Wheat Gluten, Leaky Gut, and Autoimmune Disease Part Four

by Jeffrey Dach MD

Paradigm Shift about “Leaky Gut”

I simply had to attend a recent medical meeting,held literally in my back yard at the Ft. Lauderdale Harbor Marriot, presenting information about a paradigm shift in our understanding of the origin and cause of autoimmune diseases.

Above left image: Norman Borlaug standing in wheat field in Mexico posing for LIFE Magazine in November 1970, courtesy of Time/Life Magazine. Borlaug received the Nobel Prize for his semi-dwarf high yield wheat which averted global famine, literally saving 3 billion lives.

My Own Clinical Experience

From my own clinical experience over the past ten years evaluating and treating patients with autoimmune disease, it has become blatantly obvious that wheat gluten consumption is a major causative factor.

Latest Medical Research Conclusively Proves Connection

Working as a solo medical practitioner brought me to this conclusion.  However the meeting brought home a gratifying point that this is indeed correct.  I was astounded as I listened to William Davis MD and Alessio Fasano MD describe the latest research proving conclusively the connection between wheat leaky gut and autoimmune disease. The exact mechanism has been elucidated.

Three previous newsletters have discussed this connection.
This article is Part Four. See Part One, See Part Two.  See Part Three.

The GI Mucosa, Tight Junction , Zonulin, Guten and “Leaky Gut”

For the past century, medical science believed the gastrointestinal tract is a closed tube representing a sealed mucosal barrier.  This barrier keeps the “bad things” out, such as bacteria and large macromolecules.   The idea of a “leaky gut” expounded by alternative medicine docs and naturopaths has been vehemently rejected by mainstream medicine for decades.

Monumental Paradigm Shift

In a monumental paradigm shift, groundbreaking research has been published in the mainstream medical literature accepting the  concept of leaky gut and autoimmune disease.  Imagine Max Kaiser or Alex Jones getting a half hour time slot on CNN news every night, something that could never happen in a million years. This is the kind of thing we are talking about.

Doctors Who Know the Game

There are many doctors who have been aware of this connection, and publicized it for many years.  This list includes:  Jonathan Wright MD , James Braly MD (powerpoint) and Dr. Christopher Reading. The meeting established overwhelming medical evidence that, yes,  they were right all along.

How It Works: Tight Junctions Open and Close in Response to Zonulin

Electron microscopy from Japan shows the “Tight Junctions” between GI mucosa epithelial cells opening and closing in response Zonulin release (this is a controller protein ). (5-12 )(link).  Click Here to see images of tight junction.

Zonulin is a protein involved in control of the Tight Junctions.

Thanks to Alessio Fasano MD for his discovery of the Zonulin molecule, and much of the published research comes from his lab at the University of Maryland.  He was there at the meeting presenting his findings.(5-12)

Above left image: Schematic Diagram of the Tight Junction which regulates passage of macromolecules across the GI tract mucosal barrier into the blood stream. Courtesy of wikimedia commons.

Gliadin, and Excess Zonulin  in Genetically Susceptible Individuals

In genetically susceptible individuals, possessing the HLA DQ gene, an excessive amount of Zonulin is released upon ingestion of gliadin, a protein in wheat products. (5-12) The excess Zonulin then opens the Tight Junctions between the GI epithelial cells allowing large macromolecules to leak through the GI epithelial layer and allows larger partially digested food particles, proteins and peptide fragments , as well as enteric micro-organisms (gram negative rods)  to leak into the blood stream.  (5-12)

Not Normally Found in the Blood Stream

Needless to say, these particles are not normally found in the blood stream, end up being recognized as “foreign” by the immune system, and then produce inflammatory infiltrate in the wall of the GI tract, as well antibodies which can be picked up in the blood sample for IgG Food allergy testing.

Molecular Mimicry

Through the wonders of “molecular mimicry” this immune response may “cross-react” with our own tissues in an unpredictable manner producing auto-immune diseases such as Celiac disease, Rheumatoid arthritis, Type One Diabetes, Multiple Sclerosis, Hashimoto’s Thyroiditis, Graves Disease, Myasthenia Gravis, Psoriatic Arthritis, Sjogrens Syndrome, Ankylosing Spondylitis , Polymyositis, Dermatomyositis  and many others.

