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    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. Dunne C, O'Mahony L, Murphy L, Thornton G, Morrissey D, O'Halloran S, Feeney M, Flynn S, Fitzgerald G, Daly C, Kiely B, O'Sullivan GC, Shanahan F, Collins JK. In vitro selection criteria for probiotic bacteria of human origin: correlation with in vivo findings. Am J Clin Nutr 2001 Feb;73(2 Suppl):386S-392S. Mai V, Morris JG Jr. Colonic bacterial flora: changing understandings in the molecular age. J Nutr 2004 Feb;134(2):459-64 Gronlund MM, Arvilommi H, Kero P, Lehtonen OP, Isolauri E. Importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged 0-6 months. Arch Dis Child Fetal Neonatal Ed 2000 Nov;83(3):F186-92. Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. Molecular analysis of commensal host-microbial relationships in the intestine. Science 2001 Feb 2;291(5505):881-4. Hooper LV, Xu J, Falk PG, Midtvedt T, Gordon JI. A molecular sensor that allows a gut commensal to control its nutrient foundation in a competitive ecosystem. Proc Natl Acad Sci U S A 1999 Aug 17;96(17):9833-8. Stappenbeck TS, Hooper LV, Gordon JI. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc Natl Acad Sci U S A 2002 Nov 26;99(24):15451-5. Hooper LV, Stappenbeck TS, Hong CV, Gordon JI. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nat Immunol 2003 Mar;4(3):269-73. Lanning D, Sethupathi P, Rhee KJ, Zhai SK, Knight KL. Intestinal microflora and diversification of the rabbit antibody repertoire. J Immunol 2000 Aug 15;165(4):2012-9. Rhee KJ, Sethupathi P, Driks A, Lanning DK, Knight KL. Role of commensal bacteria in development of gut-associated lymphoid tissues and preimmune antibody repertoire. J Immunol 2004 Jan 15;172(2):1118-24. Garcia-Lafuente A, Antolin M, Guarner F, Crespo E, Malagelada JR. Modulation of colonic barrier function by the composition of the commensal flora in the rat. Gut 2001 Apr;48(4):503-7. Bai AP, Ouyang Q, Zhang W, Wang CH, Li SF. Probiotics inhibit TNF-alpha-induced interleukin-8 secretion of HT29 cells. World J Gastroenterol 2004 Feb 1;10(3):455-7. Guarner F, Malagelada JR. Gut flora in health and disease. Lancet 2003 Feb 8;361(9356):512-9. Hill MJ. Intestinal flora and endogenous vitamin synthesis. Eur J Cancer Prev 1997 Mar;6 Suppl 1:S43-5. Card T, Logan RF, Rodrigues LC, Wheeler JG. Antibiotic use and the development of Crohn's disease. Gut 2004 Feb;53(2):246-50. Sollid LM. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2002 Sep;2(9):647-55. Dewar D, Pereira SP, Ciclitira PJ. The pathogenesis of coeliac disease. Int J Biochem Cell Biol 2004 Jan;36(1):17-24. Farrell RJ, Kelly CP. Celiac sprue. N Engl J Med 2002 Jan 17;346(3):180-8. Daum S, Bauer U, Foss HD, Schuppan D, Stein H, Riecken EO, Ullrich R. 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.

