Celiac, Gluten and Trypsin Inhibitor

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Wheat

Summary

Forget the gluten.  Celiac is caused by trypsin inhibitors (ATI) that were increased in wheat fifty years ago to combat pests.  Immune response to ATI spreads to include gluten and transglutaminase that perpetuates the disease.  Celiac is an unexpected consequence of traditional plant breeding that could be fixed with GMO approaches.

Plants Protect Themselves with Antibiotics, Pesticides and Trypsin Inhibitors.

Plants respond to pathogens and pests by making themselves toxic.  Thus, plants produce natural antibiotics, phytoalexins, a.k.a. phytochemicals, polyphenolics or antioxidants, to kill bacteria and fungi.  They also produce chemical pesticides and proteins, e.g. trypsin inhibitor, that block the digestion and utilization of plant proteins by insects.  One of these trypsin inhibitors makes ground soybeans inedible until it is removed in water rinses during the production of tofu.  Another of these trypsin inhibitors, in wheat, is the cause of celiac.

Plants Target the Nerves, Immune Cells and Intestines

Plants have evolved chemicals and proteins that attack and punish plant-eating animals.  A single molecule of caster bean toxin protein, for example, can kill a human cell.  Plants produce some of the most toxic molecules on earth.  The nervous system of insects and other herbivores is typically targeted by plants.  Many recreational drugs, e.g. opioids, THC, nicotine, caffeine, etc., for example, are made by plants in self defense.  Human nerves respond to these natural pesticides and the bitter taste and the vomit reflex help us to detect and avoid toxic phytochemicals.  Gluten proteins contain polyglutamine stretches of amino acids that resist digestion and bind to intestinal cells.  Seed lectins bind to the glycoproteins on the surface of the intestines and inhibit digestion.  Wheat seeds also contain an inhibitor of starch and protein digestion, the amylase/trypsin inhibitor, ATI.  ATI binds to the receptors on immune cells that trigger general inflammatory responses to pathogens, e.g. TLR4.  It is the ATI in wheat that starts an immune response to gluten and celiac.

Wheat trypsin inhibitor causes celiac and autoimmunity

ATI Increased to Make Wheat Resistant to Pests

More than fifty years ago, plant breeders began to screen wheat varieties for resistance to pests.  Breeding ultimately resulted in enhanced pest resistance that resulted from increased production of ATI in wheat kernels.  Modern wheat flour contains modest changes in gluten and other components over the last century with the singular exception of ATI, which has increased about 50 fold.  It is also interesting that ATI is a major wheat allergen.  This suggests that celiac starts as an allergy to ATI present in wheat flour.

Celiac Results from Superfine Milling of High-ATI Wheat

Wheat has been milled more and more finely to improve the shelf-life of bread flour.  The inedible bran and the germ are first removed from the wheat kernels and then the endosperm is ground so finely that the starch granules are broken.  Even "whole wheat flour" is ground in the same way and the bran and germ are simply added back to make it “whole.”  The important point here is that superfine milling results in starch that is readily digested by amylase in the small intestines, instead of acting as soluble fiber to feed gut flora.  The result of eating bread from superfine flour is that gut flora are starved for soluble fiber and the immune system is depleted of Tregs that would otherwise suppress allergy and autoimmunity.  Superfine milling of high-ATI wheat presents ATI to an immune system that is primed for allergy.

ATI is a Good Immunogen

Allergy development requires 1) inflammation, 2) an appropriate immunogen and 3) lack of Tregs (immune system cells that develop in the lining of the intestines and block allergies and autoimmunity.)  The modern milling of wheat flour eliminates a major source of soluble fiber, starves gut flora and reduces Tregs, but allergy development still requires inflammation and an appropriate immunogen.  An immunogen is a protein that will interact with cells of the immune system to produce antibodies and activate aggressive attacks.  I have found that all proteins of food or the environment, i.e. allergens, or of the body, i.e. autoantigens, that act as immunogens to initiate allergies or autoimmunity have the same sequence of three amino acids, a "basic triplet."  ATI has a characteristic basic triplet in its protein amino acid sequence and that is why it is a good immunogen to initiate allergies.

Allergy to ATI is Aggrevated by TLR Recognition of ATI

ATI enriched, superfine flour Is a powerful initiator of allergies, because it starves gut flora to block Treg production and is a good immunogen, but the immune system will still ignore ATI in the gut, unless inflammation is also activated.  Unfortunately, ATI actively stimulates inflammation of the intestines by specifically binding to TLR4, which is the receptor that also binds/recognizes the LPS of bacteria.  Thus, ATI is a way for the wheat plant to defend its seeds by triggering excessive Intestinal inflammation.  Inflammation, immunogen and Treg insufficiency is the ATI allergy trifecta.

