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  • Dr. Ron Hoggan, Ed.D.
    Dr. Ron Hoggan, Ed.D.

    Gluten and Immunity

    Reviewed and edited by a celiac disease expert.

    Journal of Gluten Sensitivity Autumn 2010 Issue. NOTE: This article is from a back issue of our popular subscription-only paper newsletter. Some content may be outdated.

    Gluten and Immunity - Image: CC--matsuyuki
    Caption: Image: CC--matsuyuki

    Celiac.com 05/17/2019 (Originally published 10/08/2010)  - There are many ways in which the immune system is compromised in the context of celiac disease.  A lack of fats (due to fat malabsorption) can limit production of eicosanoids and other fat-dependent immune system components.  Malabsorption of minerals such as zinc, copper, iron, selenium, or magnesium can also impair immune function in several ways.  Malabsorption of non-metalic elements such as iodine can also impair our immune function through impairing T cell production by the thymus.  The leaky gut, a chronic feature of untreated celiac disease can induce autoimmunity and deplete the very resources that protect us from infection and toxic agents.  The recent successes of Larazotide are highly suggestive that it is the leaky gut that is at the very root of celiac disease, since many celiacs can consume gluten with little harm when taking this drug.  


    Our cells can make use of three separate sources of energy.  They can burn glucose, from carbohydrates, amino acids, from proteins, or fats which can be saturated, monounsaturated, or polyunsaturated fats.  Any or all of these can be used for fuel at the cellular level.  Celiac disease has long been characterized as a condition of fat malabsorption, and some fats are essential to our survival and wellness.  Stephen Cunnane makes an excellent case for these essential fats in his book about the evolution of the human brain titled “Survival of the Fattest”.  He shows that the human brain cannot develop normally without adequate supplies of omega 3 fatty acids.  We also need fats to make many elements of the immune system.  We must consume and absorb omega 3 and omega 6 fatty acids because our bodies are unable to efficiently produce them.

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    Similarly, as our understanding has expanded, we have come to recognize that absorption of other nutrients such as minerals can also be compromised in untreated celiac disease.  (Some people with celiac disease continue to battle mineral malabsorption for many years after adopting the gluten-free diet.)  Patients with iron deficiency that does not respond to supplementation should be investigated for celiac disease, as refractory iron deficiency is common in untreated celiac disease (1).  Iron is an important constituent of immune function and Stephen J.  Oppenheimer has identified seven separate dynamics through which iron deficiency can compromise immune function.  These include:  

    1. Reduced neutrophil function which can be reversed through iron supplementation;
    2. Reduced numbers of T-lymphocytes;
    3. Reduced T-lymphocyte responsiveness;
    4. Impaired natural killer cell activity;
    5. Impaired interleukin 2 production;
    6. Altered macrophage migration;
    7. Altered cutaneous hypersensitivity (2).   

    Magnesium deficiency, in the context of celiac disease, has been identified as a factor in damage to the parathyroid gland and consequent bone demineralization.  Rude et al have shown that magnesium supplementation alone will reverse this problem (3).   

    Similarly, mineral malabsorption may impede our supplies of zinc, copper, and selenium, each of which may have a negative impact on the immune system.  Even a mild zinc deficiency can impair T cells, interfere with hormonal regulation of the thymus, and activation of tumor necrosis factor and natural killer cells (4).  I have previously reported that natural killer cells are the body’s first line of defense against malignancy (5).  Natural killer cells also help to protect us from a variety of infectious agents.  

    Malabsorption of non-metallic elements such as iodine can also impair immune function.  Not only does the thyroid gland require iodine to function properly, the healthy thymus gland contains large reserves of iodine and a wide range of immune functions require iodine.  The antibacterial uses of iodine have a long history and this element was discovered early in the nineteenth century.  Although iodine is now added to most table salts in the industrialized world deficiency continues to plague the third world causing preventable mental retardation.  Failure to absorb this important nutrient can cause disturbances to many facets of the immune system and impair heat regulation through compromised thyroid function.  Added problems with the thyroid gland can also come to the untreated celiac through autoimmunity induced by a process called molecular mimicry (more on this later) which is one of the means by which the leaky gut can also create havoc with the immune system.