    Jefferson Adams

    Patients Diagnosed in Childhood Might Evolve toward Latency on a Normal Diet
    Celiac.com 05/23/2007 - The results of a study recently published in the journal Gut indicate that some people who suffer from celiac disease might not need to remain on a gluten free diet for their entire lives, and that some celiac patients might be able to safely introduce gluten containing foods without suffering a relapse.
    Previous Studies Showing Positive Response to Wheat Introduction in Patients with Celiac Disease are Promising, But Incomplete
    Several studies have shown that some patients diagnosed with celiac disease in childhood were able to remain on a gluten-containing diet after gluten challenge without suffering a relapse. However, most of these studies included a small number of patients, or followed the patients for only a short period after gluten was reintroduced into their diets.
    These previous studies also limited their evaluation largely to assessment of celiac disease serology and histology of duodenal biopsies, and did not attempt to identify what factors might predict the development of tolerance to gluten.
    Determining Long-term Response to Gluten Consumption in Celiac Disease Patients
    A research team made up of doctors Tamara Matysiak-Budnik (1), Georgia Malamut (1,2), Natacha Patey-Mariaud de Serre (3), Etienne Grosdidier (2), Sylvie Seguier (3), Nicole Brousse (3), Sophie Caillat-Zucman (4), Nadine Cerf-bensussan (1), Jacques Schmitz (5) and Christophe Cellier (1,2), set out to determine whether children diagnosed with celiac disease must follow a gluten free diet for life.
    To determine the effects of reintroducing gluten into the diets of celiac patients, the research team set out to monitor the clinical and physical progress of adult celiac patients who had been diagnosed as children, who underwent a gluten challenge, and who were asymptomatic.
    The study focused on a specific group of patients, all but two of whom were diagnosed as children and followed until adulthood in the Department of Pediatric Gastroenterology in Necker Hospital and thereafter at the Georges Pompidou European Hospital in Paris; after which, they were entered into a local register of adult celiac patients and were recruited for the study based on two criteria: celiac disease diagnosed in childhood; and adherence to a normal diet.
    The patients in the study were from 18 to 65 years old, and had been diagnosed with celiac disease in childhood. The research team recorded data in the following categories: biological parameters of malabsorption; bone mineral density; clinical celiac status; gluten intake; HLA genotype; serological markers of celiac disease; as well as histological and immuno-histochemical parameters in duodenal biopsies.

    Results Show 20% Long-term Latency in Celiac Patients who Eat Normal Diet
    Of those studied, 61 patients had returned to a normal diet, and were asymptomatic. 48 showed various degrees of villous atrophy (silent celiac disease), and 13 had no detectable atrophy (latent celiac disease) on duodenal biopsies. Compared to those with silent celiac disease, patients with latent celiac disease showed markedly less osteopenia/osteoporosis [1/9 (11%) versus 23/33 (70%), p<0.001)], and lower TcR- + intraepithelial T cell counts (38±20 vs. 55±15, p<0.01).
    Patients with latent celiac disease had a lower mean age at the time of their first gluten free diet compared to patients with silent celiac disease (14.4±5 vs 40.1±47 months, p<0.05).
    Compared to the seven control patients on a long-term gluten free diet, the latent patients did not differ significantly, except for a higher frequency of celiac disease-specific serum antibodies. However, a follow-up found that two of the patients with latent celiac disease had suffered a clinical and histological relapse.
    Results showed that of those patients who remained asymptomatic after the reintroduction of gluten, 20% showed long-term latency.
    The study concludes that some patients with celiac disease may not need to remain on a life-long gluten free diet, and that some may indeed be able to safely reintroduce gluten into their diets with no adverse effects. However, the latency patients may experience may be transient, and therefore a regular follow-up is necessary. Also, patients with silent celiac disease should remain on a gluten free diet.
    Participating hospitals:
    (1) INSERM, U793, Faculté de Médecine René Descartes, IFR94, Paris, France.
    (2) AP-HP, H&OCIRC;pital Européen Georges Pompidou, Department of Hepato-Gastroenterology,
    Paris, France.
    (3) AP-HP, H&OCIRC;pital Necker-Enfants Malades, Department of Pathology, Paris, France.
    (4) INSERM, Equipe Avenir, Faculté de Médecine René Descartes, Paris, France.
    (5) AP-HP, H&OCIRC;pital Necker-Enfants Malades, Department of Pediatric Gastroenterology, Paris, France.
    Gut 2006;13(10).
    Comments on this Study by Ron Hoggan
    This is dressed up like a new finding, but it isn't. There are a number of studies that show similar findings. Part of that problem lies in the interpretation of the biopsies, and part of the problem arises out of failing to recognize the variable nature of the disease. It has long been known to wax and wane for reasons beyond our ken. Samuel Gee (1888) and Gibbons (1889) both reported the cyclic nature of their patients symptoms. They cited a study to support the idea of a two year rule saying that relapse would usually occur within two years, yet Kuitunen P, Savilahti E, Verkasalo M., in Late mucosal relapse in a boy with coeliac disease and cows milk allergy. Acta Paediatr Scand. 1986 Mar;75(2):340-2. reported one patient who at 4.3 years on a normal diet showed normal villous architecture. It was not until a follow-up biopsy at more than 8 years of eating a gluten-containing diet that he showed villous atrophy. These findings, along with all the other studies that have shown long delays in some patients before relapsing, argue strongly for Michael N. Marsh's position that we should concentrate on treating any immune system that is sensitized to gluten with a gluten-free diet. His rectal challenge is an excellent tool for identifying such sensitized immune systems. Dr. Fines fecal antibody test probably fits into the same category. The underlying assumption is that the biopsy will identify all cases of intestinal lesion regardless of the possibility of patchy lesions that are well documented in the literature. They deal with increased IEL counts as if they were a feature of latent celiac disease when that is not the case. There are several other points on which this study falters. They admit that the latency can be transient. Unfortunately, they have not exchanged emails with people where they have returned to eating gluten and have developed an abdominal cancer. I exchanged emails with such a young man who blamed himself for having killed himself with his carelessness about his diet. How awful that was for him! Yet these authors seem to think it is quite acceptable for patients to indulge during their latency periods and only consider a diet if there is a relapse of intestinal lesion.
     

