bacteria in the gut lumen and mucosa tissues outside the epithelium34-37.
    Immature dendritic cells express a variety of surface receptors which when stimulated cause dendritic cells to mature and respond in specific ways which can result in tolerance or immune activity. These receptors include Toll-like receptors (TLR), cytokine receptors, TNF (tumor necrosis factor) receptor, immunoglobulin (antibody) receptors, and sensors for cell death. TNF and other cykotine inflammatory mediators signal infections. In particular, interleukin-1 (IL-1) can prevent oral tolerance in mice by altering the response of normally tolerogenic dendritic cells into an active immune response32,34.
    Toll-like receptors are known as pattern recognition receptors which identify structural components found only on the surface of bacteria and other pathogens. These components are referred to as pathogen-associated molecular patterns (PAMPs). At least 10 types of TLR have been identified in humans and given the designations, TLR1-TLR10. Examples of PAMP include microbial carbohydrates like the toxin lipopolysaccharides (LPS), flagellin, products from bacterial cell walls, bacterial RNA and DNA. Signaling through different TLR evokes distinct biological responses. TLR expressed differently by different dendritic cell subsets may determine the manner in which dendritic cell subsets respond to particular microbial structures34,39.
    Mature dendritic cells can produce cytokines while activating CD4+ T cells which may influence T cell differentiation and function. Activated T cells divide and proliferate and differentiate into a variety of types. Tolerance and immunity induction are influenced most by differentiation into type 1 and type 2 helper T cells (Th1 and Th2) and regulatory T cells. The type of cytokines produced by the T cells determine their classification. Th2 responses favor tolerance. Th1 responses favor immunity and inflammation. Regulatory T cells suppress immune responses. IL-10 produced by dendritic cells appears to contribute to Th2 and regulatory T cell responses. Dendritic cell production of IL-12, IL-18, and IL-23 contribute to a Th1 response34,40.
    Why Does Tolerance to Gluten Fail?
    Okay. So why does the immune system fail to tolerate gluten in celiac disease? The immune system receives and responds to all kinds of signals from a pathogen, but how can a simple gluten peptide turn this complex immune machinery into a force against itself? Thinking about this leads to a very provocative question:
    What if instead of responding to gluten peptides alone, the immune system responds to a pathogenic gut bacteria which routinely ingests gluten peptides?
    A 33 amino acid gluten peptide has been identified as the primary initiator of the inflammatory response in celiac disease. This peptide contains a number of amino acid sequences which correspond to epitopes known to activate T cells and initiate celiac disease response. In particular, this 33-mer peptide was identified because it remained intact in the residue of a solution of gliadin mixed with gastric and pancreatic enzymes. This demonstrates some gluten peptides are difficult to breakdown by normal digestive processes. Another experiment identified a 17 amino acid gluten peptide which also contained epitopes associated with celiac disease41,42.
    Bacteria do not ingest nutrients in the normal sense. Nutrients are transported across cell membranes via several different mechanisms. Transported nutrients are necessarily limited in size. Nutrients are broken down externally by enzymes and by processes such as fermentation, an oxidation process resulting from acids produced by bacteria. Growth factors consisting of purines, pyrimidines, vitamins and amino acids are required by some bacteria in order to grow. Other bacteria are able to synthesize these essential growth factors. Researchers have found that some bacteria can transport and internalize amino acids in the form of peptides. Studies so far have found peptides up to 18 amino acids in length can be internalized by bacteria43-46.
    Epitopes of gluten peptides deamidated by tissue transglutaminase (tTG) are believed central to celiac disease pathogenesis. However, a study of gluten response in children with celiac disease found that T cells can respond to native gluten peptides independent of deamidation47. Celiac disease may begin its course without deamidation. As the disease progresses, inflammation may cause an increase in expression of tTG. An increase in tTG expression has been shown during wound healing, in liver injury, and in response to an inflammatory stimulus by lipopolysaccharide48-50. Through a process called epitope spreading and with the increase in tTG expression, deamidation of gluten peptides is more likely to occur and T cell response to deamidated gluten peptides likely develops. tTG is expressed in the epithelial brush border and extracellularly in the subepithelial region26 (The brush border is composed of the microvilli found on each individual epithelial cell).
