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    Galectin-1 Expression Reflects Gluten-Free Treatment Response in Celiac Disease Patients


    Jefferson Adams
    • Galectins control several immune cell processes and influence both innate and adaptive immune responses. Researchers recently explored the role of galectins in intestinal inflammation, particularly Crohn’s disease, ulcerative colitis, and celiac disease.

    Galectin-1 Expression Reflects Gluten-Free Treatment Response in Celiac Disease Patients
    Image Caption: Image: CC--Lauri Heikkinen

    Celiac.com 05/16/2018 - Galectins are a family of animal lectins marked by their affinity for N-acetyllactosamine-enriched glycoconjugates. Galectins control several immune cell processes and influence both innate and adaptive immune responses. A team of researchers recently set out to assess the role of galectins, particularly galectin-1 (Gal-1), in the treatment of celiac disease.

    The research team included Victoria Sundblad, Amado A. Quintar, Luciano G. Morosi, Sonia I. Niveloni, Ana Cabanne, Edgardo Smecuol, Eduardo Mauriño, Karina V. Mariño, Julio C. Bai, Cristina A. Maldonado, and Gabriel A. Rabinovich.

    The researchers examined the role of galectins in intestinal inflammation, particularly in Crohn’s disease, ulcerative colitis, and celiac disease patients, as well as in murine models resembling these inflammatory conditions. 

    Maintaining the fine balance between host immunity and tolerance promotes gut homeostasis, and helps to prevent inflammation. To gain insight into the role of Gal-1 in celiac patients, the team demonstrated an increase in Gal-1 expression following a gluten-free diet along with an increase in the frequency of Foxp3+ cells. 

    The resolution of the inflammatory response may promote the recovery process, leading to a reversal of gut damage and a regeneration of villi. Among other things, the team’s findings support the use of Gal-1 agonists to treat severe mucosal inflammation. In addition, Gal-1 may serve as a potential biomarker to follow the progression of celiac disease treatment.

    Gut inflammation may be governed by a coordinated network of galectins and their glycosylated ligands, triggering either anti-inflammatory or pro-inflammatory responses. That network may influence the interplay between intestinal epithelial cells and the highly specialized gut immune system in physiologic and pathologic settings.

    The team’s results demonstrate that the anti-inflammatory and tolerogenic response associated with gluten-free diet in celiac patients is matched by a substantial up-regulation of Gal-1. This suggests a major role of this lectin in favoring resolution of inflammation and restoration of mucosal homeostasis. 

    This data highlights the regulated expression of galectin-1 (Gal-1), a proto-type member of the galectin family, during intestinal inflammation in untreated and treated celiac patients. Further study of this area could lead to better understanding of the mechanisms behind celiac disease, and potentially to a treatment of the disease.

    Source:

     

    The researchers in this study are variously affiliated with the Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina; the Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina; the Instituto de Investigaciones en Ciencias de la Salud (INICSA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina; the Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina; the Sección Intestino Delgado, Departamento de Medicina, Hospital de Gastroenterología Dr. C. Bonorino Udaondo, Buenos Aires, Argentina; the Unidad de Patología, Hospital de Gastroenterología, Bonorino Udaondo, Buenos Aires, Argentina; the Instituto de Investigaciones, Universidad del Salvador, Buenos Aires, Argentina; and the Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.

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  • About Me

    Jefferson Adams earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,000 articles on celiac disease. His coursework includes studies in biology, anatomy, medicine, and science. He previously served as Health News Examiner for Examiner.com, and provided health and medical content for Sharecare.com.

    Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book Dangerous Grains by James Braly, MD and Ron Hoggan, MA.