    Jefferson Adams
    Celiac.com 02/04/2013 - Ever wonder what happens to all those celiac disease patients who volunteer to do a gluten-challenge in the name of science? Well, the short answer is that they likely suffer, and may incur gut damage, at least in the short term.
    A team of researchers looking for ways to reduce or eliminate that problem recently conducted a study using larazotide acetate, a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated problems.
    The research team included C. P. Kelly, P. H. R. Green, J. A. Murray, A. DiMarino, A. Colatrella, D. A. Leffler, T. Alexander, R. Arsenescu, F. Leon, J. G. Jiang, L. A. Arterburner, B. M. Paterson, R. N. and Fedorak. They are affiliated with the Celiac Center of Beth Israel Deaconess Medical Center at Harvard Medical School in Boston, the Celiac Disease Center at Columbia University in New York, NY, the Division of Gastroenterology and Hepatology at the Mayo Clinic in Rochester, MN, Thomas Jefferson University Hospital in Philadelphia, PA, the Pittsburgh Gastroenterology Associates in Pittsburgh, PA, with Gastrointestinal Specialists of Troy, MI, the Department of Internal Medicine at the University of Kentucky, in Lexington, KY, with Alba Therapeutics Corporation in Baltimore, MD, and with the Division of Gastroenterology at the University of Alberta in Edmonton, AB.
    The team wanted to find out how well larazotide acetate worked and how well it was tolerated by celiac disease patients undergoing a gluten challenge.
    To do this, the team conducted an exploratory, double-blind, randomized, placebo-controlled study that included 184 patients who maintained a gluten-free diet before and during the study.
    After a gluten-free diet run-in, the team randomly divided patients into groups and gave them either larazotide acetate in doses of 1, 4, or 8 mg three times daily, or a placebo. Both groups also received 2.7 grams of gluten daily for six weeks.
    The team then assessed ratios of lactulose-to-mannitol (LAMA), an experimental biomarker of intestinal permeability, and measured clinical symptoms by Gastrointestinal Symptom Rating Scale (GSRS) and anti-transglutaminase antibody levels.
    They found no significant differences in LAMA ratios between larazotide acetate and placebo groups. Larazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS (P = 0.002 vs. placebo).
    They did find that the average ratio of anti-tissue transglutaminase IgA levels was 19.0 over baseline in the placebo group compared with 5.78 (P = 0.010) in the 1mg larazotide acetate group, 3.88 (P = 0.005) in the 4mg larazotide acetate group, and 7.72 (P = 0.025) in the 8mg larazotide acetate group.
    Both the larazotide acetate and placebo groups showed similar rates of "adverse events."
    Overall, the team found that larazotide acetate reduced gluten-induced immune reactivity and symptoms in celiac disease patients undergoing gluten challenge and was generally well tolerated.
    However, the team found no significant difference in LAMA ratios between the larazotide acetate and placebo groups.
    Even though they did not find anything revolutionary, the results and design of their study will likely be helpful in shaping future gluten-challenge studies in patients with celiac disease.
    Source: 
    Aliment Pharmacol Ther. 2013;37(2):252-262.