    In the course of evolution of bacteria in the gut, it would seem highly plausible that at least one or more bacteria species have evolved and adapted in some way to transport, internalize and utilize gluten peptides as a source of amino acids. Since tTG is expressed in the epithelial brush border, deamidated gluten peptides are available to such bacteria (though in the early stage of celiac disease deamidation may not be required). If these bacteria colonize the gut and exhibit some pathogenic characteristic, such as expressing lipopolysaccharide, dendritic cells may be signaled to reach through the epithelial barrier into the lumen to sample and phagocytize the bacteria. When this bacteria is digested and processed by the dendritic cells, the antigens bound to HLA molecules and expressed on the dendritic cell surface are likely to include the difficult to breakdown, intact gluten peptides that have been internalized by the bacteria. As far as the immune system is concerned, these gluten peptides are indistinguishable from the other bacterial peptides bound to HLA molecules expressed on the dendritic cell surface. When these gluten peptide antigens are bound to HLA-DQ2 or -DQ8 molecules and presented to CD4+ T cells, the T cells simultaneously receive all the signals telling them that the gluten peptide is an antigen from a pathogenic bacteria. The result is that the immune system responds to the presence of gluten as though pathogenic bacteria were present. Such gluten-ingesting bacteria may be the missing link in the pathogenesis of Celiac Disease.
    If these bacteria exist, there is now a clear explanation as to why one identical twin may develop celiac disease and not the other. Of course, the presence of such a bacteria in the gut of one twin and not the other would fully explain the discordance. It is also possible that such a bacteria may exist in both twins, but is kept under control by the mix of commensal bacteria colonizing the gut of one twin. Some disturbance to this mix, such as an infection or use of antibiotics, might provide an opportunity for this gluten-ingesting bacteria to colonize and proliferate to a level where its pathogenic properties, such as production of endotoxins, are sensed by the immune system initiating the onset of celiac disease. The existence of such bacteria could also explain why there may be varying degrees of gluten sensitivity, even in individuals without DQ2 and DQ8 molecules.
    The possibility that these gluten-ingesting bacteria may exist raises another intriguing question: If these gluten-ingesting bacteria are controlled or eliminated from the gut, could tolerance to gluten be restored? There could be a very real possibility that celiac disease might be cured by eliminating these bacteria. After all, peptic ulcers can be cured by eliminating Helicobacter pylori.
    The Future
    So where should research go from here? The most obvious path would be first to try to find and identify any gut bacteria that has gluten peptides present within its cell membranes. From there, the possible link to celiac disease could be studied. Additionally, it would be quite valuable to initiate a large long-term study of the makeup of commensal bacteria in identical twins beginning at birth via fecal samples. By comparing the differences in microflora and the onset and discordance of diseases in identical twins over many years, the relationships of specific species of bacteria to specific diseases, including celiac disease, could be established. And if it proves to be true that gluten-ingesting bacteria cause celiac disease, a similar mechanism involving bacteria and peptides from other proteins may be the root cause for many other autoimmune diseases. A whole class of autoimmune diseases might be cured by eliminating specific species of bacteria.
    Roy Jamron holds degrees in physics and engineering from the University of Michigan and the University of California at Davis and actively pursues and investigates research on celiac disease and related disorders.