  • Related Articles

    Jefferson Adams
    Study Shows Celiac, Crohn's Disease Share Genetic Links
    Celiac.com 02/18/2011 - In their search for a deeper understanding of the connections between celiac disease and Crohn’s disease, scientists have begun to focus on genetic variants that trigger inflammation in the gut.
    A research team examining associations between celiac disease and Crohn’s disease has now confirmed four common genetic variations between the two diseases.
    Their discovery may help to explain why people with celiac disease suffer Crohn’s disease at higher rates than the general population.
    Better understanding the genetic connections will likely pave the way for new treatments for symptoms common to both conditions, such as inflammation.
    The study used a new method of analysis called a genome-wide association study, or GWAS. This allows researchers to look at hundreds of thousands of genetic variations, called single nucleotide polymorphisms, or SNPs, that may be involved in any one disease.
    The research team compared 471,504 SNPs, representing the genomes of about 10,000 people, some of whom had Crohn’s disease, some of whom had celiac disease, and others who were healthy.
    They found four genes that seemed to raise the risk for both diseases. Two of these genes, IL18RAP and PTPN2, had already been associated with each disease.
    Another, called TAGAP, had previously been identified as a risk factor in celiac disease, but was newly associated with Crohn’s disease.
    The fourth gene, PUS10, had been previously been tied to Crohn’s disease, celiac disease, and ulcerative colitis.
    Three of the four genes seem to influence immune system response to perceived threats.
    “The first three we can say are involved in T-lymphocyte function,” Rioux says. “They seem to have a role to play in how these cells respond to a given stimulus.”
    In celiac disease, gluten-induced intestinal inflammation causes damage that prevents the intestine from absorbing nutrients in food. This can cause a wide range of problems, from anemia to osteoporosis to lactose intolerance.
    In Crohn’s disease, inflammation of the digestive tract often causes the bowel to empty frequently, resulting in diarrhea, among other problems.
    Some research shows that people with one condition are more likely to have the other. One study, for example, found that more than 18.5% of people with Crohn’s disease also have celiac disease.
    The study has “completely changed the way we can identify genetic risk factors,” says study co-author John D. Rioux, PhD, an associate professor of medicine at the University of Montreal, in Quebec, Canada.
    “There are sequence differences at the genetic level that get translated down to the protein levels,” Rioux notes. “And these differences may really nudge a person toward inflammation."
    He adds that "we’re just in the beginning, but we hope they may elucidate a common pathway and one day help us discover treatments that correct the underlying genetic changes.”
    Source:

    Jan. 27 issue of PLoS Genetics

    Betty Wedman-St Louis, PhD, RD
    Lectins Are Toxins
    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.
    As carbohydrate binding proteins, lectins are difficult to digest and irritate the brush border of the small intestine. Consequently, the tight junctions of the microvilli are damaged by prolamin and agglutinins which can lead to numerous disorders of the gastrointestinal tract and autoimmune diseases. Lectins are also a major contributor to leptin resistance which contributes to obesity.
    As described in The Handbook of Plant Lectins: Properties and Biomedical Applications (John Wiley, 1998), foods that contain these toxic lectins are members of the pea family and include peanuts, pigeon peas, soybeans, kidney beans, mung beans, lima beans, lentils, fava beans, chickpeas, carob, green and yellow peas. Green beans, snow peas and snap peas are usually well tolerated once the gut has been healed since they are immature protein sources with minor amounts of lectins.
    Lectins are found in other foods including grains and pseudo-grains. Grains are seeds from grasses—barley, oats, rice, rye, millet, wheat, teff, corn, kamut, spelt and possibly wild rice. Many gastroenterologists believe that the detrimental affects of lectins in grains are a factor in the development of celiac disease. Genetics and frequent consumption possibly play a critical role in the severity of sensitivities to these foods.
    Pseudo-grains are seeds from broadleafed plants—amaranth, buckwheat, chia, and quinoa. These seed products were geographically limited to specific populations and only available on a limited basis seasonally. But modern agriculture has greatly increased the consumption of these pseudo-grains because they can be labeled “gluten-free” because US standards allow any grain with less than 20 ppm gluten to be called gluten-free.
    Omitting toxic lectins—prolamins and agglutinins—from the diet is critical for gut health. Prolamins are predominately found in the seeds of plants. Gluten is the most widely known source of prolamins. They get their name from the high content of the amino acid proline. Research studies have shown that the prolamins in quinoa, corn and oats can cause damage to the digestive tract in people with celiac disease, yet these grains are frequently included in a gluten-free diet.
    Aggltinins are named for their ability to cause clumping of red blood cells. The most recent example of how this toxic lectin works is the bioterrorism threat caused from ricin. Ricin is the compound in castor beans that is so toxic that only tiny amounts are needed to cause death. Agglutinins are found on the seed coatings of grains and pseudo-grains and serve to protect the seed from fungus growth. Genetically modified crops—wheat, corn, soybeans—have higher amounts of agglutinins to insure higher yields.
    A leaky gut is harmful to the innate and adaptive immune systems. Toxic lectins cause inflammation and induce cytokine production. As few as five soaked, uncooked kidney beans can lead to gut distress for the raw foodies while 1 tablespoon of peanut butter leads to peanut agglutinins entering the bloodstream soon after consumption.
    Paolo Zatto and Pamela Zambenedetti from Padova, Italy studied lectins, microglia and Alzheimer's Disease (AD) as reported in Lectins and Pathology, 2000. The microglia of 10 AD brains stained intensely for agglutinins. Their research concluded that the glycation reaction seen in AD from lectins may serve as a significant factor in amyloid plaque development and disease progression.
    Bacteria overgrowth in the gut is associated with a wide variety of diseases- septicemia, pulmonary infections, enteropathies. Adhesion of pathogenic bacteria to epithelial cells in the gut can be a critical first stage in the infectious disease process. Michele Mouricout and Bruno Vedrine of Limoges, France described how lectins cause adhesion of numerous bacterial strains to intestines, brain tissues, urinary tract, lung and corneal cells. Their research is reported in Lectins and Pathology, 2000 illustrates the mosiac effect of how agglutinins cause tissue damage.
    Even though lectins have been identified for decades, little interest has been shown by biological and medical science. Since they are so widely distributed in foods consumed daily, lectins may finally become recognized as partners in the pathogenesis of diseases like cancer. Galectin-3 (gal 3) galactoside-binding lectin is found on the surface of most cancer cells and has been reported to promote angiogenesis. Lectins are not oncogenes but they help in cancer progression once initiated. Some are implicated in adhesion while others cause metatasis.
    Isn't it about time that nutrition science took a closer look at the lectin levels in foods consumed daily and customize the diet for lectin sensitivity to better manage inflammation and auto immune diseases? The higher intact of GMO food in the diet, the more lectins are consumed. Without food labeling of GMOs, consumers will continue to be misled and many will remain sick.