    Jefferson Adams
    Celiac.com 06/16/2014 - Differentiating between celiac disease and non-celiac gluten sensitivity (NCGS) is important for appropriate treatment, but is often challenging.
    A team of researchers recently set out to assess the best way to distinguish between celiac disease and non-gluten sensitivity. The research team included Toufic A Kabbani, Rohini R Vanga, Daniel A Leffler, Javier Villafuerte-Galvez, Kumar Pallav, Joshua Hansen, Rupa Mukherjee, Melinda Dennis and Ciaran P Kelly.
    For their study, the team reviewed records for 238 patients who were assessed for symptoms responsive to gluten restriction without having celiac disease ruled in or out. For each patient, clinicians noted the demographic information, presenting symptoms, serologic, genetic, and histologic data, nutrient deficiencies, personal history of autoimmune diseases, and family history of celiac disease.
    They define NCGS as symptoms responsive to a gluten-free diet, together with negative celiac blood tests and negative duodenal biopsies while on a gluten-containing diet, or negative human leukocyte antigen (HLA) DQ2/DQ8 testing. Of the 238 patients in the study, 101 had celiac disease, 125 had NCGS, 9 had non-celiac enteropathy, and 3 remained undetermined. Nearly 70% of celiac disease subjects suffered symptoms of malabsorption compared with just under 25% of the NCGS subjects (P<0.0001).
    In addition, the patients with celiac disease were far more likely to have a family history of celiac disease (P=0.004), personal history of autoimmune diseases (P=0.002), or nutrient deficiencies (P<0.0001).
    The positive likelihood ratio for celiac disease diagnosis of a >2× upper limit of normal IgA trans-glutaminase antibody (tTG) or IgA/IgG deaminated gliadan peptide antibody (DGP) with clinical response to a gluten-free diet was 130 (confidence interval (CI): 18.5–918.3).
    The positive likelihood ratio of the combination of gluten-responsive symptoms and negative IgA tTG or IgA/IgG DGP on a regular diet for NCGS was 9.6 (CI: 5.5–16.9).
    When individuals with negative IgA tTG or IgA/IgG DGP also lacked symptoms of malabsorption (weight loss, diarrhea, and nutrient deficiencies) and celiac disease risk factors (personal history of autoimmune diseases and family history of celiac disease), the positive likelihood ratio for NCGS increased to 80.9.
    Based on their findings, the team developed a diagnostic algorithm to distinguish celiac disease from NCGS.
    People with negative celiac blood tests (IgA tTG or IgA/IgG DGP, who are eating a regular gluten-containing diet, are unlikely to have celiac disease.
    Those with negative serology who show no clinical signs of malabsorption, and show no celiac disease risk factors, are highly likely to have NCGS and may not require further testing. Those with positive blood tests should undergo HLA typing to determine the need for biopsy.
    Source:
    The American Journal of Gastroenterology 109, 741-746 (May 2014) doi:10.1038/ajg.2014.41

  • Recent Articles

    Connie Sarros
    Celiac.com 04/21/2018 - Dear Friends and Readers,
    I have been writing articles for Scott Adams since the 2002 Summer Issue of the Scott-Free Press. The Scott-Free Press evolved into the Journal of Gluten Sensitivity. I felt honored when Scott asked me ten years ago to contribute to his quarterly journal and it's been a privilege to write articles for his publication ever since.
    Due to personal health reasons and restrictions, I find that I need to retire. My husband and I can no longer travel the country speaking at conferences and to support groups (which we dearly loved to do) nor can I commit to writing more books, articles, or menus. Consequently, I will no longer be contributing articles to the Journal of Gluten Sensitivity. 
    My following books will still be available at Amazon.com:
    Gluten-free Cooking for Dummies Student's Vegetarian Cookbook for Dummies Wheat-free Gluten-free Dessert Cookbook Wheat-free Gluten-free Reduced Calorie Cookbook Wheat-free Gluten-free Cookbook for Kids and Busy Adults (revised version) My first book was published in 1996. My journey since then has been incredible. I have met so many in the celiac community and I feel blessed to be able to call you friends. Many of you have told me that I helped to change your life – let me assure you that your kind words, your phone calls, your thoughtful notes, and your feedback throughout the years have had a vital impact on my life, too. Thank you for all of your support through these years.