    References:
    Greco L, Romino R, Coto I, Di Cosmo N, Percopo S, Maglio M, Paparo F, Gasperi V, Limongelli MG, Cotichini R, D'Agate C, Tinto N, Sacchetti L, Tosi R, Stazi MA. The first large population based twin study of coeliac disease. Gut 2002 May;50(5):624-8. Bardella MT, Fredella C, Prampolini L, Marino R, Conte D, Giunta AM. Gluten sensitivity in monozygous twins: a long-term follow-up of five pairs. Am J Gastroenterol 2000 Jun;95(6):1503-5. Bingley PJ, Williams AJ, Norcross AJ, Unsworth DJ, Lock RJ, Ness AR, Jones RW. Undiagnosed coeliac disease at age seven: population based prospective birth cohort study. BMJ 2004 Feb 7;328(735):322-3. Sollid LM. Breast milk against coeliac disease. Gut 2002 Dec;51(6):767-8. Nash S. Does exclusive breast-feeding reduce the risk of coeliac disease in children? Br J Community Nurs 2003 Mar;8(3):127-32. Ivarsson A, Hernell O, Stenlund H, Persson LA. Breast-feeding protects against celiac disease. Am J Clin Nutr 2002 May;75(5):914-21. Peters U, Schneeweiss S, Trautwein EA, Erbersdobler HF. A case-control study of the effect of infant feeding on celiac disease. Ann Nutr Metab 2001;45(4):135-42. Stepankova R, Kofronova O, Tuckova L, Kozakova H, Cebra JJ, Tlaskalova-Hogenova H. Experimentally induced gluten enteropathy and protective effect of epidermal growth factor in artificially fed neonatal rats. J Pediatr Gastroenterol Nutr 2003 Jan;36(1):96-104. Martin R, Langa S, Reviriego C, Jiminez E, Marin ML, Xaus J, Fernandez L, Rodriguez JM. Human milk is a source of lactic acid bacteria for the infant gut. J Pediatr 2003 Dec;143(6):754-8. Goldman AS. Modulation of the gastrointestinal tract of infants by human milk. Interfaces and interactions. An evolutionary perspective. J Nutr 2000 Feb;130(2S Suppl):426S-431S. Fanaro S, Chierici R, Guerrini P, Vigi V. Intestinal microflora in early infancy: composition and development. Acta Paediatr Suppl 2003 Sep;91(441):48-55. 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Increased expression of mRNA for matrix metalloproteinases-1 and -3 and tissue inhibitor of metalloproteinases-1 in intestinal biopsy specimens from patients with coeliac disease. Gut 1999 Jan;44(1):17-25. Louka AS, Sollid LM. HLA in coeliac disease: unravelling the complex genetics of a complex disorder. Tissue Antigens 2003 Feb;61(2):105-17. DeMeyer ES, Baar J. Dendritic Cells: The Sentry Cells of the Immune System. Oncology Education Services, Inc. http://oes.digiton.com/dcell/ Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S. Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol 2002;20:621-67. Klein J, Sato A. The HLA system. First of two parts. N Engl J Med 2000 Sep 7;343(10):702-9. Stagg AJ, Hart AL, Knight SC, Kamm MA. The dendritic cell: its role in intestinal inflammation and relationship with gut bacteria. Gut 2003 Oct;52(10):1522-9. Sundquist M, Rydstrom A, Wick MJ. Immunity to Salmonella from a dendritic point of view. Cell Microbiol 2004 Jan;6(1):1-11. Suhonen J, Komi J, Soukka J, Lassila O, Viljanen MK. Interaction between Borrelia burgdorferi and immature human dendritic cells. Scand J Immunol 2003 Jul;58(1):67-75. Uhlig HH, Powrie F. Dendritic cells and the intestinal bacterial flora: a role for localized mucosal immune responses. J Clin Invest 2003 Sep;112(5):648-51. Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, Granucci F, Kraehenbuhl JP, Ricciardi-Castagnoli P. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2001 Apr;2(4):361-7. Singh BP, Chauhan RS, Singhal LK. Toll-like receptors and their role in innate immunity. Current Science 2003 Oct;85(8):1156-1164. Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol 2003 Apr;3(4):331-41. Shan L, Molberg O, Parrot I, Hausch F, Filiz F, Gray GM, Sollid LM, Khosla C. Structural basis for gluten intolerance in celiac sprue. Science 2002 Sep 27;297(5590):2275-9. Anderson RP, Degano P, Godkin AJ, Jewell DP, Hill AV. In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat Med 2000 Mar;6(3):337-42. Todar K. Todar's Online Textbook of Bacteriology. Univ of Wisconsin Department of Bacteriology. http://www.textbookofbacteriology.net Monnet V. Bacterial oligopeptide-binding proteins. Cell Mol Life Sci 2003 Oct;60(10):2100-14. Foucaud C, Hemme D, Desmazeaud M. Peptide utilization by Lactococcus lactis and Leuconostoc mesenteroides. Lett Appl Microbiol 2001 Jan;32(1):20-5. Detmers FJ, Kunji ER, Lanfermeijer FC, Poolman B, Konings WN. Kinetics and specificity of peptide uptake by the oligopeptide transport system of Lactococcus lactis. Biochemistry 1998 Nov 24;37(47):16671-9. Vader W, Kooy Y, Van Veelen P, De Ru A, Harris D, Benckhuijsen W, Pena S, Mearin L, Drijfhout JW, Koning F. The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides. Gastroenterology 2002 Jun;122(7):1729-37. Haroon ZA, Hettasch JM, Lai TS, Dewhirst MW, Greenberg CS. Tissue transglutaminase is expressed, active, and directly involved in rat dermal wound healing and angiogenesis. FASEB J 1999 Oct;13(13):1787-95. Nardacci R, Lo Iacono O, Ciccosanti F, Falasca L, Addesso M, Amendola A, Antonucci G, Craxi A, Fimia GM, Iadevaia V, Melino G, Ruco L, Tocci G, Ippolito G, Piacentini M. Transglutaminase type II plays a protective role in hepatic injury. Am J Pathol 2003 Apr;162(4):1293-303. Bowness JM, Tarr AH. Increase in transglutaminase and its extracellular products in response to an inflammatory stimulus by lipopolysaccharide. Mol Cell Biochem 1997 Apr;169(1-2):157-63.

