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  • Dr. Ron Hoggan, Ed.D.

    Metabonomics and Celiac Disease: A New Frontier

      Journal of Gluten Sensitivity Winter 2011 Issue. NOTE: This article is from a back issue of our popular subscription-only paper newsletter. Some content may be outdated.

    Caption: Image: CC--Mypouss

    Celiac.com 03/29/2019 - What are we looking for when we ask for testing for celiac disease? The primary objective is usually to discover whether a given set of troubling symptoms are the result of eating gluten. With asymtomatic family members, the objective is likely to avoid developing the many health problems that are in the offing for those with untreated celiac disease. But maybe there is another reason to test for celiac disease. Perhaps some people could achieve optimum health— a better and longer life—through eliminating gluten from their diets. Two relatively new developments in the field of celiac disease research may open the path to testing aimed at optimal health. These discoveries may offer a better understanding of the dynamics of celiac disease and others who are genetically susceptible to gluten’s negative impact on human health. In 2009, Dr. Ivano Bertini and colleagues reported their discovery of a metabonomic signature of celiac disease (1). Metabonomics is a field of study involving an examination of blood and urine looking for signs of multiple metabolic changes caused by a biological irritant or perturbation. These signs are formed by the products of food digestion, cellular assimilation of these nutrients, and the by-products of cellular conversion of  food products to energy, as well as the enzymes produced to facilitate these conversions. These metabolites are identified, quantified, and the patterns they form are determined through a process of nuclear magnetic resonance and subsequent statistical analysis of these findings.  

    Bertini et al discovered that those with untreated celiac disease show a pattern of these various  substances in both their blood and urine (1). This offers a new, holistic approach to the study and understanding of celiac disease. Although, for diagnostic purposes, it is not as accurate as serum antibody tests. This is partly because it does not do as well at distinguishing between latent and active celiac disease. However, this investigative approach does explain some of the variations in the many manifestations of celiac disease, while it transcends many of the controversies that currently surround appropriate treatment of celiac disease, potential celiac disease, latent celiac disease, and asymptomatic celiac disease. It may even offer insight into some elements of non-celiac gluten sensitivity. 

    I have previously described some of the problems with the diagnosis of celiac disease on the basis of intestinal biopsy. In short, these problems include improper sample orientation or harvesting damage done during the endoscopic procedure. Sometimes an inadequate number of biopsies (in the past a single sample was often considered adequate to exclude celiac disease) impedes accurate diagnosis or exclusion. Sampling errors can also cause problems due to patchy villous atrophy in the intestine. There are still some pathologists who do not use the Marsh system, or one of its derivatives, or refuse to count intra-epithelial lymphocytes. They also inhibit accurate diagnosis of this common disease. Sometimes, just getting a referral to see a gastroenterologist can also pose a diagnostic problem. General practitioners can serve as gate-keepers who will not refer patients to gastroenterologists for a variety of reasons. If patients are demonstrating symptoms of celiac disease but are overweight or even of normal weight, or if the patient is demonstrating signs and symptoms of celiac disease with which the practitioner is unfamiliar, they are often refused a referral. These same practitioners will also resist ordering serological antibody testing, despite requests from their patients, citing similar reasons.  When patients have experienced improvements after a trial of a gluten free diet, and now want a diagnosis, they will likely be disappointed. Whether under the supervision of specialists or general practitioners, gluten challenges are particularly difficult as nobody can predict the duration or quantity of gluten that should be consumed to ensure an accurate test.   

    The problems with serum antibody tests are at least equally perplexing. They will often miss milder cases of celiac disease and sometimes fail to identify serious cases, both of which might have been caught if an endoscopic biopsy had been done. Without a concurrent measurement of total IgA, those with IgA deficiency will also be overlooked. IgA deficiency has been reported to constitute about 14% of celiac patients (2). False positive serological tests can also pose a diagnostic problem. Some reports contend that these false positive antibody tests constitute potential or latent celiac disease, while others report them in the context of other bowel diseases, arthritis, and other autoimmune diseases. Still others insist that a gluten free diet should only be recommended to people who have celiac disease with demonstrable villous atrophy. 