    Leaky Gut

    Jon Meddings has characterized the gastrointestinal tract as a long tube running through our bodies that contains materials from the outside environment (6).  Unlike our skin, we have only one layer of cells in the intestine that protects us from the outside world.  These cells must selectively absorb nutrients from this material, while providing a protective barrier against constituents of our food that might harm us.  These nutrients are absorbed through the epithelial cells and are released on the other side of the cells into the bloodstream.  

    The leaky gut, as induced by gluten, is a state where excessive zonulin is produced in the intestinal lumen.  This protein attaches to the epithelial cells that line the intestine.  The epithelial cells move further apart leaving gaps between the cells, thus allowing matter to enter the bloodstream on the other side of the epithelial barrier.  Depending on the size of these gaps, various toxins, infectious agents from our food, undigested and partly digested food particles, and even the friendly bacteria that inhabit our intestines may reach the bloodstream and beyond.  

    Whether in the form of partial or complete proteins from foods, microbes from the external environment, or friendly bacteria from our intestines, once in the bloodstream our immune systems recognize these proteins as foreign.  We produce antibodies to attack and destroy them.  If these same proteins arrive in the circulation repeatedly, we will have elevated serum antibodies specifically sensitized to these proteins.  Protein structures can contain enormously variable sequences of amino acids.  Perhaps for the sake of efficiency, these selective antibodies recognize only one segment of the foreign protein structure, in the form of a single sequence of amino acids.  According to the theory of molecular mimicry, this or a very similar sequence of amino acids may be found in proteins that form some of our own tissues.  If we have elevated levels of antibodies that are made to attack such a string of amino acids, they will also attack self tissues.  This is process results in autoimmune disease.  

    Because it is difficult to predict what sequence of amino acids the immune system will choose, we cannot predict the specific self tissues that will be attacked by our immune systems.  Nonetheless, if the theory of molecular mimicry is correct, gluten may be at the root of many forms of autoimmunity because of its impact on zonulin production.  

    Celiac Disease vs. Gluten Sensitivity

    The greater hazard appears to lie with celiac disease rather than non-celiac gluten sensitivity, as celiac patients not only have to contend with all the problems that come from a leaky gut, they also have all the problems associated with malabsorption.  However, Anderson et al report that people with gluten sensitivity showed a greater rate of all cause mortality as well as significantly increased rates of non-Hodgkin’s lymphoma and cancers of the digestive tract than were found among patients with celiac disease (7).  These unfortunate data may be the direct result of the many physicians and other health care practitioners who consistently urge their patients to continue to consume gluten despite the clear evidence, in the form of anti-gliadin antibodies, that these patients are mounting an immune reaction against the most common food in their diet.  Peter Green, professor of Medicine at Columbia University, has called for more attention to be paid to “the lesser degrees of intestinal inflammation and gluten sensitivity” (8).


    1. Farhad Zamani, Mehdi Mohamadnejad, Ramin Shakeri, Afsaneh Amiri, Safa Najafi, Seyed Meysam Alimohamadi, Seyed Mohamad Tavangar, Ardeshir Ghavamzadeh, Reza MalekzadehGluten sensitive enteropathy in patients with iron deficiency anemia of unknown originWorld J Gastroenterol 2008 December 28; 14(48): 7381-7385
    2. Oppenheimer Stephen J, Iron and Its Relation to Immunity and Infectious Disease.  The American Society for Nutritional Sciences Supplement, Journal of Nutrition.  2001;131:616S-635S.   
    3. Rude RK, Olerich M.  Magnesium deficiency: possible role in osteoporosis associated with gluten-sensitive enteropathy.  Osteoporos Int.  1996;6(6):453-61.
    4. Prasad AS.  Zinc and immunity.  Mol Cell Biochem.  1998 Nov;188(1-2):63-9.
    5. Hoggan R.  Considering wheat, rye, and barley proteins as aids to carcinogens.  Med Hypotheses.  1997 Sep;49(3):285-8.
    6. Meddings J.  National Conference, Canadian Celiac Association, Calgary, Alberta, Canada, 1999 
    7. Anderson LA, McMillan SA, Watson RGP, Monaghan P,  Gavin AT,  Fox C,  Murray LI Malignancy and mortality in a population-based cohort of patients with coeliac disease or ‘gluten sensitivity’.  World J Gastroenterol 2007 January 7; 13(1): 146-151
    8. Green P H R, Mortality in Celiac Disease, Intestinal Inflammation, andGluten Sensitivity.  JAMA.  2009;302(11):1225-1226.

