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  • Scott Adams
    Scott Adams

    By Scott Adams •

    What Can Topographic Lectin Mapping Reveal About Celiac Disease?

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    Reviewed and edited by a celiac disease expert.

    A recent study suggests that this microenvironment may have an important role to play in understanding the origins and development path of celiac disease and other sprue-like conditions.

    What Can Topographic Lectin Mapping Reveal About Celiac Disease? - N-acetylglucosaminyl sugars are shown in green (WGA lectin). Image: CC by 4.0--Erin Rod.
    Caption: N-acetylglucosaminyl sugars are shown in green (WGA lectin). Image: CC by 4.0--Erin Rod.

    Celiac.com 04/07/2020 - In the past few years, clinicians have begun to use of specific sugar residue seeking dietary proteins, called lectins, to topographically map the small intestinal cell surface and goblet cell secretory mucins to reveal the tissue's structure and function. Better understanding of the gut microbiome may be crucial to discovering the origins and modes of development of celiac disease and other sprue-like intestinal disorders.

    Researcher Hugh James Freeman of the Department of Medicine, Gastroenterology, at the University of British Columbia, Vancouver, BC, Canada recently set out to examine the relationship between topographic lectin mapping of the epithelial cell surface in normal intestine and celiac disease.


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    Researchers are still in the dark about the exact origins and modes of development of celiac disease, though they generally agree that the culprit is likely an immune-mediated small intestinal mucosal disorder that can cause diarrhea, impaired nutrient assimilation and weight loss. 

    An important part of this process takes place at the surface of the intestinal epithelial cell, which is closely associated with the luminal intestinal microbiome. 

    On that surface, epithelial membrane glycoproteins and glycolipids occur alongside adsorbed molecules that allow interaction with the intestinal microbiome. 

    In recent years, use of specific sugar residue seeking proteins, lectins, that can be found in the diet have been employed topographically to map the small intestinal cell surface and goblet cell secretory mucins to further elucidate the structure and function of this tissue. 

    A growing body of evidence suggests that this microenvironment may have an important role to play in helping researchers understand the origins and development path of celiac disease and other sprue-like conditions.

    Further study might help to shed more light on the role played by this microenvironment, especially in people who suffer from these disorders.

    Read more in the International Journal of Celiac Disease. 2019, 7(3), 69-73

    Edited by Scott Adams


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  • About Me

    Scott Adams

    Scott Adams was diagnosed with celiac disease in 1994, and, due to the nearly total lack of information available at that time, was forced to become an expert on the disease in order to recover. In 1995 he launched the site that later became Celiac.com to help as many people as possible with celiac disease get diagnosed so they can begin to live happy, healthy gluten-free lives.  He is co-author of the book Cereal Killers, and founder and publisher of the (formerly paper) newsletter Journal of Gluten Sensitivity. In 1998 he founded The Gluten-Free Mall which he sold in 2014. Celiac.com does not sell any products, and is 100% advertiser supported.

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    Betty Wedman-St Louis, PhD, RD
    Celiac.com 12/01/2015 - Lectins are carbohydrate binding proteins which promote inflammatory responses like Crohn's disease, systemic lupus, asthma, and rheumatoid arthritis. They were discovered over 100 years ago and cause leaky gut and gastrointestinal dysbiosis yet the push for a plant-based diet focusing on legumes as meat alternatives has overlooked the damage lectins cause to the gut. Legumes offer inferior nutrition compared to animal proteins so toxicity needs to be considered when recommending food choices.
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    Celiac.com 11/02/2019 - 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 draw attention to the powerful little chemical in wheat known as ‘wheat germ agglutinin’ (WGA) which is largely responsible for many of 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.  
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    Lectins are glycoproteins, and through thousands of years of selectively breeding wheat for increasingly larger 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 cellular walls of bacteria are 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 foundational substance for building 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 is not 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 garnered a reputation for “wholesome goodness” the world over, could contain a powerful health-disrupting anti-nutrient, which is only now coming to public attention.  WGA has been overshadowed by the other proteins in wheat.  Humans—not Nature—have spent thousands of years cultivating and selecting for larger and larger quantities of these proteins.  These pharmacologically active, opiate-like proteins in gluten are known as gluten exorphins (A5, B4, B5, C) and gliadorphins.  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 also 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 quest for nourishment from the soil, its roots are challenged with fungi and bacteria that seek to invade the plant.  In its quest for sunlight and other nourishment from the heavens the plant’s leaves become prey to insects, birds, mammals, etc.  Even after the plant has developed beyond the germination and sprouting stages it contains almost 50% of the levels of lectin found in the dry seeds.  Approximately one third of this WGA is in the roots and two thirds is in the shoot, for at least 34 days [3] 
    Each grain contains about 1 microgram of WGA.  That seems hardly enough to do any harm to animals our size.  Lectins, however, are notoriously dangerous even in minute doses and can be fatal when inhaled or injected directly into the bloodstream.  According to the U.S.  Centers for Disease Control it takes only 500 micrograms (about half a grain of sand) of ricin (a lectin extracted from castor bean casings) to kill a human.  A single, one ounce slice of wheat bread contains approximately 500 micrograms of WGA, which if it were refined to 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 such 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 profoundly adverse effects, given suitable conditions.  Ironically, WGA is exceptionally small, at 36 kilodaltons (approximately the mass of 36,000 hydrogen atoms) and 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, 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 are formidable 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.  The common consumption of both wheat and NSAIDs may suggest the frequency of the WGA vicious cycle.  Anti-inflammatory medications, such as ibuprofen and aspirin, increase intestinal permeabilty and may cause absorption of even larger than normal quantities of pro-inflammatory WGA.  Conversely, the inflammation caused by the absorption of WGA lectin is the very reason there is a great need for the inflammation-reducing effects of NSAIDs.  
      