    To further confound this issue, some of these antibody tests require the technician to make subtle color distinctions while others are impugned because intestinal parasites and other autoimmune diseases will also cause production of these antibodies, and for any of a number of other reasons. Further, no antibody tests produce results that are completely congruent with intestinal biopsies, so they carry the added problem of being dismissed by many practitioners who recognize celiac disease only on the basis of intestinal biopsies. To further confound this situation, the cyclic nature of celiac disease may also interfere with diagnosis on the basis of either intestinal biopsies or blood tests. This is because a series of intestinal biopsies may appear normal, or blood tests may produce normal results, at one time, yet subsequent testing will reveal celiac disease. 

    Testing for the metabonomic signature of celiac disease, on the other hand, identifies specific metabolite patterns in the urine and blood, and may someday circumvent every one of these problems. The metabonomic signature may prove to be unsurpassed as a tool for increasing our understanding of celiac disease. This investigative process has already reflected three important components of  untreated celiac disease: malabsorption; changes to cellular energy metabolism, and; altered gut microflora/intestinal permeability. 

    While some of this information has been found by other means, this research has produced some new insights into impaired glycolysis at the cellular level, in the context of active celiac disease. This leads to reduced pyruvate and lactate with concurrent increases in blood glucose levels. This compromises our ability to make full use of one of our two main sources of cellular energy. Because of fat malabsorption, which is characteristic of celiac disease, the other major source of cellular nutrients is also compromised. Ketone bodies, a by-product of cellular use of fat, also become an important source of brain fuel in cases of active celiac disease.  Thus, we now know a little more about the lethargy and malaise that often accompanies celiac disease. Our cells are starving for energy and we are incurring much of the same damage that is seen in poorly controlled diabetes, due to chronically elevated blood glucose levels, while some brain functions may be spared through utilizing ketone bodies.  

    Such features of this metabonomic signature are abolished after a year of gluten avoidance.  In subsequent research reported in December of 2010, metabonomic testing has shown similar metabolite patterns in latent or potential celiac disease, which also normalize after a year of following a gluten free diet (3). This is powerful evidence that those with latent or potential celiac disease can benefit as much from the gluten free diet as those who already have villous atrophy. It also opens the door for understanding the dynamics whereby some celiac patients can be overweight while others are underweight but both suffer malnutrition with respect to some micro-nutrients. And it clarifies the importance and therapeutic value of a gluten free diet for those who might otherwise be told that they have potential or latent celiac disease and therefore don’t need the diet.

    Susan, a friend of mine in Arizona who has celiac symptoms and a suggestive family history, was recently told by her gastro that “we don’t believe in gluten sensitivity where there is no villous atrophy”.  Bertini and colleagues comment on their findings with respect to patients such as Susan saying: “They already experience some subtle alteration of the enterocytes (at the microscopic functional level but not at the macroscopic level) and metabolically appear similar to overt celiac disease also without any histological evidence of intestinal damage.” Yet their blood and urine carries a metabonomic signature that clearly demonstrates they would benefit from a gluten-free diet. So despite her negative biopsy, Susan really should follow a gluten-free diet. Bertini and colleagues have demonstrated the benefits through metabolic research.    

    Metabonomics is an exciting new field of research that is poised to reveal hidden facets of many ailments, but it may be particularly helpful to improving our understandings of intestinal ailments and a variety of psychiatric illnesses where we are already aware of altered urinary peptide profiles. Perhaps we will soon see support for the therapeutic use of the gluten free diet in many intestinal, autoimmune, and psychiatric illnesses because of this unique approach to understanding the exquisitely complex machinations of our bodies in sickness and in health.  

