[As published in the 2009 winter edition of the Journal of Gluten Sensitivity]

by Sayer Ji

Now that celiac disease has been allowed official entry into the Pantheon of established medical conditions, and gluten intolerance is no longer entirely a fringe medical concept, the time has come to bring attention to the powerful little chemical in wheat known as ‘wheat germ agglutinin’ (WGA) which is largely responsible for wheat’s pervasive and difficult to diagnose ill effects.  Not only does WGA throw a monkey wrench into our assumptions about the primary causes of wheat intolerance, but due to the fact that WGA is found in highest concentrations in “whole wheat,” including its supposedly superior sprouted form, it also pulls the rug out from under one of the health food industry’s favorite poster children.

Beneath the radar of conventional serological testing for antibodies against the various gluten proteins and genetic testing for disease susceptibility, the WGA “lectin problem” remains almost entirely obscured. Lectins, though found in all grains, seeds, legumes, dairy and our beloved nightshades: the tomato and potato, are rarely discussed in connection with health or illness, even when their presence in our diet may greatly reduce both the quality and length of our lives.

Although great progress has been made in the direction of revealing the dark side of wheat over the past decade, gluten receives a disproportionate amount of the attention. Given that modern bread wheat (Triticum Aestivum) is a hexaploid species containing three distinct sets of chromosomes capable of producing well over 23,000 unique proteins, it is not surprising that we are only just now beginning to unravel the complexities of this plant’s many secrets. [1] What is unique about the WGA glycoprotein is that it can do direct damage to the majority of tissues in the human body without requiring a specific set of genetic susceptibilities and/or immune-mediated articulations. This may explain why chronic inflammatory and degenerative conditions are endemic to wheat-consuming populations, even when overt allergies or intolerances to wheat gluten appear exceedingly rare.  The future fate of wheat consumption, and by implication our health, may depend largely on whether or not the toxic qualities of WGA come to popular light.

Nature engineers within all species a set of defenses against predation, though not all are as obvious as the thorns of a rose or the horns of a rhinoceros. Plants do not have the cell-mediated immunity of higher life forms, like ants, nor do they have the antibody-based secondary immune systems of jawed vertebrates. They must rely on a much simpler innate immunity.  It is for this reason that seeds of the grass family, e.g. rice, wheat, spelt, rye, are designed with exceptionally high levels of defensive glycoproteins known as lectins. Cooking, sprouting, fermentation and digestion are the traditional ways in which man, for instance, deals with the various anti-nutrients found within this family of plants, but lectins are, by design, particularly resistant to degradation through a wide range of pH and temperature.

WGA lectin is an exceptionally tough adversary as it is composed of the same disulfide bonds that make vulcanized rubber and human hair so strong, flexible and durable. Like man-made pesticides, lectins are extremely small, difficult to break down by living systems, and tend to accumulate and become incorporated into tissues where they interfere with normal biological processes.  Indeed, WGA lectin is so powerful an insecticide that biotech firms have used recombinant DNA technology to create genetically modified WGA-enhanced plants.  We can only hope that these virtually unregulated biotech companies, who are in the business of playing God with the genetic infrastructure of Life, will realize the potential harm to humans genetic modification in which this will result.

Lectins are glycoproteins, and through thousands of years of selectively breeding wheat for bread-making purposes to contain increasingly higher quantities of protein, the concentration of WGA lectin has increased proportionately.  This, no doubt, has contributed to wheat’s global dominance as one of the world’s favored monocultures, offering additional “built-in” pest resistance. The word lectin comes from the same etymological root as the word select, and literally means “to choose.”  Lectins are designed “to choose” specific carbohydrates that project off the surface of cells and upon which they attach. In the case of WGA the two glycoproteins it selects for, in order of greatest affinity, are N-Acetyl Glucosamine and N-Acetylneuraminic acid (sialic acid).