    Jefferson Adams
    Celiac.com 04/20/2018 - A digital media company and a label data company are teaming up to help major manufacturers target, reach and convert their desired shoppers based on dietary needs, such as gluten-free diet. The deal could bring synergy in emerging markets such as the gluten-free and allergen-free markets, which represent major growth sectors in the global food industry. 
    Under the deal, personalized digital media company Catalina will be joining forces with Label Insight. Catalina uses consumer purchases data to target shoppers on a personal base, while Label Insight works with major companies like Kellogg, Betty Crocker, and Pepsi to provide insight on food label data to government, retailers, manufacturers and app developers.
    "Brands with very specific product benefits, gluten-free for example, require precise targeting to efficiently reach and convert their desired shoppers,” says Todd Morris, President of Catalina's Go-to-Market organization, adding that “Catalina offers the only purchase-based targeting solution with this capability.” 
    Label Insight’s clients include food and beverage giants such as Unilever, Ben & Jerry's, Lipton and Hellman’s. Label Insight technology has helped the Food and Drug Administration (FDA) build the sector’s very first scientifically accurate database of food ingredients, health attributes and claims.
    Morris says the joint partnership will allow Catalina to “enhance our dataset and further increase our ability to target shoppers who are currently buying - or have shown intent to buy - in these emerging categories,” including gluten-free, allergen-free, and other free-from foods.
    The deal will likely make for easier, more precise targeting of goods to consumers, and thus provide benefits for manufacturers and retailers looking to better serve their retail food customers, especially in specialty areas like gluten-free and allergen-free foods.
    Source:
    fdfworld.com

    Jefferson Adams
    Celiac.com 04/19/2018 - Previous genome and linkage studies indicate the existence of a new disease triggering mechanism that involves amino acid metabolism and nutrient sensing signaling pathways. In an effort to determine if amino acids might play a role in the development of celiac disease, a team of researchers recently set out to investigate if plasma amino acid levels differed among children with celiac disease compared with a control group.
     
    The research team included Åsa Torinsson Naluai, Ladan Saadat Vafa, Audur H. Gudjonsdottir, Henrik Arnell, Lars Browaldh, and Daniel Agardh. They are variously affiliated with the Institute of Biomedicine, Department of Microbiology & Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; the Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; the Department of Pediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital and Division of Pediatrics, CLINTEC, Karolinska Institute, Stockholm, Sweden; the Department of Clinical Science and Education, Karolinska Institute, Sodersjukhuset, Stockholm, Sweden; the Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden; the Diabetes & Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden; and with the Nathan S Kline Institute in the U.S.A.
    First, the team used liquid chromatography-tandem mass spectrometry (LC/MS) to analyze amino acid levels in fasting plasma samples from 141 children with celiac disease and 129 non-celiac disease controls. They then crafted a general linear model using age and experimental effects as covariates to compare amino acid levels between children with celiac disease and non-celiac control subjects.
    Compared with the control group, seven out of twenty-three children with celiac disease showed elevated levels of the the following amino acids: tryptophan; taurine; glutamic acid; proline; ornithine; alanine; and methionine.
    The significance of the individual amino acids do not survive multiple correction, however, multivariate analyses of the amino acid profile showed significantly altered amino acid levels in children with celiac disease overall and after correction for age, sex and experimental effects.
    This study shows that amino acids can influence inflammation and may play a role in the development of celiac disease.
    Source:
    PLoS One. 2018; 13(3): e0193764. doi: & 10.1371/journal.pone.0193764

