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Found 11 results

  1. 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."
  2. Celiac.com 10/30/2006 - Two recent scientific publications have now shown that a rotavirus protein may be linked to celiac disease through a molecular mimicry mechanism and that the risk of developing celiac disease appears to increase in children in relation to the number of rotavirus infections. What does this mean? Does rotavirus cause celiac disease? Research has not yet determined the exact role of rotavirus in celiac disease. Researchers found, in active celiac disease, a subset of anti-tTG IgA antibodies recognize the rotavirus protein, VP-7. This means, in celiacs, that the immune system appears to respond to the rotavirus protein the same as it would to a gluten peptide. Hence, a rotavirus infection might, in part, look just like a large dose of ingested gluten in individuals predisposed to celiac disease. In the study, children genetically susceptible to celiac disease seemed to develop celiac disease in greater numbers after experiencing rotavirus infections than did those children who did not have rotavirus infections. Note that children NOT experiencing a rotavirus infection STILL developed celiac disease. Hence, some OTHER mechanism must be the actual CAUSE of celiac disease, NOT rotavirus. The fact is, the study does NOT show whether the children having rotavirus infections would have eventually developed celiac disease if they were NOT infected with rotavirus (and no study would be able to do so.) The study followed the children from infancy. The study needs to follow the children for many more years to see if the risk rates of children developing celiac disease who experience or do not experience rotavirus infections eventually match. This would eliminate rotavirus as a significant risk factor. Think of it this way. If instead of experiencing rotavirus infection, some children were fed large quantities of gluten and some children were fed small amounts of gluten, wouldnt it be expected that children fed MORE gluten would be more likely to develop celiac disease SOONER than the children receiving LESS gluten? Now, due to molecular mimicry, think of a rotavirus infection as being a large daily feeding of gluten. Hence, children experiencing rotavirus infections would be more likely to develop celiac disease SOONER than those children who are uninfected. Eventually, ALL children who would have developed celiac disease, sooner or later, would develop the disease. A previous study found a molecular mimicry mechanism may associate a rotavirus protein with celiac disease. Now a new study of rotavirus antibodies in 1,931 children carrying HLA alleles for celiac disease in the Denver metropolitan area seems to show that the risk of developing celiac disease increases as the frequency of rotavirus infection increases. The study followed children from infancy, taking blood samples at 9, 15, and 24 months and annually, thereafter. 54 children developed celiac disease at a median age of 4.4 years. The study found "Frequent rotavirus infections predicted a higher risk of celiac disease autoimmunity (compared with zero infections, rate ratio 1.94, 95% confidence interval [CI] 0.39-9.56, for one infection and rate ratio 3.76, 95% CI 0.76-18.7, for 2 or more infections, rate ratio for trend per increase in number of infections = 1.94, 95% CI 1.04-3.61, p= 0.037)." Could rotavirus infection as an adult trigger celiac disease? Not likely. Though symptoms and diagnosis of celiac disease may come late in life, it has been shown celiac disease begins in early childhood. The prevalence of celiac disease in studies of children is the same as the prevalence of celiac disease in adults and does not increase with age. New Study: Am J Gastroenterol. 2006 Oct;101(10):2333-40. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Stene LC, Honeyman MC, Hoffenberg EJ, Haas JE, Sokol RJ, Emery L, Taki I, Norris JM, Erlich HA, Eisenbarth GS, Rewers M. Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado. Previous study: PLoS Medicine Volume 3, Issue 9, SEPTEMBER 2006 In Celiac Disease, a Subset of Autoantibodies against Transglutaminase Binds Toll-Like Receptor 4 and Induces Activation of Monocytes Giovanna Zanoni, Riccardo Navone, Claudio Lunardi, Giuseppe Tridente, Caterina Bason, Simona Sivori, Ruggero Beri, Marzia Dolcino, Enrico Valletta, Roberto Corrocher, Antonio Puccetti
  3. Celiac.com 04/27/2006 - Liver abnormalities have been found in a high percentage of celiacs when first diagnosed, around 42% according to some studies. Gluten toxicity and increased intestinal permeability have both been suspected as a cause of liver abnormalities. Serious liver disorders, including cirrhosis, have been found in association with a number of celiac disease cases which appear to resolve upon treatment and maintaining a gluten-free diet. It is not clear whether some damage to the liver may remain long term even after maintaining a gluten-free diet. Below is an interesting study (Hepatology. 