    Sources: 
    1. Bertini I, Calabrò A, De Carli V, Luchinat C, Nepi S, Porfirio B, Renzi D, Saccenti E, Tenori L. The metabonomic signature of celiac disease. J Proteome Res. 2009 Jan;8(1):170-7.
    2. Bahari A, Karimi M, Sanei-Moghaddam I, Firouzi F, Hashemi M. Prevalence of celiac disease among blood donors in Sistan and Balouchestan Province, Southeastern Iran. Arch Iran Med. 2010 Jul;13(4):301-5.
    3. Bernini P, Bertini I, Calabrò A, la Marca G, Lami G, Luchinat C, Renzi D, Tenori L. Are Patients with Potential Celiac Disease Really Potential? The Answer of Metabonomics.  J Proteome Res. 2010 Dec 13.

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  • About Me

    As co-author of "Dangerous Grains" and "Cereal Killers", the study of the impact of gluten continues to be a driving passion in my life. I am fascinated by the way that gluten induces illness and impedes learning while it alters mood, behavior, and a host of other facets of our existence. Sure, the impact of gluten on health is an important issue, but that is only the most obvious area of impact. Mood disturbances, learning disabilities, and the loss of quality of life due to psychiatric and neurological illness are even more tragic than the plethora of physical ailments that are caused or worsened by gluten. The further I go down this rabbit hole, the more I realize that grains are a good food for ruminants - not people. I am a retired school teacher. Over the last decade, I have done some college and university level teaching, but the bulk of my teaching career was spent working with high school students. My Web page is: www.DangerousGrains.com

  • Related Articles

    Kathleen La Point
    Celiac.com 12/23/2008 - Metabolites are small–molecule products of biochemical processes in the body’s cells. Analysis of these metabolites can detect changes in the body caused by chemical toxicity, disease, gene mutations, or diet. Bacteria in the gut also contribute to this “metabolic signature”, so it is also a way to understand changes in gut microbe populations.
    Because metabolites are excreted from the cells into blood and urine, collecting these samples can be easy, noninvasive, and inexpensive. Chemical techniques like nuclear magnetic resonance (NMR) spectroscopy are used to analyze the samples. The results of NMR spectroscopy are chemical patterns, showing the simultaneous alterations of many compounds. The measurement and analysis of multiple metabolite changes in response to genetic changes or environmental stimuli is known as metabonomics.
    Metabonomics has a number of potential applications. Ease of sample collection may enable researchers to develop a rapid screening tool for diseases like celiac disease. Using metabonomics, it is not necessary to know the specific metabolites that differ in people with a given disease (the disease biomarkers). Rather than looking for the presence or absence of a particular biomarker, the overall pattern of metabolite concentrations is compared to patterns of people known to have the disease (the metabolic signature of the disease) and patterns of people who do not have the disease. Large numbers of metabolites are analyzed simultaneously, instead of one by one, providing a snapshot into what is happening in the cells at a given time.
    In this first study to investigate the metabonomic signature of celiac disease, blood and urine samples of 34 people with celiac disease were analyzed at the time of diagnosis, which was based on antibody tests and confirmed with biopsies of the small intestine. These patterns were compared to the metabolite patterns of 34 people without celiac disease. Using blood samples, researchers were able to predict celiac disease up to 83% of the time. Analysis of urine samples gave accuracy of about 70%.
    These accuracy rates are lower than those achieved with antibody tests, but this is only the first small study and refining the techniques may significantly improve accuracy rates.In addition, analyzing the metabolic signature may lead to a greater understanding of celiac disease and the cause of its various symptoms. For example, results from this study included lower levels of some metabolites such as pyruvate (a product of glucose breakdown) coupled with elevated levels of other metabolites such as glucose and 3-hydroxybutyric acid (a by-product of fat breakdown) in people with celiac disease.
    These results suggest a possible explanation for chronic fatigue experienced by up to 87% of patients with celiac disease—a possible impairment in the body’s ability to use glucose for energy. As expected, evidence of altered gut bacteria was also found, as were an increase in metabolites that indicate an increased intestinal permeability (“leaky gut”). After 12 months of a strict gluten-free diet, these altered metabolite patterns reverted to normal.
    Metabonomics is an emerging field of study, which like genomics, holds great promise in the understanding, diagnosis, and treatment of diseases like celiac disease.
    Reference:
    Bertini I, et al. The metabonomic signature of celiac disease. Journal of Proteome Research. 2008 Dec 11 [Epub ahead of print]

