Gluten and Immunity

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.  

Malabsorption

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).

Sources:

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.