    Roy Jamron
    Celiac.com 04/10/2006 - This study looks at innate immune response to gliadin. The innate immune system responds to gliadin inducing zonulin release and increasing intestinal permeability and may be a factor in the onset of celiac disease, but I question if this leads ultimately to the Ag-specific adaptive immune response seen in patients with celiac disease. This innate response fails to explain why one identical twin may have celiac disease and not the other. Both of the twins as well as people not even susceptible to celiac disease would presumably have this same innate response to gliadin. I again urge celiac disease researchers to consider gluten-internalizing bacteria as the necessary trigger for the onset of celiac disease. The presence or absence of such bacteria does indeed offer an explanation as to why one twin gets celiac disease and not the other. Zonulin does not. In the commercial supplement product, Glisodin, the properties of gliadin have, in fact, already been used for the last few years to facilitate the delivery of the antioxidant enzyme superoxide dismutase (SOD) protecting it from digestive acids and getting it through the intestinal mucosa, probably taking advantage of the zonulin effect. Aware of celiac disease, the developer of Glisodin tried to use other peptides as a carrier of SOD, but the only gliadin was effective. Unfortunately, this denies celiacs the benefit of using Glisodin to treat oxidative stress.
    Abstract of Study:


    J Immunol. 2006 Feb 15;176(4):2512-21.
    Gliadin Stimulation of Murine Macrophage Inflammatory Gene Expression and Intestinal Permeability Are MyD88-Dependent: Role of the Innate Immune Response in Celiac Disease.
    Thomas KE, Sapone A, Fasano A, Vogel SN. Department of Microbiology and Immunology.
    Recent studies have demonstrated the importance of TLR signaling in intestinal homeostasis. Celiac disease (celiac disease) is an autoimmune enteropathy triggered in susceptible individuals by the ingestion of gliadin-containing grains. In this study, we sought to test the hypothesis that gliadin initiates this response by stimulating the innate immune response to increase intestinal permeability and by up-regulating macrophage proinflammatory gene expression and cytokine production. To this end, intestinal permeability and the release of zonulin (an endogenous mediator of gut permeability) in vitro, as well as proinflammatory gene expression and cytokine release by primary murine macrophage cultures, were measured.
    Gliadin and its peptide derivatives, 33-mer and p31-43, were found to be potent inducers of both a zonulin-dependent increase in intestinal permeability and macrophage proinflammatory gene expression and cytokine secretion. Gliadin-induced zonulin release, increased intestinal permeability, and cytokine production were dependent on myeloid differentiation factor 88 (MyD88), a key adapter molecule in the TLR/IL-1R signaling pathways, but were neither TLR2- nor TLR4-dependent. Our data support the following model for the innate immune response to gliadin in the initiation of celiac disease. Gliadin interaction with the intestinal epithelium increases intestinal permeability through the MyD88-dependent release of zonulin that, in turn, enables paracellular translocation of gliadin and its subsequent interaction with macrophages within the intestinal submucosa. There, the interaction of gliadin with macrophages elicits a MyD88-dependent proinflammatory cytokine milieu that facilitates the interaction of T cells with APCs, leading ultimately to the Ag-specific adaptive immune response seen in patients with celiac disease.