    Dr. Ron Hoggan, Ed.D.
    Gluten Grains are a Problematic Food for Humans
    Celiac.com 01/26/2016 - One part of our natural protection from the microbes and toxins in our environment is the innate part of our immune systems. This includes everything from our skin, to the mucous we produce in various tissues which engulfs unwanted or harmful particles, isolating them and ultimately expelling them from the body in fecal matter and mucous, such as from our sinuses. While our immune systems have other components, it is the innate system that provides most of our protection from the world outside our bodies. The intestinal mucosa is very much a part of this system. Thus, since Hollon et al found that "Increased intestinal permeability after gliadin exposure occurs in all individuals" (1), there should be little doubt that humans are not well adapted to consuming these storage proteins from wheat, or gliadin's near relatives from rye and barley. Anyone eating these grains is opening a portal into their bloodstreams so toxins, microbes, along with undigested and partly digested proteins can enter their circulation. Without gliadin's impact, these various substances would probably not have entered the bloodstream and would have been wasted with feces.
    Just as few of us would ever consider putting fecal matter on an open wound, neither would we knowingly introduce this same material into the bloodstream through the intestinal wall. Yet, that is the net effect of humans consuming gluten grains. We are giving microbes access to our circulation. These harmful substances may be destroyed by other parts of our immune systems. Or perhaps we will develop episodic or chronic inflammation, leading to vascular damage where plaques can accumulate to cause atherosclerosis. Or the inflammation may use up available serotonin and its precursor, tryptophan, leading to depression. Or this they may cause one of the many other forms of damage that can be induced by inflammation. Or perhaps these infectious agents will manifest in other ailments, the causes of which will often remain obscure, as they degrade our health. Just one example of this risk can be found in a recent report in which antibiotic resistant staph infections were detected in 13% of pasteurized milk samples, and in 75% of raw milk samples (2). The acid in our stomachs, another part of the innate immune system, may provide some protection against this hazard. 

    On the other hand, microbes that have gained entrance into the circulation have also been implicated in some cases of arthritis, where the infectious agent binds to proteins in synovial fluid. Selective antibodies then target these complexes, causing damage to both the invader and the self tissues (3, 4).
    Toxins, especially those from insecticides and other chemicals likely to be found in or on our food supply are also cause for concern. Although most cases of organophosphate insecticide poisoning were the result of suicide attempts, these substances are widely used on a variety of food crops, and can be very dangerous (5). After all, both herbicides and pesticides are designed to kill small organisms. Because of our size, we may require more of these substances to get the job done but we, too, are organisms.
    One component of such substances is inorganic arsenic, which can also be found in natural rock deposits, some wood preservatives, rice, and sea foods, any or all of which can find its way to our bloodstreams (7) especially if we consume gluten grains. Of particular concern is that rice is often a staple of the gluten-free diet and it has been shown to have a strong affinity for inorganic arsenic, which "is a chronic, non-threshold carcinogen" (7). Thus, unlike smoking tobacco, even the smallest dose can result in cancer. Further, there are many areas of the United States where the groundwater is significantly contaminated with arsenic (8). Either drinking such water or excessive dietary reliance on rice grown in such a contaminated area can result in arsenic poisoning, as reported by Signes-Pastor et al (7) in a housewife in Saudi Arabia, who had celiac disease and relied heavily on rice. These authors first suspected dietary non-compliance until urine tests revealed an arsenic concentration at 46 times the highest value of the normal range (7). Her symptoms included: "progressive fatigue, profound watery diarrhea (12 times/d), palpitation, dry mouth, poor appetite, poor taste, sleeplessness, impaired concentration, and short-term memory" (7).