2006 Mar 23;43(4):837-846) of the effects of induced liver cirrhosis on the intestinal mucosa which results in oxidative stress and an alteration of intestinal permeability, intestinal bacteria makeup, and bacterial overgrowth. Hence not only does damage to the intestine in response to gluten often result in bacterial overgrowth, but damage to the liver by gluten may also contribute to bacterial overgrowth and mucosal alterations. Damage to the liver caused by celiac disease may also have other consequences, as the liver plays many important roles including storage and production of important compounds and proteins and the removal of fat soluble toxic substances. As we are increasingly exposed to endocrine disrupting xenobiotic environmental chemicals and toxic substances, a dysfunctional livers inability to remove fat soluble toxic substances may leave celiacs more susceptible to adverse effects from these chemicals which can accumulate in adipose (fatty) tissue. In the Winter 2006 issue of Scott Adams' Celiac.com Newsletter, I discuss in detail, in Unraveling Fibromyalgia, how a dysfunctional liver and fat soluble toxic substances accumulating in innervated and vascularlized adipose tissue in the vicinity of joints may be the cause of fibromyalgia. Bacterial overgrowth has also been found in association with fibromyalgia. But clearly, lesser degrees of fatigue, muscle and joint pain, thyroid disorders, and other symptoms could also result from liver dysfunction caused by celiac disease. The inability of the liver to remove xenobiotic chemicals may also increase the risk of breast and other cancers. Recently a new review on liver disorders and celiac disease has appeared (See below - World J Gastroenterol 2006 March 14;12(10): 1493-1502 and 1503-1508): Liver Damage and the Intestinal Mucosa. One cannot ignore the secondary effects and symptoms that liver damage may add to those symptoms caused by glutens effect on the intestinal mucosa. Those unexplained aches and pains and other symptoms and disorders which have frequently been reported by some celiacs may be a result of liver dysfunction. Some notes: Elevated liver enzymes are the result of liver enzymes released by damaged liver cells. The article cites one study stating A gluten-free diet for 1 to 10 years resulted in complete normalization of liver chemistry tests in 95% patients. Normal liver chemistry tests DO NOT necessarily mean that the liver is functioning normally and that no damage remains. See: Special Considerations in Interpreting Liver Function Tests - http://www.aafp.org/afp/990415ap/2223.html Referenced Abstracts: Hepatology. 2006 Mar 23;43(4):837-846 Intestinal mucosal alterations in rats with carbon tetrachloride-induced cirrhosis: Changes in glycosylation and luminal bacteria. Natarajan SK, Ramamoorthy P, Thomas S, Basivireddy J, Kang G, Ramachandran A, Pulimood AB, Balasubramanian KA. The Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College, Vellore, India. Spontaneous bacterial peritonitis is a major cause of mortality after liver cirrhosis. Altered permeability of the mucosa and deficiencies in host immune defenses through bacterial translocation from the intestine due to intestinal bacterial overgrowth have been implicated in the development of this complication. Molecular mechanisms underlying the process are not well known. In order to understand mechanisms involved in translocation of bacteria, this study explored the role of oxidative stress in mediating changes in intestinal mucosal glycosylation and luminal bacterial content during cirrhosis. CCl(4)-induced cirrhosis in rats led to prolonged oxidative stress in the intestine, accompanied by increased sugar content of both intestinal brush border and surfactant layers. This was accompanied by changes in bacterial flora in the gut, which showed increased hydrophobicity and adherence to the mucosa. Inhibition of xanthine oxidase using sodium tungstate or antioxidant supplementation using vitamin E reversed the oxidative stress, changes in brush border membrane sugar content, and bacterial adherence. In conclusion, oxidative stress in the intestine during cirrhosis alters mucosal glycosylation, accompanied by an increased hydrophobicity of luminal bacteria, enabling increased bacterial adherence onto epithelial cells. This might facilitate translocation across the mucosa, resulting in complications such as spontaneous bacterial peritonitis. World J Gastroenterol 2006 March 14;12(10):1503-1508 Hepatobiliary and pancreatic disorders in celiac disease Hugh James Freeman Free full text: http://www.wjgnet.com/1007-9327/12/1503.asp A variety of hepatic and biliary tract disorders may complicate the clinical course of celiac disease. Some of these have been hypothesized to share common genetic factors or have a common immunopathogenesis, such as primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune forms of hepatitis or cholangitis. Other hepatic changes in celiac disease may be associated with malnutrition resulting from impaired nutrient absorption, including hepatic steatosis. In addition, celiac disease may be associated with rare hepatic complications, such as hepatic T-cell lymphoma. Finally, pancreatic exocrine function may be impaired in celiac disease and represent a cause of treatment failure. World J Gastroenterol 2006 March 14;12(10):1493-1502 Gut flora and bacterial translocation in chronic liver disease John Almeida, Sumedha Galhenage, Jennifer Yu, Jelica Kurtovic, Stephen M Riordan Free full text: http://www.wjgnet.com/1007-9327/12/1493.asp Increasing evidence suggests that derangement of gut flora is of substantial clinical relevance to patients with cirrhosis. Intestinal bacterial overgrowth and increased bacterial translocation of gut flora from the intestinal lumen, in particular, predispose to an increased potential for bacterial infection in this group. Recent studies suggest that, in addition to their role in the pathogenesis of overt infective episodes and the clinical consequences of sepsis, gut flora contributes to the pro-inflammatory state of cirrhosis even in the absence of overt infection. Furthermore, manipulation of gut flora to augment the intestinal content of lactic acid-type bacteria at the expense of other gut flora species with more pathogenic potential may favorably influence liver function in cirrhotic patients. Here we review current concepts of the various inter-relationships between gut flora, bacterial translocation, bacterial infection, pro-inflammatory cytokine production and liver function in this group.