    Roy Jamron
    Celiac.com 05/31/2006 - I previously discussed how liver abnormalities are highly prevalent in celiac disease. Why damage to the liver occurs is unknown, and gluten toxicity and increased intestinal permeability have been proposed as factors. The following free full text article appearing in the current issue of Gastroenterology may shed light on why liver damage occurs in celiacs.
    Toll-like receptors (TLRs) reside on the surface of many cells which participate in the immune system. TLRs sense molecules present in pathogens but not the host, and when the immune system senses these molecules, chemicals are released which set off inflammatory and anti-pathogen responses. One class of molecules recognized by TLRs and common to most pathogenic bacteria is lipopolysaccharides (LPS).
    Gluten increases intestinal permeability in celiacs. The disruption of the intestinal barrier permits endotoxins, such as LPS, from gut bacteria to reach the portal vein of the liver triggering a TLR response from immune cells in the liver. Proinflammatory mediators are released cascading into the release of more chemicals leading to inflammation and liver damage. This may be the cause of liver damage in celiacs. Gluten itself could also trigger a liver immune response. Kupffer cells in the liver are capable of antigen presentation to T cells, along with liver dendritic cells, and could initiate a T cell response to gluten within the liver.
    The following article is somewhat technical, but discusses the role of various liver cells involved in the immune process and how intestinal permeability and TLRs contribute to liver injury. The article is a good read and provides valuable information about the liver I have not seen elsewhere.
    Gastroenterology Volume 130, Issue 6, Pages 1886-1900 (May 2006)
    Toll-Like Receptor Signaling in the Liver
    Robert F. Schwabe, Ekihiro Seki, David A. Brenner
    Free Full Text:
    http://www.gastrojournal.org/article/PIIS0016508506000655/fulltext

    Roy Jamron
    Celiac.com 09/12/2006 - Symptoms of celiac disease prominently include fat malabsorption. One would expect this to impact levels of essential fatty acids in celiacs. The omega-3 essential fatty acids, especially eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids available in fish oil supplements have been demonstrated to have numerous health benefits. However, there are almost no studies on the effect of celiac disease on essential fatty acid levels. I am currently in the process of writing an article on essential fatty acids that will appear in Celiac.coms Scott-Free Newsletter, so a new study on lipid profiles in celiac disease caught my eye with promise. I was disappointed to find the study only measured cholesterol levels in celiacs, which showed an improvement in the "bad" to "good", LDL to HDL, ratio and an increase in "good" HDL cholesterol in patients on a gluten-free diet. The opportunity to study essential fatty acid levels in celiacs was again missed. However, omega-3 fatty acids have a proven beneficial effect on cholesterol levels, and improved fat absorption of omega-3 fatty acids due to a gluten-free diet may be responsible for the results presented in this new celiac disease lipid profile study.
    Below are the abstract of this study and two studies on the effects of omega-3 fatty acids on cholesterol levels:
    Am J Med. 2006 Sep;119(9):786-90.
    Change in lipid profile in celiac disease: beneficial effect of gluten-free diet.
    Brar P, Kwon GY, Holleran S, Bai D, Tall AR, Ramakrishnan R, Green PH.
    Am J Cardiol. 2006 Aug 21;98(4 Suppl 1):71-6.
    Clinical overview of omacor: a concentrated formulation of omega-3 polyunsaturated Fatty acids.
    Bays H.
    Am J Clin Nutr. 2000 May;71(5):1085-94.
    Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men.
    Mori TA, Burke V, Puddey IB, Watts gluten-free, ONeal DN, Best JD, Beilin LJ.
    New Fatty Acid Celiac Disease Study
    No sooner do I complain there arent any studies of essential fatty acid levels in celiac disease then, at least, a limited pediatric study of essential fatty acids appears! The results of this study on 7 pediatric patients with active celiac disease, 6 with celiac disease in remission, and 11 controls, show serum levels of fatty acids are similar between celiac disease and control patients, but abnormal fatty acid levels exist in intestinal mucosa tissue of active celiac disease patients. Results suggest an omega-6 fatty acid deficiency, at least in the mucosa. Not too surprising because prostaglandin E2 secretion increases in the intestines of active celiac disease patients, and prostaglandin E2 is produced from omega-6 fatty acids. It should be noted that fatty acid profiles may prove to be different in adult celiac disease patients. Also while omega-6 fatty acids may be deficient, increasing intake of omega-3 fatty acids may help reduce inflammatory processes in celiac disease.