Wheat ATI Allergy Leads to Celiac

First exposure to ATI and development of an allergy will make subsequent expose to wheat proteins more immunologically intense.  I discussed the response of the intestinal lining to gluten in previous posts.  Wheat gluten proteins are adapted to provide nutrients for growing wheat embryos and to provide defense against pathogens and herbivores.  Gluten proteins contain long stretches of amino acid glutamine, which is poorly digested by gut enzymes.  The glutamine is also converted into glutamate by the gut enzyme, transglutaminase, tTG.  Unfortunately, during the process, the enzyme is covalently connected to the undigested gluten fragments.  The allergic ATI reaction combined with gluten/tTG conjugates, leads to presentation of the gluten/tTG to the immune system and antibody production agains both gluten and tTG.  Subsequent exposure to gluten results in the autoimmune disease of celiac.

Celiac is Self-Perpetuating

The aggressive immune attack on the intestines in response to eating gluten-containing grains, is bad in itself, but it also causes a series of related autoimmune diseases.  Attack on the intestines also disrupts the development of the lining of the intestines, which in turn disrupts the community of bacteria and fungi, gut flora, that are essential for digestion of plant polysaccharides, soluble fiber, and the development of the immune system.  Gut flora dysfunction results in vitamin deficiencies, food intolerances and autoimmunity.  Thus, celiac is self-perpetuating, because it causes inflammation, immunogen presentation and Treg deficiency.

Celiac Causes Numerous Autoimmune Diseases

Celiac is often associated with other autoimmune diseases, because it causes them.  Antibodies to tTG are diagnostic for celiac and the autoimmune attack on the intestines is mediated by anti-tTG antibodies.  But anti-tTG antibodies of celiac don’t just attack the intestines, they attack any other tissues that have tTG, such as the thyroid gland and hair follicles.  Thus, it should not be a surprise that celiacs are at high risk for autoimmune disease, e.g. Hashimoto’s thyroiditis, of the thyroid gland, including both hypothyroid and hyperthyroid diseases, depending on which region of the thyroid is attacked.  Some forms of hair loss, alopecia, are also initiated by autoimmune attack on the tTG in hair follicles.  Persistent exposure of celiacs to gluten will result in a cascade of autoimmune diseases as other body antigens are presented to the immune system and tissues with those antigens are targeted and attacked to produce arthritis, vitiligo, etc.

Pest Resistance, Plant Breeding and GMO Solutions

Genetic modification of plants occurs every time seeds are planted.  Traditional plant breeding by selecting desirable individual plants grown from crosses of selected parents is one form of genetic modification.  Specifically introducing desired genes using recombinant DNA techniques is another, more controlled method.  Traditional plant breeding has systematically destroyed the diversity of crop plants by loss of genes that are not selected, but even the traits, such as pest resistance, that provide benefit, have also brought unintended consequences.  We now have grains with many desirable features of high yield and disease resistance, but they also provide increased risk of celiac, gluten intolerance and associated autoimmune diseases.  Maybe it is time to consider GM techniques as a safer alternative to fix modern wheat and to examine milling approaches to save our gut flora.

Health Diagrams II — Curing Autoimmunity and Allergies

Cure for Celiac and Autoimmunity

Celiac and other autoimmune diseases are perpetuated by the presence of the corresponding autoantigen/allergen, in this case tTG and gluten proteins, and a deficiency of Tregs.  Oddly enough, some pathogens (Helicobacter pylori) and parasites (Helminth worms) stimulate Treg development in the lining of the intestines, in addition to normal gut flora, Clostridium spp.  It may be the relative absence of pathogens and parasites in affluent societies that reduces Tregs and enhances the incidence of allergies and autoimmunity.  Antibiotics and the antibiotic activity of pharmaceuticals in general may also contribute to Treg deficiencies by damage to gut flora.  Clearly, the repair of gut flora and reestablishment of the associated immune system will go a long way toward curing autoimmune diseases such as celiac.  Celiac, however, provides the added complexity that it damages the ability of the intestines to maintain a functional gut flora.  Thus, the cure for celiac would require simultaneous repair of both the gut and its flora, e.g. by a  fecal transplant and supportive diet containing numerous soluble fibers to which the donor flora have been previously adapted, i.e. lacking antigenic triggers.