    Jefferson Adams
    Celiac.com 04/18/2018 - To the relief of many bewildered passengers and crew, no more comfort turkeys, geese, possums or other questionable pets will be flying on Delta or United without meeting the airlines' strict new requirements for service animals.
    If you’ve flown anywhere lately, you may have seen them. People flying with their designated “emotional support” animals. We’re not talking genuine service animals, like seeing eye dogs, or hearing ear dogs, or even the Belgian Malinois that alerts its owner when there is gluten in food that may trigger her celiac disease.
    Now, to be honest, some of those animals in question do perform a genuine service for those who need emotional support dogs, like veterans with PTSD.
    However, many of these animals are not service animals at all. Many of these animals perform no actual service to their owners, and are nothing more than thinly disguised pets. Many lack proper training, and some have caused serious problems for the airlines and for other passengers.
    Now the major airlines are taking note and introducing stringent requirements for service animals.
    Delta was the first to strike. As reported by the New York Times on January 19: “Effective March 1, Delta, the second largest US airline by passenger traffic, said it will require passengers seeking to fly with pets to present additional documents outlining the passenger’s need for the animal and proof of its training and vaccinations, 48 hours prior to the flight.… This comes in response to what the carrier said was a 150 percent increase in service and support animals — pets, often dogs, that accompany people with disabilities — carried onboard since 2015.… Delta said that it flies some 700 service animals a day. Among them, customers have attempted to fly with comfort turkeys, gliding possums, snakes, spiders, and other unusual pets.”
    Fresh from an unsavory incident with an “emotional support” peacock incident, United Airlines has followed Delta’s lead and set stricter rules for emotional support animals. United’s rules also took effect March 1, 2018.
    So, to the relief of many bewildered passengers and crew, no more comfort turkeys, geese, possums or other questionable pets will be flying on Delta or United without meeting the airlines' strict new requirements for service and emotional support animals.
    Source:
    cnbc.com

    admin
    WHAT IS CELIAC DISEASE?
    Celiac disease is an autoimmune condition that affects around 1% of the population. People with celiac disease suffer an autoimmune reaction when they consume wheat, rye or barley. The immune reaction is triggered by certain proteins in the wheat, rye, or barley, and, left untreated, causes damage to the small, finger-like structures, called villi, that line the gut. The damage occurs as shortening and villous flattening in the lamina propria and crypt regions of the intestines. The damage to these villi then leads to numerous other issues that commonly plague people with untreated celiac disease, including poor nutritional uptake, fatigue, and myriad other problems.
    Celiac disease mostly affects people of Northern European descent, but recent studies show that it also affects large numbers of people in Italy, China, Iran, India, and numerous other places thought to have few or no cases.
    Celiac disease is most often uncovered because people experience symptoms that lead them to get tests for antibodies to gluten. If these tests are positive, then the people usually get biopsy confirmation of their celiac disease. Once they adopt a gluten-free diet, they usually see gut healing, and major improvements in their symptoms. 
    CLASSIC CELIAC DISEASE SYMPTOMS
    Symptoms of celiac disease can range from the classic features, such as diarrhea, upset stomach, bloating, gas, weight loss, and malnutrition, among others.
    LESS OBVIOUS SYMPTOMS
    Celiac disease can often less obvious symptoms, such fatigue, vitamin and nutrient deficiencies, anemia, to name a few. Often, these symptoms are regarded as less obvious because they are not gastrointestinal in nature. You got that right, it is not uncommon for people with celiac disease to have few or no gastrointestinal symptoms. That makes spotting and connecting these seemingly unrelated and unclear celiac symptoms so important.
    NO SYMPTOMS
    Currently, most people diagnosed with celiac disease do not show symptoms, but are diagnosed on the basis of referral for elevated risk factors. 

    CELIAC DISEASE VS. GLUTEN INTOLERANCE
    Gluten intolerance is a generic term for people who have some sort of sensitivity to gluten. These people may or may not have celiac disease. Researchers generally agree that there is a condition called non-celiac gluten sensitivity. That term has largely replaced the term gluten-intolerance. What’s the difference between celiac disease and non-celiac gluten-sensitivity? 
    CELIAC DISEASE VS. NON-CELIAC GLUTEN SENSITIVITY (NCGS)
    Gluten triggers symptoms and immune reactions in people with celiac disease. Gluten can also trigger symptoms in some people with NCGS, but the similarities largely end there.