    J Pediatr Gastroenterol Nutr. 2006 Sep;43(3):318-323.
    Abnormal Fatty Acid Pattern in Intestinal Mucosa of Children with Celiac Disease is Not Reflected in Serum Phospholipids.
    Steel DM, Ryd W, Ascher H, Strandvik B.


    Abstract:
    "Objective: Celiac disease (celiac disease) is characterized by chronic inflammation of the small intestinal mucosa with disturbed epithelial transport. The fatty acid (FA) composition of intestinal membranes is important for epithelial function, and disturbances may contribute to the pathophysiology of the disease. We aimed to evaluate whether the intestinal mucosal FA status was reflected in serum phospholipids of patients with celiac disease."
    "Patients and Methods: Samples were obtained from 7 pediatric patients with active celiac disease showing mucosal atrophy, 6 pediatric patients with celiac disease in remission, and 11 control pediatric patients with morphologically healthy intestinal mucosa. Small intestinal biopsies were obtained using a Watson biopsy capsule under fluoroscopic control. Blood samples were collected on the same morning after an overnight fast. Tissue phospholipids were isolated by high-performance liquid chromatography, and FAs were analyzed by capillary gas-liquid chromatography."
    "Results: Serum phospholipid FA showed marginal differences between the patients with celiac disease and the controls. Significant differences were observed in mucosa with active celiac disease compared with controls. Linoleic acid (18:2n-6) level was decreased, whereas those of its derivatives were elevated, indicating increased transformation of n-6 FA. Mead acid (20:3n-9) level was increased, with an increased ratio of Mead acid to arachidonic acid (20:4n-6) levels, suggesting essential fatty acid deficiency. The n-3 FA levels were not significantly changed. During remission, the FA pattern of the intestinal mucosa was mainly similar to that in controls."
    "Conclusions: The FA abnormality of intestinal mucosa in patients with active celiac disease was not reflected in serum values. Altered FA content may contribute to the pathophysiology of the disease because FAs are important for enzymes and for the transport and receptor functions of epithelial membranes."

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    • Maureen and Cyclinglady, Of the foods you listed. . .. I would focus on the Chocolate. Chocolate has Tyramine in it and it could/can cause rashes that  might be confused for DH. Sometimes Tyramine get's confused for/in high sulfite foods as triggers. Here is a great overview article on this topic. http://www.chicagotribune.com/lifestyles/health/sc-red-wine-headache-health-0608-20160525-story.html you might also have trouble with headaches if it tyramine is causing you your trouble. People who have trouble Tyramine might also have trouble with consuming cheeses. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738414/ As for the Milk causing/triggering your DH don't rule Adult onset dairy allergy. While rare it does occur in the literature/research when you search it out. I am including the research here in the hopes it might help you or someone else entitled "Adult onset of cow's milk protein allergy with small‐intestinal mucosal IgE mast cells" https://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.1996.tb04640.x It is generally thought most of grow out of a Milk Allergy at approx. 3 years old. But for some lucky one (I guess) we never do apparently.  (I speak for my friend on this board JMG).  He found out he was having trouble with dairy as an adult better never realized until about 6 months ago. With delayed onset allergies it is often hard to tell if it (allergen) is effecting us because we might not associate it with our dairy consumption because it might happen a day or two latter. See this WHFoods article about food allergens/sensitivies.  It is very long/exhaustive but it is very helpful if you have time to study it in more detail. http://www.whfoods.com/genpage.php?pfriendly=1&tname=faq&dbid=30 I will quote some key points for your information. Symptoms of Food Allergies "The most common symptoms for food allergies include vomiting, diarrhea, blood in stools, eczema, hives, skin rashes, wheezing and a runny nose. Symptoms can vary depending upon a number of variables including age, the type of allergen (antigen), and the amount of food consumed. It may be difficult to associate the symptoms of an allergic reaction to a particular food because the response time can be highly variable. For example, an allergic response to eating fish will usually occur within minutes after consumption in the form of a rash, hives or asthma or a combination of these symptoms. However, the symptoms of an allergic reaction to cow's milk may be delayed for 24 to 48 hours after consuming the milk; these symptoms may also be low-grade and last for several days. If this does not