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    Thank you for this article. It explains a lot towards my ongoing problems. For some reason doctors do not want to admit that other issues can arise from Celiac and even gluten sensitivity. From a prior hospitalization and the magnesium deficiency(?), continual low iron counts and so on, this article has helped me. I would like permission to print this article so I can take it to my Internist and my general physician. Thank you!!

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  • About Me

    Dr. Ron Hoggan, Ed.D.

    As co-author of "Dangerous Grains" and "Cereal Killers", the study of the impact of gluten continues to be a driving passion in my life. I am fascinated by the way that gluten induces illness and impedes learning while it alters mood, behavior, and a host of other facets of our existence. Sure, the impact of gluten on health is an important issue, but that is only the most obvious area of impact. Mood disturbances, learning disabilities, and the loss of quality of life due to psychiatric and neurological illness are even more tragic than the plethora of physical ailments that are caused or worsened by gluten. The further I go down this rabbit hole, the more I realize that grains are a good food for ruminants - not people. I am a retired school teacher. Over the last decade, I have done some college and university level teaching, but the bulk of my teaching career was spent working with high school students. My Web page is: www.DangerousGrains.com

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    Celiac.com 05/06/2013 - After a diagnosis of celiac disease, it is unlikely a gluten-free diet alone will provide expeditious relief from its various associated symptoms and health problems.  Additional steps and remedies to restore the integrity of the damaged intestinal mucosal barrier are often needed, at least, to hasten the process.  The first step all patients should take after a celiac disease diagnosis is to establish a "baseline" measurement of the intestinal damage which can be used to assess how well the gut is healing over time.  Assessing the status of the gut via multiple endoscopic biopsy procedures is not a very practical choice of method. It is expensive, invasive, uncomfortable, subject to possible risks and complications, and only assesses the intestinal mucosa at the sites biopsied.[1]  The downsides of biopsies can be avoided by using a low-cost, non-invasive leaky gut or intestinal permeability test to provide a useful baseline measurement and following up with future periodical testing for comparison.   
    A new, simple and easy-to-use home Carbon-13 or 13C-Sucrose Breath Test to assess for leaky gut is now available.  The 13C-Sucrose Breath Test takes only 90 minutes, requiring drinking a sucrose (20 grams) solution and collecting 4 breath samples 30 minutes apart following an 8 hour fast.  13C-Sucrose Breath Test samples, collected in 4 small screw-capped glass tubes, are simply mailed to the laboratory within 14 days in the original shipping box that also serves as a pre-paid U.S. Postal Service First Class Mailer.  13C-Sucrose Breath Test results are emailed back within 24 hours after the breath test samples are received.[2] 
    In comparison, the better known and established Lactulose/Mannitol Intestinal Permeability Test requires an 8 hour overnight fast, collecting a pretest urine specimen, drinking a Lactulose(5 grams)/Mannitol(1 gram) solution, drinking water every 2 hours, and sampling and collecting all the urine excreted over a 6 hour period.  The Lactulose/Mannitol Test urine specimens must be kept refrigerated and shipped to and received by the laboratory within 24 hours in a special frozen gel pack shipper via FedEx overnight delivery.  Lactulose/Mannitol Test results are emailed around 7 days after the specimens are received.[3]
    The 13C-Sucrose Breath Test is based on the level of sucrase activity in cells of the intestinal mucosa.  Sucrase enzymes break down sucrose into its constituent components, fructose and glucose, which, when metabolized in the liver, produce carbon dioxide (CO2) exhaled in the breath.  Sucrase enzymes are synthesized and embedded in the "brush border" of cells comprising the villi of the intestinal mucosa.  The brush border is composed of numerous microvilli which extend into the intestinal lumen from the face of the villus cells.[1,4,5]
    Natural sucrose from cane sugar contains 2 forms of carbon atoms, carbon-12 (12C) and the stable, non-radioactive isotope, carbon-13 (13C).  12C and 13C carbon dioxide can be detected and measured using an isotope ratio mass spectrometer (IRMS).  By using natural 13C-enriched sucrose in which the ratio of 13C to 12C has been previously measured, measurement and analysis of the relative amounts of 13C and 12C in the carbon dioxide exhaled by an individual after ingesting a known quantity of the 13C-enriched sucrose provides an indicator of the sucrase activity in the brush border.  Damage to villus cells and the brush border results in both a decrease in sucrase activity and an increase intestinal permeability.  This forms the basis for a leaky gut test where low carbon-13 measured in the breath means the intestinal villi are damaged.[1,4]