Graves’ Disease Caused by Yersinia Molecular Mimicry (23-29)

An example of this molecular mimicry is found in Graves Disease, in which antibodies to the enteric gram negative organism, Yersinia, have been found to cross react with the TSH receptor, producing hyperthyroidism by stimulating the TSH receptors in the thyroid gland.(23-29)

Gluten consumption opens the tight junctions allowing the Yersinia organism to pass across the mucosal barrier into the blood stream.  The immune system generates antibodies to the Yersinia which crossreact with the TSH receptors, producing Graves hyperthyroidism.  Elimination of wheat products will eventually prove to be curative.  However, medical treatment with Beta Blockers (propranolol, atenolol) and PTU-type drugs (Tapazole) to prevent thyroid storm is advisable in the short term.

How does the Yersinia from the gastrointestinal tract get into the blood stream?  You guessed it: Gluten ingestion triggers Zonulin release causing Tight Juctions to open, causing “leaky gut” in genetically susceptible individuals.  This “leaky gut” allows the Yersinia organism to enter the blood stream.

Microbial Peptides, Molecular Mimicry and Autoimmune Disease

Rheumatoid Arthritis (RA) has been linked to molecular mimicry with the Proteus bacteria, and Ankylosing Spondylitis is associated with Klebsiella microbe. (15-17)

Mouse Model of Multiple Sclerosis – Inducing MS with Molecular Mimicry

Microbial peptides common to several different classes of bacteria can induce Multiple Sclerosis (MS-like) disease in humanized mice.  The anti-microbial antibodies also crossreact with myelin basic protein, a candidate MS auto-antigen.(17)

Type One Diabetes (Juvenile Diabetes) and Celiac Disease are additional text book examples of autoimmune diseases associated with Gluten induced leaky gut.(5-12)

Elimination of Wheat From the Diet Cures Auto-Immune Disease

I was taught in medical school that auto-immune diseases are incurable with unknown etiology, meaning the cause is unknown, and once you get it, there is no known cure for it.  Mainstream treatment of auto-immune disease has changed very little over the last 60 years, using an array of immune suppressive drugs such as prednisone, methotrexate, AZT azothiprine, cyclophosphamide etc.   The newer agents, the TNF alpha inhibitor drugs such as infliximab, adalimumab and etanercept also suppress the inflammatory response without addressing the cause of the illness.  Needless to say, these treatments leave much to be desired, and in some cases may cause horrendous side effects which end up worse than the underlying disease.

The Real Cause is Wheat Gluten in Genetically Suspectible Individuals

As brought to light at the meeting, the real cause of autoimmune disease is wheat gluten ingestion, and the real cure is elimination of wheat products from the diet.  As simple and straight forward as this sounds, mainstream medicine is still deaf to this message,refusing to discuss the evidence already published in their own mainstream medical journals.  Such is the way of medical science.  The wheels of progress turn slowly.

Our Testing Protocol for Auto-Immune Disease

Our testing protocol for gluten sensitivity includes a blood panel which may reveal a typical pattern of vitamin and mineral deficiencies (low B12, low Iron, Low Ferritin, Low Selenium, etc) caused by malabsorption.  Low triglycerides or low cholesterol levels are also useful indicators of underlying gluten sensitivity, leaky gut, and malabsorption.

IgG Food Allergy Testing- Blood Test

In our office we routinely use an IgG food allergy kit.  This kit is inexpensive and easy to do at home.  The test kit comes in a small box containing a spring loaded lance for puncturing the finger, as well as the paper blotter collection strip for the sample blood spots which are air dried and sent to the lab in a mailer.  This is done at home.   Results have been extremely useful. The web site for this kit is Here.

Anti-Gliadin Antibody- Stool Test

In addition, we use Enterolab for anti-gliadin antibody testing.  Enterolab provides a home kit for antibody testing for gluten sensitivity.  This is done on a stool sample sent into the lab from your home.  The kit also include cheek swab for genetic testing.  The web site to obtain the kit is Enterolab.com

ALCAT testing- another excellent test

Perhaps more accurate and sensitive than IgG blood antibody testing is the ALCAT technique which examines white blood cell response to various food antigens.  After all, the immune cell is the white blood cell.  Their technique isolates the white cell layer from the blood sample and runs it through a sophisticated “Coulter Counter” which compares white cell morphology to controls after allowing the white cells to react with the offending food antigens.  The ALCAT test is done by Cell Science Systems, conveniently  located near my office at 852 South Military Trail in Deerfield Beach.  They offer a free blood draw service at the lab for patients who live in the area.