    One way to gauge just how pervasive the adverse effects of WGA are among wheat-consuming populations is the popularity of the dietary supplement glucosamine.  In the USA, a quarter billion dollars’ worth of the glucosamine is sold annually.  The main source of glucosamine on the market is from the N-Acetylglucosamine rich chitin exoskelotons of crustaceans, like shrimp and crab.  Glucosamine is used for reducing pain and inflammation.  We do not have a dietary deficiency of the pulverized shells of dead sea critters, just as our use of NSAIDs is 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 greatly reduced their pain and suffering by ingesting glucosamine and NSAIDs may be better served by removing wheat, the underlying cause of their malaise, from their diets.  This would result in even greater relief from pain and inflammation along with far less dependency on palliative supplements and medicines alike.   
    To further underscore this point, the following are several ways that WGA depletes our health while glucosamine works against it:  
    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 free radicals called 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, and activate, leukocytes [8].  Anti-WGA antibodies in human sera have been shown to cross-react with other proteins, indicating that they may contribute to autoimmunity [9].  Indeed, WGA appears to play a role in the pathogenesis of celiac disease (CD) that is entirely distinct from that of gluten, due to significantly higher levels of IgG and IgA antibodies against WGA found in patients with CD, when compared with patients with other intestinal disorders.  These antibodies have also shown not to cross-react with gluten antigens [10] [11] 
    WGA may be Neurotoxic 
    WGA can pass through the blood brain barrier (BBB) through a process called “adsorptive endocytosis”[12] and is able to travel freely among 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, pulling bound substances with it, has piqued the interest of pharmaceutical developers who are looking to find ways of 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, as receptors, and whose dysfunction has been implicated in neurodegenerative disorders.  WGA may attach to the protective coating on 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 affect 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 intestinal mucosa 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 as a great surprise to 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 claims to the contrary, man does not have dominion over nature.  All that he deems fit for his consumption may not be his inborn right.  Though the wheat plant’s apparently defenseless disposition would seem to make it suitable for mass human consumption, it has been imbued with a multitude of invisible “thorns,” with WGA being its smallest and perhaps most potent defense against predation.  While WGA may be an uninvited guest at our table, wheat is equally inhospitable to us.  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.
    Sources: 
    Desmond S.  T.  Nicholl, An Introduction to Genetic Engineering, 3rd Edition ISBN-13: 9780521615211  Ji, Sayer “The Dark Side of Wheat—New Perspectives on Celiac Disease & Wheat Intolerance.” Winter, 08’, Journal of Gluten Sensitivity  Distribution of Wheat Germ Agglutinin in Young Wheat Plants.  Plant Physiol.  1980 Nov;66(5):950-955.  PMID: 16661559  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  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  Lectin glycosylation as a marker of thin gut inflammation.  The FASEB Journal.  2008;22:898.3  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  Lectinlike properties of pertussis toxin.  .  Infection and Immunity 1989 Jun;57(6):1854-7.  PMID: 2722243  Natural human antibodies to dietary lectins.  FEBS Lett.  1996 Nov 18;397(2-3):139-42.  PMID: 8955334  Antibodies to wheat germ agglutinin in coeliac disease.  Clin Exp Immunol.  1986 January; 63(1): 95–100.  PMID: 3754186  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  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  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  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  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  Wheat germ lectin induces G2/M arrest in mouse L929 fibroblasts.  J Cell Biochem.  2004 Apr 15;91(6):1159-73.  PMID: 15048871  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  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  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  Analysis of lectin binding in benign and malignant thyroid nodules.  Arch Pathol Lab Med.  1989 Feb;113(2):186-9.  PMID: 2916907  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  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  Decreased levels of heat shock proteins in gut epithelial cells after exposure to plant lectins.  Gut.  2000 May;46(5):679-87.  PMID: 10764712 

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