    The Metabolic Solutions, Inc. 13C-Sucrose Breath Test is taken after a minimum 8 hour fast.  No sleep or exercise is allowed during the test.  A baseline breath sample is first collected.  Then a 20 gram packet of 13C-enriched sucrose is stirred into an 8 ounce glass of water and ingested.  Breath samples are then collected at 30, 60, and 90 minutes after sucrose ingestion.  Breath samples are collected into 4 small labeled 10 ml glass tubes with color-coded screw caps by simply unscrewing the cap, taking a full breath, and blowing into the tube through an ordinary straw.  Breath will be felt escaping out of the tube as it is blown through the straw.  That is normal.  All that is required is to screw the cap back on the tube, finger-tight, within 5 seconds.  If screwing the cap back on takes more than 5 seconds, one can simply take another breath and blow again.  After the test, the 4 tubes and the instruction sheet, filled-in with the test taker's name, email address, date of birth, sex, height and weight, are repacked into the original shipping box and dropped into any U.S. mail box within 14 days.  A prepaid U.S. Postal Service First Class mailing label is printed on the box.  Test results are emailed back within 24 hours after receipt by Metabolic Solutions, Inc.  If the percentage cumulative dose of 13C recovered from the sucrose at 90 minutes is less than 5.10% 13C for females or less than 3.91% 13C for males, the test is considered positive for intestinal damage.[2,4]
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    13C-Sucrose Breath Leaky Gut Test Kits are available directly from:
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    To Order Home Test Kits:
    Lactulose/Mannitol Intestinal Permeability Test Kits are available (through retail website sellers) from:
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    I have personally taken the Metabolic Solutions, Inc. 13C-Sucrose Breath Leaky Gut Test.  A kit ordered online on a Monday was picked up from my post office box on Friday of the same week.  The test was taken on the following Monday, and the prepaid shipping box was dropped off at the U.S. Post Office the next day, Tuesday.  The test result was received in an email sent from Metabolic Solutions, Inc. Thursday evening, only 2 days later.  The test result was normal, 6.97% cumulative dose of 13C recovered, well above the cut-off of 3.91% for males. 
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    1. Mucositis and non-invasive markers of small intestinal function.
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    2. Instructions for Leaky Gut Breath Test.
    Metabolic Solutions, Inc.
    3. GDX Lactulose/Mannitol Intestinal Permeability Test Kit Instructions.
    Genova Diagnostics.
    4. 13C-Sucrose Breath Test for Leaky Gut Syndrome.
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    5. Small Intestine: Brush Border Enzymes.
    R. Bowen.
    Pathophysiology of the Digestive System, Colorado State University.
    6. Recent Results of the Development and Application of 13C–Breath Tests.
    Klaus Wetzel and Heinz Fischer.
    Fischer ANalysen Instrumente GmbH (FAN), Leipzig, December 1999, Page 33.
    7. Breath Test.
    Butler RN, Tivey D, Davidson GP, Pelton N.
    U.S. Patent 7338454, March 4, 2008.
    8. Breath Test.
    Butler RN, Tivey D, Davidson GP, Pelton N.
    U.S. Patent Application 20080160504, July 3, 2008.
    9. Breath test.
    Butler RN, Tivey D, Davidson GP, Pelton N.
    International Application No.: PCT/AU2002/001666, December 9, 2002.
    10. Zinc homeostasis and gut function in children with celiac disease.
    Tran celiac disease, Katsikeros R, Manton N, Krebs NF, Hambidge KM, Butler RN, Davidson GP.
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    11. Follow-up of adult celiac patients: which noninvasive test reflects mucosal status most reliably?
    Vecsei AK, Graf UB, Vogelsang H.
    Endoscopy. 2009 Feb;41(2):123-8.
    12. Intestinal permeability in long-term follow-up of patients with celiac disease on a gluten-free diet.
    Duerksen DR, Wilhelm-Boyles C, Parry DM.
    Dig Dis Sci. 2005 Apr;50(4):785-90.
    13. Lactulose-mannitol intestinal permeability test: a useful screening test for adult coeliac disease.
    Johnston SD, Smye M, Watson RG, McMillan SA, Trimble ER, Love AH.
    Ann Clin Biochem. 2000 Jul;37 ( Pt 4):512-9.
    14. Lactulose-mannitol intestinal permeability test: a useful screening test for adult coeliac disease.
    Johnston SD, Smye M, Watson RG, McMillan SA, Trimble ER, Love AH.
    Ann Clin Biochem. 2000 Jul;37 ( Pt 4):512-9.
    15. Is the sugar intestinal permeability test a reliable investigation for coeliac disease screening?
    Catassi C, Fabiani E, Rätsch IM, Bonucci A, Dotti M, Coppa GV, Giorgi PL.
    Gut. 1997 Feb;40(2):215-7.