Cyrex Lab Testing

Perhaps the one lab most dedicated to sophistated and high end gluten sensitivity testing is  Cyrex Labs.  They offers several useful “arrays” of antibody testing to evaluating wheat gluten sensitivity, leaky gut, cross reactive foods, and autoimmune susceptibility.

Why Wheat is the Culprit- William Davis MD – Wheat Has Been Changed !!

We previously discussed how the new high yield semi dwarf wheat is a major cause of our epidemic of auto-immune disease, which has increased by a factor of four over the past two decades.    Wheat consumption is also a major cause of our current epidemic of obesity and diabetes. (4)

William Davis MD explains how modern wheat was genetically modified in the 1970’s  by Norman Borlaug, a plant geneticist and pathologist who won the Nobel Prize and Congressional Gold Medal for developing a high yield dwarf wheat which averted a global famine crisis.  This new high yield wheat was a blessing because it literally saved two or three billion people from dying of starvation. See Norman Borlaug web site. Norman Borlaug died at the age of 95 in 2009 .  See Obituary in the LA Times.

Upper Left image : Photo of Norman Borlaug at time of Nobel Prize, courtesy of Nobel Prize web site.

Blessing and Curse- Adverse Health Effects of Modern Wheat

The new high yield wheat was no doubt a blessing, however, the “curse” or downside is the magnified adverse health effects.  Changes made to the gliadin protein in the new “high yield, semi-dwarf” wheat have quadrupled the incidence of celiac disease(6) and other auto-immune diseases.

Opiate Activity of Wheat

Opiate activity of semi-digested peptide fragments from the gliadin protein stimulate the appetite centers of the brain causing “constant hunger” increased caloric intake and obesity.  Because the wheat opiates are addictive, elimination of wheat may cause withdrawal effects in susceptible people.(7)

Wheat Induces Hyperglycemia and Diabetes

Dr Davis spoke extensively on the wheat- Amylopectin component causing hyperglycemia and insulin resistance diabetes, now reaching epidemic proportions in our population.

Wheat protein fragments called peptides act as opiates and stimulate appetite.
Wheat amylopectin A raises blood sugar higher than nearly all other foods.
Wheat germ agglutinin (a lectin) is a direct intestinal toxin.
Modern Wheat is inherently unhealthy and everyone should eliminate wheat from the diet.

For further reading see Dr. William Davis’s new book, Wheat Belly .

Another good book is Dangerous Grains: Why Gluten Cereal Grains May Be Hazardous To Your Health by James Braly MD

Articles with Related Interest:

This article is Part Four. See Part One, See Part Two.  See Part Three.

The Meeting :  Gluten, “Leaky Gut” and Autoimmune Disease.(1)

The speakers were:

1) Alessio Fasano MD, Keynote Speaker, Pediatric Gasteroenterologist and medical researcher from  University of Maryland (

2)William Davis, MD, practicing Wisconsin cardiologist and author of the book, Wheat Belly.(3) Visit his Wheat Belly Blog. You can listen to a William Davis You-Tube lecture.

3) Liz Lipski, PhD, CCN , expert on probiotics and fermented foods

4) David M. Brady, ND, DC  I previousky met Dr Brady at a Metametrix lab seminar in Atlanta.

5) David Perlmutter MD, Integrative neurologist from Naples Florida

6) Gerard Mullin MD, Integrative GI specialist discussed SIBO (small intestine bacterial overgrowth.)

Links and References

Conference information

1) www.a4m.com/anti-aging-conference-fort-lauderdale-nov-2012.html
Gut, Brain, and Auto-immune Disorders: The Role of Food

Alessio Fasano, MD

2) medschool.umaryland.edu/facultyresearchprofile/viewprofile.aspx?id=1891 www.scientificamerican.com/article.cfm?id=celiac-disease-insights

Biography

William Davis MD

3) www.cbsnews.com/8301-505269_162-57505149/modern-wheat-a-perfect-chronic-poison-doctor-says
Modern wheat a “perfect, chronic poison,” doctor says 2012-09-03, CBS News Posted: 2012-09-18 09:13:28

Modern wheat is a “perfect, chronic poison,” according to Dr. William Davis, a cardiologist who has published a book, [Wheat Belly: Lose the Wheat, Lose the Weight, and Find Your Path Back to Health] all about the world’s most popular grain.