    Proteins from outside our bodies are eschewed by our selective immune systems, identifying them as foreign, and mount an attack against these "aliens". So any undigested proteins from the foods we eat, if they arrive in our bloodstream, are going to result in the mobilization of antibodies aimed at the destruction of these proteins. This sounds like a process for developing an allergic response against common foods.
    However, some proteins are worse than others. Gliadin, for instance, has long been recognized as harmful to many human cells (9). Humans also lack the necessary enzymes to fully digest it (10). Thus, after gliadin has caused increased zonulin production, leading to increased intestinal permeability, it can enter the bloodstream and travel to various tissues and organs where this undigested or partly digested family of proteins will induce one or more of their range of damaging impacts on the cells each molecule contacts. Dolfini et al have also reported that gliadin "induces an imbalance in the antioxidative mechanism of cells" (11) and it wreaks havoc on human cells by changing their shape, structure, and reducing their viability, as well as inhibiting enzyme production within the cell and/or inducing cell death (11).
    Since some humans have been consuming these grains for more than 10,000 years, one might expect that we would have evolved a digestive tract that could neutralize this threat to our wellness. Unfortunately, the issue isn't that simple. Only a small segment of the human population started cultivating gluten grains so long ago. The early development of this agriculture was also very localized and episodic. It would begin in one area then, for some unknown reason, the fields would be abandoned after some period of time. Then it would (excuse the pun) crop up in another, nearby area of the Fertile Crescent (what is now parts of Iraq, Iran, Kuwait, Syria, Lebanon, Jordan, Palestine, Israel, and Egypt). The net result was that it took some time before cereal agriculture was a thriving concern. This may be explained by the illnesses that are reflected in the bones of those early farmers (11). Gluten grains appear to have taken a much greater toll on their health than it does on us now, so some adaptation has probably occurred. Nonetheless, once grain cultivation got a good start, it spread fairly quickly across Europe, arriving in England by about 5,000 years ago.
    Populations living in environments that were not conducive to grain cultivation, either due to climate or soil conditions would wait much longer to incorporate gluten grains as a staple in their diets. Modern transportation systems were required to bring this crippling food to some doorsteps in Scandanavia, parts of Scotland and Ireland, and many other such environments throughout Europe. However, even in those halcyon days when the sun never set on the British Empire, Europeans really weren't the only people on the planet. They may have behaved as if they were, but that's an issue for another discussion. In the meantime, the bulk of the world's population had not eaten gluten grains until much more recently, when Europeans "shared" these grains almost everywhere they traveled. Most of the populations these Europeans met during their travels had also missed out on the many European plagues, including bubonic plague, smallpox, and typhoid fever, as well as the filthy living conditions that were common in Europe. These conditions had selected only those with the most vigorous immune systems to carry on as Europeans. When gifts such as smallpox-infected blankets were given to natives, these naive populations succumbed, in large numbers.
    Further, only a small percentage of these naive populations who were very recently introduced to gluten were developing celiac disease. For instance, only about 5.6% of Saharawi children of Northern Africa had developed celiac disease when tested by Dr. Catassi and colleagues some 50 years or so after they had begun to eat gluten (12).
    European "explorers" probably didn't really notice such illnesses among their grain-naive hosts. Nobody had the technology or the medical understanding to identify celiac disease or the many neurological ailments that gluten causes anyway. Many of us still deal with deep wells of medical ignorance, in the context of a very modern medical system, when it comes to our disease, so how could we expect anything more from those sea-faring Europeans of four or five centuries ago?
    Perhaps those gluten derived opioids probably felt pretty good to people who tried gluten. Whatever the reason, the rest of the world seems to have adopted Europe's dietary choices, pursuing the "comfort" of gluten grains while developing myriad forms of autoimmune disease, neurological dysfunction, gastrointestinal complaint, and a variety of other ailments. And most of the people I encounter would rather deny the health risks than give up donuts, cake, pie, and toast (13).
    Note: I'm proud to announce that I've been given the privilege of reviewing a new book that will be published early next year, under the Touchstone imprint, by Simon and Schuster. I will be writing about some interesting new insights this exciting book offers into the world of gluten sensitivity in the next issue of the Journal of Gluten Sensitivity.
    Sources:
    Hollon J, Puppa EL, Greenwald B, Goldberg E, Guerrerio A, Fasano A. Effect of Gliadin on Permeability of Intestinal Biopsy Explants from Celiac Disease Patients and Patients with Non-Celiac Gluten Sensitivity. Nutrients 2015, 7, 1565-1576. Akindolire MA, Babalola OO, and Ateba CN. Detection of Antibiotic Resistant Staphylococcus aureus from Milk: A Public Health Implication. Int. J. Environ. Res. Public Health 2015, 12, 10254-10275. Li S, Yu Y, Koehn celiac disease, Zhang Z, Su K. Galectins in the Pathogenesis of Rheumatoid Arthritis. J Clin Cell Immunol. 2013 Sep 30;4(5). Cordain L, Toohey L, Smith MJ, Hickey MS. Modulation of immune function by dietary lectins in rheumatoid arthritis. Br J Nutr. 2000 Mar;83(3):207-17. Coskun R, Gundogan K, Sezgin GC, Topaloglu US, Hebbar G, Guven M, Sungur M. A retrospective review of intensive care management of organophosphate insecticide poisoning: Single center experience. Niger J Clin Pract. 2015 Sep-Oct;18(5):644-50. Hasanato RM, Almomen AM. Unusual presentation of arsenic poisoning in a case of celiac disease. Ann Saudi Med. 2015 Mar-Apr;35(2):165-7. Signes-Pastor AJ, Carey M, Meharg AA. Inorganic arsenic in rice-based products for infants and young children. Food Chem. 2016 Jan 15;191:128-34. United States Geological Survey. 2005. Arsenic in ground water in the United States. http://water.usgs.gov/nawqa/trace/arsenic/ Last Modified: Thursday, 17-Nov-2011 Hudson DA, Purdham DR, Cornell HJ, Rolles CJ. Non specific cytotoxicity of wheat gliadin components towards cultured human cells. Lancet 1976; 1: 339-341. Kagnoff M. Private communication. 2005 Dolfini E, Elli L, Roncoroni L, Costa B, Colleoni MP, Lorusso V, Ramponi S,Braidotti P, Ferrero S, Falini ML, Bardella MT. Damaging effects of gliadin on three-dimensional cell culture model. World J Gastroenterol. 2005 Oct 14;11(38):5973-7. Rätsch IM, Catassi C. Coeliac disease: a potentially treatable health problem of Saharawi refugee children. Bull World Health Organ. 2001;79(6):541-5. Cordain L. Cereal grains: humanity's double-edged sword. World Rev Nutr Diet. 1999;84:19-73.