    Jefferson Adams
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     Clin Nutr. 2015 Apr 30. pii: S0261-5614(15)00124-7. doi: 10.1016/j.clnu.2015.04.014.

    Jefferson Adams
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    A team of researchers recently set out to describe 20 selected patients with fibromyalgia, but without celiac disease, whose symptoms improved when they followed a gluten-free diet. The research team included Carlos Isasi, Isabel Colmenero, Fernando Casco, Eva Tejerina, Natalia Fernandez, José I. Serrano-Vela, Maria J. Castro, and Luis F. Villa.
    They are variously associated with the Department of Rheumatology, Hospital Puerta de Hierro, Majadahonda Madrid, Spain; the Department of Pathology, Hospital Infantil Niño Jesús, Madrid, Spain; the Department of Pathology, Hospital Puerta de Hierro, Majadahonda Madrid, Spain; the Department of Gastroenterology, Hospital Puerta de Hierro, Majadahonda Madrid, Spain; the Celiac and Gluten Sensitive patients Association of Madrid, Madrid, Spain; and with the Department of Immunology, Hospital Doce de Octubre, Madrid, Spain.
    What researchers now call non-celiac gluten-sensitivity is a daily common, yet treatable condition, with a range of symptoms that dovetail with many symptoms of fibromyalgia, including chronic musculoskeletal pain, asthenia, and irritable bowel syndrome.
    All patients underwent anti-transglutaminase assay, duodenal biopsy, and HLA typing. To rule out celiac disease in their test subjects, the research team used negative anti-transglutaminase assay results, together with the absence of villous atrophy in the duodenal biopsy.
    All patients showed signs of intraepithelial lymphocytosis with no villous atrophy. The doctors defined a positive clinical response as the achievement of at least one of the following: remission of fibromyalgia-associated pain, return to work, return to normal life, or the discontinuation of opioids. Doctors followed on the patients from 5 to 31 months, with a follow-up period of 16 months, on average.

    The level of widespread chronic pain improved dramatically for all patients; for 15 patients, chronic widespread pain was no longer present, indicating remission of FM. Fifteen patients returned to work or normal life. In three patients who had been previously treated in pain units with opioids, these drugs were discontinued. Fatigue, gastrointestinal symptoms, migraine, and depression also improved together with pain. Patients #2 and #3, both with oral aphthae, went into complete remission for psoriatic arthritis and undifferentiated spondyloarthritis.
    These results strengthen the idea that non-celiac gluten sensitivity may play a key role in the development of fibromyalgia syndrome.
    Rheumatol Int. 2014; 34(11): 1607–1612. Published online 2014 Apr 12. doi: 10.1007/s00296-014-2990-6

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