Davis said that the wheat we eat these days isn’t the wheat your grandma had: “It’s an 18-inch tall plant created by genetic research in the ’60s and ’70s,” he said. “This thing has many new features nobody told you about, such as there’s a new protein in this thing called gliadin. It’s not gluten. I’m not addressing people with gluten sensitivities and celiac disease. I’m talking about everybody else because everybody else is susceptible to the gliadin protein that is an opiate. This thing binds into the opiate receptors in your brain and in most people stimulates appetite, such that we consume 440 more calories per day, 365 days per year.” Davis said a movement has begun with people turning away from wheat – and dropping substantial weight. “We’re seeing hundreds of thousands of people losing 30, 80, 150 pounds. Diabetics become no longer diabetic; people with arthritis having dramatic relief. People losing leg swelling, acid reflux, irritable bowel syndrome, depression, and on and on every day.” To avoid these wheat-oriented products, Davis suggests eating “real food,” such as avocados, olives, olive oil, meats, and vegetables. “(It’s) the stuff that is least likely to have been changed by agribusiness,” he said. “Certainly not grains. When I say grains, of course, over 90 percent of all grains we eat will be wheat.”

Allessio Fasano MD

Gluten 2012

4) www.biomedcentral.com/1741-7015/10/13/ (full text)
BMC Med. 2012; 10: 13.
Spectrum of gluten-related disorders: consensus on new nomenclature and classification
Anna Sapone,1,2 Julio C Bai,3 Carolina Ciacci,4 Jernej Dolinsek,5 Peter HR Green,6 Marios Hadjivassiliou,7 Katri Kaukinen,8 Kamran Rostami,9 David S Sanders,10 Michael Schumann,11 Reiner Ullrich,11 Danilo Villalta,12 Umberto Volta,13 Carlo Catassi,1,14 and Alessio Fasano corresponding author1

A decade ago celiac disease was considered extremely rare outside Europe and, therefore, was almost completely ignored by health care professionals. In only 10 years, key milestones have moved celiac disease from obscurity into the popular spotlight worldwide. Now we are observing another interesting phenomenon that is generating great confusion among health care professionals. The number of individuals embracing a gluten-free diet (GFD) appears much higher than the projected number of celiac disease patients, fueling a global market of gluten-free products approaching $2.5 billion (US) in global sales in 2010. This trend is supported by the notion that, along with celiac disease, other conditions related to the ingestion of gluten have emerged as health care concerns. This review will summarize our current knowledge about the three main forms of gluten reactions: allergic (wheat allergy), autoimmune (celiac disease, dermatitis herpetiformis and gluten ataxia) and possibly immune-mediated (gluten sensitivity), and also outline pathogenic, clinical and epidemiological differences and propose new nomenclature and classifications.

5) http://www.midwestprs.com/wheat-belly-some-thoughts-about-norman-borlaug-green-revolution

Wheat Belly: Some thoughts about Norman Borlaug and the ‘Green Revolution’
Posted on June 1, 2012 by S. Andrei Ostric, MD

6) http://www.ncbi.nlm.nih.gov/pubmed/20664999

Theor Appl Genet. 2010 Nov;121(8):1527-39. Epub 2010 Jul 28.
Presence of celiac disease epitopes in modern and old hexaploid wheat varieties: wheat breeding may have contributed to increased prevalence of celiac disease.
van den Broeck HC, de Jong HC, Salentijn EM, Dekking L, Bosch D, Hamer RJ, Gilissen LJ, van der Meer IM, Smulders MJ.Plant Research International, Wageningen UR, P.O. Box 16, 6700 AA, Wageningen, The Netherlands.

Gluten proteins from wheat can induce celiac disease (CD) in genetically susceptible individuals. Specific gluten peptides can be presented by antigen presenting cells to gluten-sensitive T-cell lymphocytes leading to CD. During the last decades, a significant increase has been observed in the prevalence of CD. This may partly be attributed to an increase in awareness and to improved diagnostic techniques, but increased wheat and gluten consumption is also considered a major cause. To analyze whether wheat breeding contributed to the increase of the prevalence of CD, we have compared the genetic diversity of gluten proteins for the presence of two CD epitopes (Glia-α9 and Glia-α20) in 36 modern European wheat varieties and in 50 landraces representing the wheat varieties grown up to around a century ago. Glia-α9 is a major (immunodominant) epitope that is recognized by the majority of CD patients. The minor Glia-α20 was included as a technical reference. Overall, the presence of the Glia-α9 epitope was higher in the modern varieties, whereas the presence of the Glia-α20 epitope was lower, as compared to the landraces.  This suggests that modern wheat breeding practices may have led to an increased exposure to CD epitopes.