  4. 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.
  5. 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.
  6. 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
  7. Celiac.com 11/07/2006 – We should be hearing more about this in the news soon. A confocal laser endomicroscopy device developed by Optiscan, an Australian company, permits endoscopists to make an accurate real-time diagnosis of celiac disease, bypassing the need to take and prepare and evaluate biopsy specimens in a laboratory. This technique would allow the endoscopist to view and evaluate as many samples as needed to make a correct diagnosis and immediately give the results to the patient. This should reduce diagnostic errors. A paper on Confocal Laser Endomicroscopy in the diagnosis of Celiac disease by R. Leong et al. will be presented in Adelaide, Australia this Saturday, Oct. 14. Australian Gastroenterology Week (AGW) 2006 Hosted by the Gastroenterological Society of Australia (GESA) Adelaide Convention Centre, Adelaide, South Australia 11-14th October 2006. To be presented Oct. 14, 2006: Confocal Laser Endomicroscopy in the diagnosis of Celiac disease R Leong Optiscans unique and patented technology has miniaturized the microscopes scanning head, so that it is now so small it can fit inside the body. Once the miniaturized scanner is integrated into an endoscope to create an endomicroscope, doctors can for the first time safely and instantly get high quality images of tissue at a cellular level from their patients. This gives doctors new levels of information providing a highly magnified view of living tissue that is entirely consistent with the macroscopic views that they are used to seeing from their endoscopes. This breakthrough technology creates a vast array of new applications, both medical and industrial. Optiscans primary focus is in the medical arena, where it can provide a virtual biopsy, potentially revolutionizing current pathology and histology practices. About Optiscan http://www.optiscan.com.au/about/about_02.asp Sample Images http://www.optiscan.com.au/Technology/Images_01.asp
  8. Celiac.com 10/12/2006 - A new study examined Mayo Clinic medical records for the years 1970 through 2005 to identify eight male and five female patients, aged 45-79, showing cognitive decline within two years of onset or a severe exacerbation of symptoms of biopsy-proven celiac disease. Patients presented with amnesia, acalculia, confusion, and personality changes, and most also had ataxia or peripheral neuropathy. 4 had folate, vitamin B12 and/or vitamin E deficiencies with no improvement upon supplementation. Three improved on a gluten-free diet. It was concluded "A possible association exists between progressive cognitive impairment and celiac disease." Arch Neurol. Oct 2006;63:1440-1446 Cognitive Impairment and Celiac Disease William T. Hu, MD, PhD; Joseph A. Murray, MD; Melanie C. Greenaway, PhD; Joseph E. Parisi, MD; Keith A. Josephs, MST, MD This was a limited study. While it looked at folate and vitamins B12 and E, one major oversite of celiac disease research continues to be a dearth of knowledge about levels of essential fatty acids in celiac disease patients. Fat malabsorption is a primary symptom of celiac disease, and the consequences continue to be ignored. Meanwhile, an accumulation of evidence supports the critical role of omega-3 fatty acids in maintaining cognitive and mental health. Omega-3 supplementation has even reversed conditions such as schizophrenia in individuals, begging the question of whether it is gluten toxicity or a fatty acid deficiency that may cause schizophrenia in some celiacs. Check out these recent news stories and the Ness Foundation: Food for Thought for Alzheimers Emerges in Mediterranean Diet Why your brain needs fish The Ness Foundation (See "Lipids in Neurodevelopmental Conditions") Making progress through a sticking point