    Jefferson Adams
    Celiac.com 12/24/2015 - Laboratory tests for hemoglobin, ferritin, calcium, folate, vitamin B12, vitamin D, and thyroid function are regularly ordered in children with celiac disease, despite sufficient evidence for their necessity. To determine the frequency of nutritional deficiencies and levels of thyroid dysfunction in children with celiac disease, researches conducted a study that examined children before and after the initiation of a gluten-free diet.
    The research team included Margaretha Maria Susanna Wessels, MD, Iris I. van Veen, MD, Sabine Lisa Vriezinga, MD, Hein Putter, PhD, Edmond Henri Herman Maria Rings, MD, PhD, and Maria Luisa Mearin, MD, PhD. They are affiliated with the Department of Pediatrics, Department of Statistics, and the Department of Pediatrics, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
    For their study, the team evaluated test results for hemoglobin, ferritin, folate, vitamin B12, calcium, vitamin D (25[OH]D), free thyroxin, and thyroid stimulating hormone of children with celiac disease regularly seen at the Leiden University Medical Center between 2009 and 2014. The team used laboratory reference ranges to define abnormal results. For statistical analysis, they used Pearson χ2 test for trend, unpaired t test, and 1-way ANOVA. 
    Their results for 182 children evaluated, showed 119 were newly diagnosed. About 17% of results were missing for any given year, due to incomplete blood results.
    The most common deficiencies at the time of celiac diagnosis were iron deficiency, found in 28% of celiac patients, vitamin D deficiencies in 27%, and folate deficiency, in 14%. They also saw iron deficiency anemia in 9%, and vitamin B12 deficiency in 1% of celiac patients. They saw no hypocalcemia or thyroid dysfunction.
    At follow-up, they observed iron deficiency, iron deficiency anemia, and folate and vitamin D deficiency 8%, 2%, 3%, and 25% of patients, respectively. They found no vitamin B12 deficiency, hypocalcemia, and thyroid disease.
    From these results, the team concluded that complementary blood investigations are relevant at the time of celiac diagnosis, but have little follow-up use, once the patients adopt a gluten-free diet. They recommend that such tests be conducted only if there is a clear physical issue, such as fatigue or abnormal growth.
    Source:
    Journal of Pediatrics. DOI: http://dx.doi.org/10.1016/j.jpeds.2015.09.078

    Jefferson Adams
    Celiac.com 08/28/2017 - After 14-day gluten challenge, an HLA-DQ-gluten tetramer blood test provides better detection of celiac disease than biopsy. Can that lead to new disease detection methods in patients who are already on a gluten-free diet?
    Doctors attempting to diagnose celiac disease are often confronted by patients who have already given up gluten. For such patients, diagnostic guidelines currently call for a gluten challenge of at least 14 days, followed by duodenal biopsy. There isn't much good data on how many false-positive results are generated by this method. To get a better picture, a team of researchers recently studied responses to 14-day gluten challenge in subjects with treated celiac disease.
    The research team included Vikas K Sarna, Gry I Skodje, Henrik M Reims, Louise F Risnes, Shiva Dahal-Koirala, Ludvig M Sollid, and Knut E A Lundin. They are variously affiliated with the Department of Immunology and Transfusion Medicine, Oslo University Hospital, Norway; K. G. Jebsen Coeliac Disease Research Centre, University of Oslo, Norway; Department of Clinical Service, Oslo University Hospital, Norway; Department of Pathology, Oslo University Hospital, Norway; Centre for Immune Regulation, University of Oslo and Oslo University Hospital, Norway; and the Department of Gastroenterology, Oslo University Hospital, Norway.
    The research team took a group of 20 patients with biopsy-verified celiac disease, all in confirmed mucosal remission, and presented them with a dietary gluten challenge of 5.7 grams per oral gluten per day for 14 days, then conducted duodenal biopsies. They analyzed blood by multiplex assay for cytokine detection, and by flow cytometry using HLA-DQ:gluten tetramers.
    Nineteen of the twenty participants completed the challenge. Biopsy results showed villous blunting in 5 of those 19 patients. Villous height to crypt depth ratio reduced with at least 0.4 concomitantly with an increase in intraepithelial lymphocyte count of at least 50% in 9 of the 19 patients. Interleukin-8 plasma concentration increased by more than 100% after 4 hours in 7 of 19 subjects. Frequency of blood CD4+effector-memory gut-homing HLA-DQ:gluten tetramer-binding T cells increased by more than 100% on day 6 in 12 of 15 evaluated participants.
    For most celiac patients, a 14-day gluten challenge did not result in sufficient mucosal architectural changes for clear diagnosis (sensitivity ≈25%–50%).
    The team found that an increase in CD4+ effector-memory gut-homing HLA-DQ:gluten tetramer-binding T cells in blood 6 days after gluten challenge is a more sensitive and less invasive biomarker for celiac disease.
    The team is calling for further study. Being able to diagnose celiac disease without biopsy could really help to improve the entire diagnostic process, and could easily lead to an increase in diagnosis.
    Source:
    Gut