7) www.ncbi.nlm.nih.gov/pubmed/1309704

FEBS Lett. 1992 Jan 13;296(1):107-11.
Opioid peptides derived from wheat gluten: their isolation and characterization.
Fukudome S, Yoshikawa M. Research Control Department, Nisshin Flour Milling Co., Ltd., Tokyo, Japan.

Four opioid peptides were isolated from the enzymatic digest of wheat gluten. Their structures were Gly-Tyr-Tyr-Pro-Thr, Gly-Tyr-Tyr-Pro,Tyr-Gly-Gly-Trp-Leu and Tyr-Gly-Gly-Trp, which were named gluten exorphins A5, A4, B5 and B4, respectively. The gluten exorphin A5 sequence was found at 15 sites in the primary structure of the high molecular weight glutenin and was highly specific for delta-receptors. The structure-activity relationships of gluten exorphins A were unique in that the presence of Gly at their N-termini increased their activities. Gluten exorphin B5, which corresponds to [Trp4,Leu5]enkephalin, showed the most potent activity among these peptides. Its IC50 values were 0.05 microM and 0.017 microM, respectively, on the GPI and the MVD assays.

blogs –

Fasano A 2012 Aug Interview – Discovery of Zonulin

5) chriskresser.com/pioneering-researcher-alessio-fasano-m-d-on-gluten-autoimmunity-leaky-gut

Interview with Dr Fasano

RHR: Pioneering Researcher Alessio Fasano M.D. on Gluten, Autoimmunity & Leaky Gut

And then in the mid-‘80s, a group of Japanese scientists said, well, actually the spacing between cells is not cemented. They are doors, almost always closed, but they are doors. And that was quite an interesting discovery. And then over the years, more and more information came about, you know, how these doors are made, but what was the missing link was what kind of molecule, substance, or signal or whatever would modulate these doors so they can be opened and closed. And that’s where we stumbled by mistake studying celiac disease that we make a molecule that we call zonulin that regulates the permeability of this space.

And again, through celiac disease we learned that this molecule is produced in excess, in an exaggerated fashion, by people with celiac disease, now finally explaining the inexplicable, how this protein can come through, because now if you have this door stuck open, everybody from the environment can sneak into our body, including gluten, and with that, trigger the autoimmune response.

So that led us to put forward this new paradigm in which the recipe for autoimmunity is made not by two, but three ingredients: You have to be genetically predisposed, you have to have an environmental factor that is the instigator of the immune response, but at the same time you have to have a breach of this barrier so these two elements can interplay.

SIBO Small Intestine Bacterial Overgrowth

So what we understand is that at least for the zonulin pathway — and I’m sure there are going to be many others if they physiologically control the permeability — there are two major stimuli that we found to release zonulin in everybody — everybody. If you have bacteria in your small intestine, where supposedly they should not be there because we’ve been built so that bacteria will be confined in our intestinal tract all in the colon at the very end, where there are no nutrients anymore so they cannot steal. But if there are bacteria, they eventually will be able to colonize the small intestine by going through all these layers of defense that we have been evolving with as human beings, like saliva, the gastric juice defending from almost all bacteria, pancreatic juice, bile, glycocholic — in other words, if this bacteria will go through all of this and will land on the epithelial cells of the intestine and start to sit there and steal nutrients that we ingest with diet, if we have one last thing that we can do to get rid of these guys, enterocytes, i.e. these epithelial cells, when colonized by bacteria, they release a large amount of zonulin. They open this space, water comes in from underneath the intestine into the lumen, will dilute the toxins produced by these bacteria, but at the same time will flush them out so that they will be moved out and removed from the small intestine. This is one stimulus. The other stimulus — and I believe that this is more by mistake of evolution rather than planned design as for the proximal bile contamination — is gluten itself.

We identified two fragments, one of the gluten components, it’s called gliadin, that when introduced to epithelial cells they induce, like for bacteria, zonulin release. And this, again, happens to everybody. What is the difference between everybody and the people that develop a problem with gluten like celiac disease is that while for me, for example, because I don’t have a problem. I eat a Big Mac. I have gluten in there. These fragments release zonulin, which increases permeability. Stuff comes through, including gluten. My immune system that is tuned to do the job right will clean up the mess, and I will not even know that all that happened. Also because this open-and-close is short. It’s a matter of minutes that it will open and a matter of minutes that will turn to be closed.