  9. Celiac.com 09/29/2006 - A new study identified a peptide which causes an immune reaction in a majority of active celiac disease patients but no such reaction in any celiac disease patients on a gluten-free diet. Antibodies to this celiac peptide also recognize and bind to the rotavirus protein VP-7 and cause increased intestinal permeability. Antibodies to VP-7 produced in rabbits also increase intestinal permeability. The celiac peptide also binds to Toll-like receptor 4 and activates monocytes (white blood cells active in innate immunity.) IgA and IgG antibodies to rotavirus protein VP-7 are present in a majority of celiac disease patients and to a much lesser percent of the general population. This suggests VP-7 may be involved in the pathogenesis of celiac disease through a molecular mimicry mechanism. Below is the abstract of the study: PLoS Medicine Volume 3, Issue 9, SEPTEMBER 2006 In Celiac Disease, a Subset of Autoantibodies against Transglutaminase Binds Toll-Like Receptor 4 and Induces Activation of Monocytes Methods and Findings: "In our attempt to clarify the pathogenesis of celiac disease, we screened a random peptide library with pooled sera of patients affected by active disease after a pre-screening with the sera of the same patients on a gluten-free diet. We identified a peptide recognized by serum immunoglobulins of patients with active disease, but not by those of patients on a gluten-free diet. This peptide shares homology with the rotavirus major neutralizing protein VP-7 and with the self-antigens tissue transglutaminase, human heat shock protein 60, desmoglein 1, and Toll-like receptor 4. We show that antibodies against the peptide affinity-purified from the sera of patients with active disease recognize the viral product and self-antigens in ELISA and Western blot. These antibodies were able to induce increased epithelial cell permeability evaluated by transepithelial flux of [3H] mannitol in the T84 human intestinal epithelial cell line. Finally, the purified antibodies induced monocyte activation upon binding Toll-like receptor 4, evaluated both by surface expression of activation markers and by production of pro-inflammatory cytokines." Conclusions: "Our findings show that in active celiac disease, a subset of anti-transglutaminase IgA antibodies recognize the viral protein VP-7, suggesting a possible involvement of rotavirus infection in the pathogenesis of the disease, through a mechanism of molecular mimicry. Moreover, such antibodies recognize self-antigens and are functionally active, able to increase intestinal permeability and induce monocyte activation. We therefore provide evidence for the involvement of innate immunity in the pathogenesis of celiac disease through a previously unknown mechanism of engagement of Toll-like receptor 4."
  10. Celiac.com 07/31/2006 - A two-year study in the July 2006 Endoscopy showed older celiac patients on a gluten-free diet have an incomplete histological recovery even after two years. Only the younger patients (5 - 30 years) showed significant improvement of histology within 12 months (P < 0.034); older patients (>30 years) showed histological improvement but this was not statistically significant, even after 24 months on a gluten-free diet. This study was also previously discussed in an article by Dr. Antonio Tursi in the Spring 2006 Celiac.com Scott-Free Newsletter. This also means increased intestinal permeability and associated problems such as liver damage may continue to be a lasting problem in older patients beyond two years on a gluten-free diet. Below is the abstract: Endoscopy 2006 July; 38(7): 702-707 Endoscopic and histological findings in the duodenum of adults with celiac disease before and after changing to a gluten-free diet: a 2-year prospective study Tursi, A.; Brandimarte, G.; Giorgetti, G. M.; Elisei, W.; Inchingolo, C. D.; Monardo, E.; Aiello, F. Background and study aims: Published follow-up data on small-intestinal recovery in patients with celiac disease are scarce and contradictory. This is especially the case for adult patients, who often show incomplete histological recovery after starting a gluten-free diet (GFD). We conducted a 2-year prospective study to evaluate the effectiveness of a GFD in improving the endoscopic and histological duodenal findings in adults with celiac disease. Patients and methods: We studied 42 consecutive adults with newly diagnosed celiac disease (13 men, 29 women; mean age 32.7 years, range 15 - 72 years). All the patients underwent esophagogastroduodenoscopy and small bowel biopsy. We devised our own grading system for the endoscopic appearance of the duodenum, which ranged from "normal" appearance to "mild", "moderate", or "severe" alterations. Small bowel biopsies were obtained from the second part of the duodenum (and from the duodenal bulb when it had a micronodular appearance). The histopathological appearances were described according to modified Marsh criteria. Results: A normal endoscopic appearance in the duodenum was found in 5/42 patients (11.9 %) at entry and in 32/42 patients (76.2 %) after 2 years on a GFD. Subdividing the patients