    There are four main differences between celiac disease and non-celiac gluten sensitivity:
    No Hereditary Link in NCGS
    Researchers know for certain that genetic heredity plays a major role in celiac disease. If a first-degree relative has celiac disease, then you have a statistically higher risk of carrying genetic markers DQ2 and/or DQ8, and of developing celiac disease yourself. NCGS is not known to be hereditary. Some research has shown certain genetic associations, such as some NCGS patients, but there is no proof that NCGS is hereditary. No Connection with Celiac-related Disorders
    Unlike celiac disease, NCGS is so far not associated with malabsorption, nutritional deficiencies, or a higher risk of autoimmune disorders or intestinal malignancies. No Immunological or Serological Markers
    People with celiac disease nearly always test positive for antibodies to gluten proteins. Researchers have, as yet, identified no such antobodies or serologic markers for NCGS. That means that, unlike with celiac disease, there are no telltale screening tests that can point to NCGS. Absence of Celiac Disease or Wheat Allergy
    Doctors diagnose NCGS only by excluding both celiac disease, an IgE-mediated allergy to wheat, and by the noting ongoing adverse symptoms associated with gluten consumption. WHAT ABOUT IRRITABLE BOWEL SYNDROME (IBS) AND IRRITABLE BOWEL DISEASE (IBD)?
    IBS and IBD are usually diagnosed in part by ruling out celiac disease. Many patients with irritable bowel syndrome are sensitive to gluten. Many experience celiac disease-like symptoms in reaction to wheat. However, patients with IBS generally show no gut damage, and do not test positive for antibodies to gliadin and other proteins as do people with celiac disease. Some IBS patients also suffer from NCGS.

    To add more confusion, many cases of IBS are, in fact, celiac disease in disguise.

    That said, people with IBS generally react to more than just wheat. People with NCGS generally react to wheat and not to other things, but that’s not always the case. Doctors generally try to rule out celiac disease before making a diagnosis of IBS or NCGS. 
    Crohn’s Disease and celiac disease share many common symptoms, though causes are different.  In Crohn’s disease, the immune system can cause disruption anywhere along the gastrointestinal tract, and a diagnosis of Crohn’s disease typically requires more diagnostic testing than does a celiac diagnosis.  
    Crohn’s treatment consists of changes to diet and possible surgery.  Up to 10% of Crohn's patients can have both of conditions, which suggests a genetic connection, and researchers continue to examine that connection.
    Is There a Connection Between Celiac Disease, Non-Celiac Gluten Sensitivity and Irritable Bowel Syndrome? Large Number of Irritable Bowel Syndrome Patients Sensitive To Gluten Some IBD Patients also Suffer from Non-Celiac Gluten Sensitivity Many Cases of IBS and Fibromyalgia Actually Celiac Disease in Disguise CELIAC DISEASE DIAGNOSIS
    Diagnosis of celiac disease can be difficult. 

    Perhaps because celiac disease presents clinically in such a variety of ways, proper diagnosis often takes years. A positive serological test for antibodies against tissue transglutaminase is considered a very strong diagnostic indicator, and a duodenal biopsy revealing villous atrophy is still considered by many to be the diagnostic gold standard. 
    But this idea is being questioned; some think the biopsy is unnecessary in the face of clear serological tests and obvious symptoms. Also, researchers are developing accurate and reliable ways to test for celiac disease even when patients are already avoiding wheat. In the past, patients needed to be consuming wheat to get an accurate test result. 
    Celiac disease can have numerous vague, or confusing symptoms that can make diagnosis difficult.  Celiac disease is commonly misdiagnosed by doctors. Read a Personal Story About Celiac Disease Diagnosis from the Founder of Celiac.com Currently, testing and biopsy still form the cornerstone of celiac diagnosis.
    TESTING
    There are several serologic (blood) tests available that screen for celiac disease antibodies, but the most commonly used is called a tTG-IgA test. If blood test results suggest celiac disease, your physician will recommend a biopsy of your small intestine to confirm the diagnosis.
    Testing is fairly simple and involves screening the patients blood for antigliadin (AGA) and endomysium antibodies (EmA), and/or doing a biopsy on the areas of the intestines mentioned above, which is still the standard for a formal diagnosis. Also, it is now possible to test people for celiac disease without making them concume wheat products.