WGA is Nature’s ingenious solution for protecting the wheat plant from the entire gamut of its natural enemies. Fungi have cell walls composed of a polymer of n-Acetylglucosamine.  The cell wall of bacteria is made from a layered structure called the peptidoglycan, a biopolymer of N-Acetylglucosamine. N-acetylglucosamine is the basic unit of the biopolymer chitin, which forms the outer coverings of insects and crustaceans (shrimp, crab, etc).  All animals, including worms, fish, birds and humans, use N-Acetyglucosamine as a “ground substance” for building up the various tissues in their bodies, including the bones.  The production of cartilage, tendons, and joints depend on the structural integrity of N-Acetylglucosamine.  The mucous known as the glycocalyx, or literally, “sugar coat” is secreted in humans by the epithelial cells which line all the mucous membranes, from nasal cavities to the top to the bottom of the alimentary tube, as well as the protective and slippery lining of our blood vessels. The glycocalyx is composed largely of N-Acetylglucosamine and N-Acetylneuraminic acid (also known as sialic acid), with carbohydrate end of N-Acetylneuraminic acid of this protective glycoprotein forming the terminal sugar that is exposed to the contents of both the gut and the arterial lumen (opening).  WGA’s unique binding specificity to these exact two glycoproteins are not be accidental. Nature has designed WGA perfectly to attach to, disrupt and gain entry through these mucosal surfaces.

It may strike some readers as highly suspect that wheat – the “staff of life” – which has garnished a reputation for “wholesome goodness” the world over, could contain a powerful health-disrupting anti-nutrient, the likes of which are only now coming to public attention. And yet, the truth is that the presence of WGA has been overshadowed by other proteins in wheat, which humans – not Nature – have spent thousands of years cultivating in order to contain larger and larger quantities. These pharmacologically active, opiate-like proteins in gluten are known as gluten exorphines (A5, B4, B5, C) and gliadorphin, and they may effectively anesthetize us, in the short term, to the long term adverse effects of WGA. Gluten also contains exceptionally high levels of the excitotoxic l-aspartic and l-glutamic amino acids, which can be highly addictive, not unlike their synthetic shadow molecules aspartame and monosodium glutamate.¹ In a previous article on the topic, The Dark Side of Wheat: New Perspectives on Celiac Disease and Wheat Intolerance[2], we explored the role that these psychotropic qualities in grains played in ushering in civilization at the advent of the Neolithic transition 10,000 BC.  No doubt the narcotic properties of wheat are the primary reason why suspicions about its toxicity have remained merely speculation, for thousands upon thousands of years.

WGA is most concentrated in the seed of the wheat plant, likely due to the fact that the seeds are the “babies” of these plants and are invested with the entire hope for continuance of their species. Protecting the seed against predation is necessarily a first priority.  WGA is an exceedingly small glycoprotein (36 kilodaltons) and is concentrated deep within the embryo of the wheat berry (approximately 1 microgram per grain). WGA migrates during germination to the roots and tips of leaves, as the developing plant begins to project itself into the world and outside the safety of its seed. In its attempt to gain nourishment from the earth, its roots are challenged with fungi and bacteria seeking to invade, and in its attempt to receive sunlight and nourishment from the heavens, its leaves become prey to insects, birds, mammals, etc.  After the plant has passed beyond the germination and sprouting stages it continues to contain almost 50% of the levels of lectin found in the dry seeds, approximately 1/3 in the roots and 2/3rds in the shoot, for at least 34 days [3]

There exists 1 microgram per wheat grain of WGA, hardly enough it would seem to do any harm to an animal of our size. Lectins, however, are notoriously dangerous even in minute doses and can be fatal when injected directly into the blood or inhaled.  According to the U.S. Centers for Disease Control it only takes 500 micrograms (about half a grain of sand) of ricin (a lectin extracted from castor bean casings) to kill a human. A one ounce slice of wheat bread contains approximately 500 micrograms of WGA, which if it were precipitated out in its pure form and injected directly into the blood, could in theory have platelet aggregating and erythrocyte agglutinizing effects strong enough to create an obstructive clot as occurs in myocardial infarction and stroke.  This, however, is not a likely route of exposure and in reality the immediate pathologies associated with lectins like ricin and WGA are largely restricted to the gastrointestinal tract where they cause mucosal injuries. The point is that WGA, even in small quantities, could have rather profound adverse effects, given suitable conditions.  Ironically, it is only because WGA is exceptionally small at 36 kilodaltons (approximately the mass of 36,000 hydrogen atoms) that it can pass through the cell membranes of the intestine with ease. The intestines will allow passage of molecules up to 1,000 kilodaltons in size.  Moreover, since one wheat kernel contains 16.7 trillion individual molecules of WGA, with each molecule of WGA having four N-Acetylglucosamine binding sites, the disruptive and damaging effects of whole wheat bread consumption in someone whose protective mucosal barrier has been compromised by something as simple as Non-Steroidal Anti-Inflammatory Drug (NSAID) use, or a recent viral or bacterial infection, are formidable.  The common consumption of both wheat and NSAIDs represent a vicious cycle, as dependency on anti-inflammatory medications such as ibuprofen and aspirin which increase intestinal permeabilty may cause even higher than normal amounts of pro-inflammatory WGA to being absorbed. Conversely, the inflammation caused by the absorption of WGA lectin is the very reason why there is a great need for the inflammation-reducing effects of NSAIDs.