according to age, patients aged from 15 years to 60 years showed significant improvement within 12 months (P < 0.0001 for patients aged from 15 years to 45 years; P < 0.003 for patients in the 46 years to 60 years group), whereas the improvement in endoscopic findings in patients older than 60 years was not statistically significant, even 24 months after starting the GFD. "Normal" histology was reported in none of the patients at entry, but in 25 patients (59.5 %) after 24 months on a GFD, but this parameter did not show a significant improvement until the patients had been on the GFD for 12 months (P < 0.0001). Only the younger patients (5 - 30 years) showed significant improvement of histology within 12 months (P < 0.034); older patients (>30 years) showed histological improvement but this was not statistically significant, even after 24 months on a GFD. Conclusions: This study shows for the first time that endoscopic recovery is faster than histological recovery in adults with celiac disease who go on a GFD. Moreover, older patients showed incomplete endoscopic and histological recovery even 24 months after starting a GFD. We therefore advise, as a minimum recommendation, that follow-up biopsies should be taken 1 - 2 years after starting a GFD in adults with celiac disease.
  11. Celiac.com 07/01/2006 - With the likelihood that increased intestinal permeability in celiacs caused by gluten damage to the intestinal mucosa leads to a high prevalance of liver damage as well as an increase in food allergy and possible other medical conditions, emphasis on healing the intestinal mucosa should be given an elevated priority. Simply going on a gluten-free diet and waiting months or years for the intestine to heal may not be enough. Friendly commensal gut bacteria are an important part of the intestinal barrier, and thus probiotics, such as yogurt, kefir, or supplemental probiotic capsules, do help diminish the amount of endotoxins released by pathogenic gut bacteria getting through the barrier. Liver disease studies confirm the benefit of probiotics by reducing inflammation and infection. However, to date, there is no product currently available which can enhance the repair and regeneration process of the mucosal epithelia. Undergoing current clinical studies in Crohns patients, Teduglutide may enhance mucosal healing, but requires multiple daily injections: Cell Prolif. 2004 Dec;37(6):385-400. Teduglutide ([Gly2]GLP-2) protects small intestinal stem cells from radiation damage. Booth C, Booth D, Williamson S, Demchyshyn LL, Potten CS. Abstract: http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2184.2004.00320.x New Crohns Disease Drug Induces Remission Through Mucosal Healing By Martha Kerr (Free article, free Medscape registration may be required.) http://www.medscape.com/viewarticle/533109 A while back I posted an abstract about a protein called R-spondin1 which is "a specific and potent stimulator of the human epithelial cells that line the gastrointestinal tract and mouth." R-spondin1 is a product being developed by Nuvelo, Inc. of San Carlos, CA designated as NU206. The press release describing NU206 is: Nuvelo Announces NU206 Publication in Science (August 18, 2005) http://www.corporate-ir.net/ireye/ir_site.zhtml?ticker=NUVO&script=410&item_id=744876 An article discussing the discovery and potentials of R-spondin1 is available in the New England Journal of Medicine, and free full text of that article is available at the address below: NEJM.-Volume 353:2297-2299 November 24, 2005 Number 21 Inducing Intestinal Growth Clara Abraham, M.D., and Judy H. Cho, M.D. Free Full Text Reprint of NEJM article: http://www.e-medicum.com/newsletters/medicinaInterna/verNoticia.php?noticia=51479 Nuvelo has recently announced plans for the "initiation of a Phase 1 study of NU206, which is being developed for the treatment of cancer therapy-induced mucositis in the second half of 2006." Obviously the benefits of NU206 go beyond that of cancer therapy. Healing the epithelial tissues of celiacs with NU206 may rapidly eliminate increased intestinal permeability and other associated conditions. Nuvelo had a live webcast of its annual shareholder meeting this Wednesday, May 24, at 11:00 am PDT. No new information on NU206 was provided at the meeting other than that plans to initiate the NU206 Phase 1 study are proceding. Replay of Nuvelo Webcast: http://www.corporate-ir.net/ireye/ir_site.zhtml?ticker=NUVO&script=1010&item_id=1234084
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