    Jefferson Adams
    Celiac.com 01/22/2018 - Celiac disease is marked by HLA-DQ2/8-restricted responses of CD4+ T cells to gluten from wheat, barley or rye.
    Currently, in order to properly diagnose celiac disease based on serology and duodenal histology doctors need patients to be on gluten-containing diets. This is a problem for many people, who prefer not to begin ingesting wheat again once they have adopted a gluten-free diet. This can present challenges for doctors attempting to diagnose celiac disease.
    It is known that HLA-DQ–gluten tetramers can be used to detect gluten-specific T cells in the blood of patients with celiac disease, even if they are on a gluten-free diet. The team set out to determine if an HLA-DQ–gluten tetramer-based assay can accurately identify patients with celiac disease.
    The research team included Vikas K. Sarna, Knut E.A. Lundin, Lars Mørkrid, Shuo-Wang Qiao, Ludvig M. Sollid, and Asbjørn Christophersen. They are variously affiliated with the Department of Immunology, Oslo University Hospital – Rikshospitalet, Norway; the KG Jebsen Coeliac Disease Research Centre, University of Oslo, Norway; the Department of Gastroenterology, Oslo University Hospital – Rikshospitalet, Norway; the Department of Medical Biochemistry, Oslo University Hospital – Rikshospitalet, Norway; and with the Centre for Immune Regulation, Oslo University Hospital – Rikshospitalet and University of Oslo, Norway.
    For their study, the team produced HLA-DQ–gluten tetramers and added them to peripheral blood mononuclear cells isolated from 143 HLA-DQ2.5+ subjects. There were a total of 62 subjects with celiac disease on a gluten-free diet, 19 subjects without celiac disease on a gluten-free diet due to perceived sensitivity, 10 subjects with celiac disease on a non-gluten-free diet, and 52 seemingly healthy individuals as control subjects.
    The team used flow cytometry to measure T cells that bound HLA-DQ–gluten tetramers. They then used researchers blinded to sample type, except for samples from subjects with celiac disease on a gluten-containing diet, to conduct laboratory tests and flow cytometry gating analyses. They also conducted analysis on test precision using samples from 10 subjects.
    They found that an HLA-DQ–gluten tetramer-based test that detects gluten-reactive T cells identifies patients with and without celiac disease with a high level of accuracy, regardless of whether patients are on a gluten-free diet.
    This test could conceivably allow celiac diagnosis while suspected patients are still on a gluten-free diet. The team notes that their results require a larger study for validation.
    Could reliable celiac diagnosis be done without making patients consume gluten? Will that become common? Stay tuned for more developments.
    Source:
    Gastrojournal.org

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