make diagnosis difficult enough, reactions to foods made from cow's milk may also vary depending on how it was produced and the portion of the milk to which you are allergic. Delayed allergic reactions to foods are difficult to identify without eliminating the food from your diet for at least several weeks and slowly reintroducing it while taking note of any physical, emotional or mental changes as it is being reintroduced." Here is their information on Tyramine's. Tyramine "Reactions to tyramine (an amino acid-like molecule) or phenylalanine (another amino acid-like molecule) can result from eating the following foods: Fermented cheeses Fermented Sausage Chocolate Sour Cream Red wine Avocado Beer Raspberries Yeast Picked Herring Symptoms of tyramine intolerance can include urticaria (hives), angioedema (localized swelling due to fluid retention), migraines, wheezing, and even asthma. In fact, some researchers suggest that as many as 20 percent of migraines are caused by food intolerance or allergy, and tyramine intolerance is one of the most common of these toxic food responses." Here is an old thread on tyramine and especially how it can trigger headaches. https://www.celiac.com/forums/topic/95457-headache-culprit-is-tyramine/ I would also suggest your research a low histamine food diet.  Rashes/hives etc. can be triggered my disregulaton of histamine in the body. The other thing in chocolate that might be causing your problems is Sulfites. Here is a website dedicated to a Sulftie allergy. http://www.allergy-details.com/sulfites/foods-contain-sulfites/ Chocolate bars are on their list of sulfite contaning foods but probably most noted in dried fruits and red wine. Knitty Kitty on this board knows alot about a sulfite allergy. I want to go back to the possible dairy allergy for a second as a possible trigger. . .because it has been established as connected to DH . . .it is just not well known. Here is current research (as I said earlier) most dairy allergies are studied in children but it does occur in approx. 10 pct of the GP unless your of Asian descent where it is much more common. https://www.ncbi.nlm.nih.gov/pubmed/29555204 quoting the new research from this year on children. "When CMP (Cow's Milk Protein) was re-introduced, anti-tTG increased, and returned to normal after the CMP was withdrawn again." and if adults can also (though rarely) it seem develop "Adult onset of cow's milk protein allergy with small‐intestinal mucosal IgE mast cells" (see research linked above) as the research shows  you should at least trial removing dairy from your diet if you haven't already and see if your DH doesn't come back when you re-introduce it. It just takes 15 or 20 years for medical doctor' to incorporate new research/thinking into clinical practice.  And note the research on this happening in adults is 20+ years old and as far I know doctor's . . . are not aware of this.  I know I wasn't until recently and I research things alot of to help myself and my friends. But I know you can't do what you don't know about.  So this is why I am trying to share what I learned so that other might be helped and this research might not  lay hidden another 20 years before doctor's and their Celiac/DH patients become aware of it. And if it helps you come back on the board and let us know so it can help others too! If it helps you it will/can help someone else! if they know it helped you then they will/can have hope it might help them too and why I share and research these things for others'. . . who don't know or don't have time to research this for themselves. I hope this is helpful but it is not medical advice. Good luck on your continued journey. I know this is a lot of information to digest at one time but I hope at least some of if it helpful and you at least have a better idea of what in your chocolate could be causing your DH (idiopathic) as the doctor's say (of an unknown cause mild) DH symptom's. Or at least it is not commonly known yet that Milk can also cause trigger (DH) in children and adults who have a Milk allergy undiagnosed. . .because we don't don't typically think  or associate it with adults like maybe we should if we are not of Asian descent. Maureen if this doesn't help you you might want to start a thread in the DH section of the forum. As always  2 Timothy 2: 7   “Consider what I say; and the Lord give thee understanding in all things” this included. Posterboy by the grace of God,
    • I hooe you can get some answers with your new GI doc.
    • Many of us deal with doctor issues and diagnosis, you got a really bad draw indeed. Most doctors dismiss Celiac as their is no money in the cure for them IE a gluten free diet and not medications.

      Keep up updated on your new doctor and testing, good to see you finally found one that listens and can help, I got through on doc #5 I think it was.
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