    BIOPSY
    Until recently, biopsy confirmation of a positive gluten antibody test was the gold standard for celiac diagnosis. It still is, but things are changing fairly quickly. Children can now be accurately diagnosed for celiac disease without biopsy. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide.

    WHY A GLUTEN-FREE DIET?
    Currently the only effective, medically approved treatment for celiac disease is a strict gluten-free diet. Following a gluten-free diet relieves symptoms, promotes gut healing, and prevents nearly all celiac-related complications. 
    A gluten-free diet means avoiding all products that contain wheat, rye and barley, or any of their derivatives. This is a difficult task as there are many hidden sources of gluten found in the ingredients of many processed foods. Still, with effort, most people with celiac disease manage to make the transition. The vast majority of celiac disease patients who follow a gluten-free diet see symptom relief and experience gut healing within two years.
    For these reasons, a gluten-free diet remains the only effective, medically proven treatment for celiac disease.
    WHAT ABOUT ENZYMES, VACCINES, ETC.?
    There is currently no enzyme or vaccine that can replace a gluten-free diet for people with celiac disease.
    There are enzyme supplements currently available, such as AN-PEP, Latiglutetenase, GluteGuard, and KumaMax, which may help to mitigate accidental gluten ingestion by celiacs. KumaMax, has been shown to survive the stomach, and to break down gluten in the small intestine. Latiglutenase, formerly known as ALV003, is an enzyme therapy designed to be taken with meals. GluteGuard has been shown to significantly protect celiac patients from the serious symptoms they would normally experience after gluten ingestion. There are other enzymes, including those based on papaya enzymes.

    Additionally, there are many celiac disease drugs, enzymes, and therapies in various stages of development by pharmaceutical companies, including at least one vaccine that has received financial backing. At some point in the not too distant future there will likely be new treatments available for those who seek an alternative to a lifelong gluten-free diet. 

    For now though, there are no products on the market that can take the place of a gluten-free diet. Any enzyme or other treatment for celiac disease is intended to be used in conjunction with a gluten-free diet, not as a replacement.

    ASSOCIATED DISEASES
    The most common disorders associated with celiac disease are thyroid disease and Type 1 Diabetes, however, celiac disease is associated with many other conditions, including but not limited to the following autoimmune conditions:
    Type 1 Diabetes Mellitus: 2.4-16.4% Multiple Sclerosis (MS): 11% Hashimoto’s thyroiditis: 4-6% Autoimmune hepatitis: 6-15% Addison disease: 6% Arthritis: 1.5-7.5% Sjögren’s syndrome: 2-15% Idiopathic dilated cardiomyopathy: 5.7% IgA Nephropathy (Berger’s Disease): 3.6% Other celiac co-morditities include:
    Crohn’s Disease; Inflammatory Bowel Disease Chronic Pancreatitis Down Syndrome Irritable Bowel Syndrome (IBS) Lupus Multiple Sclerosis Primary Biliary Cirrhosis Primary Sclerosing Cholangitis Psoriasis Rheumatoid Arthritis Scleroderma Turner Syndrome Ulcerative Colitis; Inflammatory Bowel Disease Williams Syndrome Cancers:
    Non-Hodgkin lymphoma (intestinal and extra-intestinal, T- and B-cell types) Small intestinal adenocarcinoma Esophageal carcinoma Papillary thyroid cancer Melanoma CELIAC DISEASE REFERENCES:
    Celiac Disease Center, Columbia University
    Gluten Intolerance Group
    National Institutes of Health
    U.S. National Library of Medicine
    Mayo Clinic
    University of Chicago Celiac Disease Center