    Jefferson Adams
    Celiac Disease Linked to Nearly Every Inflammatory Disorder
    Celiac.com 12/05/2017 - It's not uncommon for people with celiac disease to have other medical conditions, including liver disease, glossitis, pancreatitis, Down syndrome, and autism.
    By the same token, people with one or more of these associated disorders can be at greater risk for having or developing celiac disease. Until recently, though researchers didn't have much good data on the numbers behind those risk levels. A new database study of more than 35 million people changes that.
    The study found that, for example, people with autism have celiac disease at rates that are 20 times higher than those without autism. You read that right. People with autism are 20 times more likely to have celiac disease than people from the general population.
    Reporting on his team's findings at the World Congress of Gastroenterology 2017, lead investigator Daniel Karb, MD, a second-year resident at University Hospitals Case Medical Center in Cleveland, says that doctors who treat autistic patients may want to keep an eye out for celiac-like symptoms. "If you have a patient who is autistic and they have all these unusual symptoms, you might want to screen them for celiac disease," said Karb.
    Researchers have long known that people with celiac disease can present with unusual symptoms that fall outside the classic celiac symptoms of malabsorption, steatorrhea, malnutrition, abdominal pain, and cramping after eating, "but this is putting numbers to it," said Dr Karb.
    For their study, Dr. Karb and his colleagues searched the Explorys database, which aggregates electronic health record data from 26 major integrated healthcare systems in the United States. Combing through the records of 35,854,260 people in the database from 2012 to 2017, they found 83,090 celiac disease diagnoses.
    The investigators uncovered significant connections between celiac disease and 13 other autoimmune disorders, such as type 1 diabetes, Crohn's disease, and ulcerative colitis. In fact, the team found that, except for a condition called primary biliary cholangitis, "[e]very autoimmune disease [they] looked at is associated with celiac disease," Dr. Karb reported.
    The study indicates that "there is a large undiagnosed burden of celiac disease," he explained. "And a lot of it is probably because of these atypical presentations."
    As research continues, look for more connections between celiac disease and other inflammatory conditions to be more fully detailed.
    For more on the World Congress of Gastroenterology 2017.
    Source:
    Medscape.com

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