Perhaps one way to gauge how pervasive the adverse effects of WGA are in wheat consuming populations is the popularity of glucosamine as a dietary supplement. A quarter billion dollars of the stuff is sold in US annually. The main source of glucosamine on the market is from the N-Acetylglucosamine rich chitin exoskelotons of crustaceans, like shrimp and crab. The pain and inflammation reducing effects of glucosamine are obviously not due to a deficiency of the pulverized shells of dead sea critters in our diet any more than the pain and inflammation reducing effects of NSAIDs are obviously not caused by a deficiency of these synthetic chemicals in our diet.  When we consume glucosamine supplements the WGA, instead of binding to our tissues, binds to the pulverized chitin in the glucosamine supplements, sparing us from the full impact of WGA.  Many millions of Americans who have experienced their pain and suffering greatly reduced by the ingestion of glucosamine and NSAIDs may be better served by removing wheat, the underlying cause of their malaise, from their diet, as this would result in even greater health and far less dependency on palliative supplements and medicines alike.

In order to underscore this point further, what follows are the numerous ways in which WGA contributes to disrupting our health, and glucosamine contributes to blocking:

WGA may be Pro-inflammatory

At exceedingly small concentrations (nanomolar), WGA stimulates the synthesis of pro-inflammatory chemical messengers (cytokines) including Interleukin 1, Interleukin 6 and Interleukin 8 in intestinal and immune cells.[4] WGA has been shown to induce NADPH-Oxidase in human neutrophils associated with the “respiratory burst” that results in the release of inflammatory reactive oxygen species[5] WGA has been shown to play a causative role in patients with chronic thin gut inflammation.[6]

WGA may be Immunotoxic

WGA induces thymus atrophy in rats[7], and may directly bind to leukocytes and activate them.[8] Anti-WGA antibodies in human sera have shown the ability to cross react with other proteins, indicating they may contribute to autoimmunity.[9] Indeed, WGA appears to play a role in the pathogenesis of celiac disease (CD), entirely distinct from that of gluten, due to the fact that IgG and IgA antibodies to WGA are significantly higher in CD than patients with other intestinal disorders and these antibodies were shown not to cross-react with gluten antigens[10] [11]

WGA may be Neurotoxic

WGA is capable of passing through the blood brain barrier (BBB) through a process called “adsorptive endocytosis”[12] and is able to travel freely throughout the tissues of the brain which is why it is used as a marker for tracing neural circuits[13] WGA’s ability to pass through the BBB without damaging it, as well as to pull through other substances to which it is bound, has perked the interest of pharmaceutical developers looking to find ways to delivering drugs to the brain. WGA has a unique binding affinity for N-Acetylneuraminic acid, a crucial component of neuronal membranes found in the brain such as gangliosides which have diverse roles such as cell-to-cell contact, ion conductance and as receptors, and whose dysfunction have been implicated in neurodegenerative disorders. WGA may attach to the protective coating of the nerves known as the myelin sheath[14] and is capable of inhibiting nerve growth factor,[15] which is important for the growth, maintenance and survival of certain target neurons. WGA binds to N-Acetylglucosamine which is believed to function as an atypical neurotransmitter functioning in nocioceptive (pain) pathways.

WGA may be Cytotoxic

WGA has been demonstrated to be cytotoxic to both normal and cancerous cell lines, capable of inducing either cell cycle arrest or programmed cell death (apoptosis). [16]

WGA may interfere with Gene Expression

WGA demonstrates both mitogenic and anti-mitogenic[17] activities. WGA may prevent DNA replication[18] WGA binds to polysialic acid (involved in posttranslational modifications) and blocks chick tail bud development in embryogenesis, indicating that it may influence both genetic and epigenetic factors.

WGA may disrupt Endocrine Function

WGA has also been shown to have an insulin-mimetic action, potentially contributing to weight gain and insulin resistance.[19] WGA has been implicated in obesity and “leptin resistance” by blocking the receptor in the hypothalamus for the appetite satiating hormone leptin.  WGA stimulates epidermal growth factor which when upregulated is associated with increased risk of cancer. WGA has a particular affinity for thyroid tissue and has been shown to bind to both benign and malignant thyroid nodules[20] WGA interferes with the production of secretin from the pancreas, which can interfere with digestion and can cause pancreatic hypertrophy.  WGA attaches to sperm and ovary cells, indicating it may adversely influence fertility.

WGA may be Cardiotoxic

WGA induces platelet activation and aggregration[21] WGA has a potent, disruptive effect on platelet endothelial cell adhesion molecule-1, which plays a key role in tissue regeneration and safely removing neutrophils from our blood vessels.[22]

WGA may adversely effect Gastrointestinal Function

WGA causes increased shedding of the intestinal brush border membrane, reduction in surface area, acceleration of cell losses and shortening of villi, via binding to the surface of the villi. WGA can mimic the effects of epidermal growth factor (EGF) at the cellular level, indicating that the crypt hyperplasia seen in celiac disease may be due to the growth-promoting effects of WGA.  WGA causes cytoskeleton degradation in intestinal cells, contributing to cell death and increased turnover.  WGA decreases levels of heat shock proteins in gut epithelial cells leaving these cells less well protected against the potentially harmful content of the gut lumen.[23]

WGA may share pathogenic similarities with certain Viruses

There are a number of interesting similarities between WGA lectin and viruses. Both viral particles and WGA lectin are several orders of magnitude smaller than the cells they enter, and subsequent to their attachment to the cell membrane, are taken into the cell through a process of endocytosis.  Both influenza and WGA gain entry through the sialic acid coatings of our mucous membranes (glycocalyx), each with a sialic acid specific substance, the neuriminidase enzyme for viruses and the sialic acid binding sites on the WGA lectin.  Once the influenza virus and WGA lectin have made their way into wider circulation in the host body they are both capable of blurring the line in the host between self-and non-self.  Influenza accomplishes this by incorporating itself into the genetic material of our cells and taking over the protein production machinery to make copies of itself, with the result that our immune system must attack its own virally transformed cell, in order to clear the infection.  Studies done with herpes simplex virus have shown that WGA has the capacity to block viral infectivity through competitively binding to the same cell surface receptors, indicating that they may effect cells through very similar pathways. WGA has the capability of influencing the gene expression of certain cells, e.g. mitogenic/anti-mitogenic action, and like other lectins associated with autoimmunity, e.g. soy lectin, and viruses like Epstein-Barr Virus, WGA may be capable of causing certain cells to exhibit class 2 human leukocyte antigens (HLA-II), which mark them for autoimmune destruction by white blood cells.  Since human antibodies to WGA have been shown to cross react with other proteins, even if WGA does not directly transform the phenotype of our cells into “other,” the resulting cross-reactivity of antibodies to WGA with our own cells would result in autoimmunity nonetheless.

Given the multitude of ways in which WGA may disrupt our health, gain easy entry through our intestine into systemic circulation, and remain refractory to traditional antibody-based clinical diagnoses, it is altogether possible that the consumption of wheat is detracting from the general health of the wheat-consuming world and that we have been, for all these years, “digging our graves with our teeth.”  This perspective may come to the great surprise of the health food industry, whose particular love affair for whole wheat products has begun to go mass market. The increasingly hyped-up marketing of ”whole wheat,” “sprouted grain,” and “wheat germ” enriched products, all of which may have considerably higher levels of WGA than their processed, fractionized, non-germinated and supposedly “less healthy” equivalents, may contribute to making us all significantly less healthy.

It is my belief that a careful study of the wheat plant will reveal that despite our projections man does not have self-proclaimed dominion over Nature, and all that he deems fit for his consumption may not be given to him for food as an inborn right. Though the wheat plant’s uniquely defenseless disposition would appear to make it a rather suitable candidate for mass human consumption, it has been designed with a multitude of invisible “thorns,” with WGA being its smallest and perhaps most potent. If WGA is an uninvited guest at our table, so too are we wheat’s uninvited guest.  Perhaps the courteous thing to do, having realized our mistaken intrusion, is to lick our wounds and simply go our separate ways. Perhaps as the distance between man and his infatuation with wheat grows, he will grow closer to himself and will discover far more suitable forms of nourishment that Nature has not impregnated with such high levels of addictive and potentially debilitating proteins.

[1] Desmond S. T. Nicholl, An Introduction to Genetic Engineering, 3rd Edition ISBN-13: 9780521615211

[2] Ji, Sayer “The Dark Side of Wheat – New Perspectives on Celiac Disease & Wheat Intolerance.” Winter, 08’, Journal of Gluten Sensitivity

[3] Distribution of Wheat Germ Agglutinin in Young Wheat Plants.  Plant Physiol. 1980 Nov;66(5):950-955.  PMID: 16661559

[4] Effects of wheat germ agglutinin on human gastrointestinal epithelium: insights from an experimental model of immune/epithelial cell interaction. Toxicol and Applied Pharmacology 2009 Jun 1;237(2):146-53. Epub 2009 Mar 28. PMID 19332085

[5] Wheat germ agglutinin induces NADPH-oxidase activity in human neutrophils by interaction with mobilizable receptors. Infection and Immunity. 1999 Jul;67(7):3461-8. PMID 10377127

[6] Lectin glycosylation as a marker of thin gut inflammation. The FASEB Journal. 2008;22:898.3

[7] Antinutritive effects of wheat-germ agglutinin and other N-acetylglucosamine-specific lectins.The British Journal of Nutrition 1993 Jul;70(1):313-21. PMID: 8399111

[8] Lectinlike properties of pertussis toxin. . Infection and Immunity 1989 Jun;57(6):1854-7.  PMID: 2722243

[9] Natural human antibodies to dietary lectins. FEBS Lett. 1996 Nov 18;397(2-3):139-42.  PMID: 8955334

[10] Antibodies to wheat germ agglutinin in coeliac disease. Clin Exp Immunol. 1986 January; 63(1): 95–100. PMID: 3754186

[11] Elevated levels of serum antibodies to the lectin wheat germ agglutinin in celiac children lend support to the gluten-lectin theory of celiac disease. Pediatr Allergy Immunol. 1995 May;6(2):98-102. PMID: 7581728

[12] Transcytotic pathway for blood-borne protein through the blood-brain barrier. Proceedings from the National Academy of Sciences U S A. 1988 Jan;85(2):632-6.  PMID: 2448779

[13] Transsynaptic transport of wheat germ agglutinin expressed in a subset of type II taste cells of transgenic mice.  BMC Neuroscience. 2008 Oct 2;9:96.  PMID: 18831764

[14] Distribution of concanavalin A and wheat germ agglutinin binding sites in the rat peripheral nerve fibres revealed by lectin/glycoprotein-gold histochemistry. The Histochem Journal. 1996 Jan;28(1):7-12.  PMID: 8866643

[15] Wheat germ agglutinin, concanavalin A, and lens culinalis agglutinin block the inhibitory effect of nerve growth factor on cell-free phosphorylation of Nsp100 in PC12h cells.  Cell Struct and Function 1989 Feb;14(1):87-93. PMID:2720800

[16] Wheat germ lectin induces G2/M arrest in mouse L929 fibroblasts. J Cell Biochem. 2004 Apr 15;91(6):1159-73. PMID: 15048871

[17] Wheat germ agglutinin and concanavalin A inhibit the response of human fibroblasts to peptide growth factors by a post-receptor mechanism. J Cell Physiol. 1985 Sep;124(3):474-80.  PMID: 2995421

[18] DNA replication in cell-free extracts from Xenopus eggs is prevented by disrupting nuclear envelope function. J Cell Sci. 1992 Jan;101 ( Pt 1):43-53. PMID: 1569128

[19] Effects of wheat germ agglutinin and concanavalin A on the accumulation of glycosaminoglycans in pericellular matrix of human dermal fibroblasts. A comparison with insulin.  Acta Biochim Pol. 2001;48(2):563-72. PMID: 11732625

[20] Analysis of lectin binding in benign and malignant thyroid nodules. Arch Pathol Lab Med. 1989 Feb;113(2):186-9. PMID: 2916907

[21] Further characterization of wheat germ agglutinin interaction with human platelets: exposure of fibrinogen receptors. Thromb Haemost. 1986 Dec 15;56(3):323-7. PMID: 3105108

[22] Wheat germ agglutinin-induced platelet activation via platelet endothelial cell adhesion molecule-1: involvement of rapid phospholipase C gamma 2 activation by Src family kinases. Biochemistry. 2001 Oct 30;40(43):12992-3001. PMID: 11669637

[23] Decreased levels of heat shock proteins in gut epithelial cells after exposure to plant lectins.  Gut. 2000 May;46(5):679-87. PMID: 10764712