Gluten Sensitive People People with celiac disease, on the other hand, when they do something like that, not only do they have much more zonulin produced than I do, but also the opening is much more prolonged because these doors get stuck open, and therefore you give much more time for substances from the environment, including gluten, to come through.

And now on this other side, you find this immune system that is not tuned to do the job right, and when they see this enemy, they start to mount an immune response to attack your own body, and that leads to celiac disease.

Dr. Aristo Vojdani’s work in Cyrex Laboratories and what your opinion is on that test, which screens for antibodies to gluten and zonulin and actinomycin and lipopolysaccharide. Zonulin geneticalluy upregulated

Dr. Alessio Fasano: Yeah, so far, we have seen this, because we had enough data, in three autoimmune diseases.

We have seen this in celiac disease and type 1 diabetes and multiple sclerosis. When we discovered what zonulin is all about in terms of genes, now we know that zonulin is the precursor of a molecule, a protein called haptoglobin 2, so we know what kind of molecule it is. And using that as a biomarker, we see that there are three major categories of conditions that see zonulin upregulated or present in a mutated fashion. These are autoimmune diseases, and besides the three that I just mentioned, it has been proven in Crohn’s disease, for example, and in another category there are tumors ovarian cancer, pancreatic cancer, glioma, these kinds of cancers, and then in diseases of the nervous system, including schizophrenia and autism. —–

next-level-nutrition.com/?p=8612
What No One Is Saying About Zonulin — Is Celiac About More Than Genes and Gluten? celiacs produce 30 times as much zonulin as non-celiacs, even though the non-celiacs were not eating gluten-free diets while the celiacs had been off gluten for over two years!

Fasano A 2005

6) www.ncbi.nlm.nih.gov/pubmed/16265432
Nat Clin Pract Gastroenterol Hepatol. 2005 Sep;2(9):416-22.

Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Fasano A, Shea-Donohue T. Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA. afasano@mbrc.umaryland.edu

When the finely tuned trafficking of macromolecules is dysregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing intestinal barrier function. Understanding the role of the intestinal barrier in the pathogenesis of gastrointestinal disease is an area of translational research that encompasses many fields and is currently receiving a great deal of attention. This review is timely given the increased interest in the role of a ‘leaky gut’ in the pathogenesis of gastrointestinal diseases and the advent of novel treatment strategies, such as the use of probiotics.

2008

7) www.ncbi.nlm.nih.gov/pmc/articles/PMC2570116/ (full text)
www.ncbi.nlm.nih.gov/pubmed/18832585
Am J Pathol. 2008 Nov;173(5):1243-52.
Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation: living life on the edge of the wall. Fasano A. University of Maryland School of Medicine, Mucosal Biology Research Center, Health Science Facility II, Baltimore,

The anatomical and functional arrangement of the gastrointestinal tract suggests that this organ, beside its digestive and absorptive functions, regulates the trafficking of macromolecules between the environment and the host through a barrier mechanism. Under physiological circumstances, this trafficking is safeguarded by the competency of intercellular tight junctions, structures whose physiological modulation is mediated by, among others, the recently described protein zonulin. To prevent harm and minimize inflammation, the same paracellular pathway, in concert with the gut-associated lymphoid tissue and the neuroendocrine network, controls the equilibrium between tolerance and immunity to nonself antigens. However, if the tightly regulated trafficking of macromolecules is jeopardized secondary to prolonged zonulin up-regulation, the excessive flow of nonself antigens in the intestinal submucosa can cause both intestinal and extraintestinal autoimmune disorders in genetically susceptible individuals.

This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing intestinal barrier competency.

2012

8) www.ncbi.nlm.nih.gov/pubmed/22109896
Clin Rev Allergy Immunol. 2012 Feb;42(1):71-8.
Leaky gut and autoimmune diseases.
Fasano A. Source Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impaired intestinal barrier function on autoimmune pathogenesis. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance.

When the zonulin pathway is deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases.

9) www.ncbi.nlm.nih.gov/pubmed/22731712
Ann N Y Acad Sci. 2012 Jul;1258:25-33.
Zonulin, regulation of tight junctions, and autoimmune diseases.
Fasano A.Mucosal Biology Research Center and Center for Celiac Research, University of Maryland School of Medicine, Baltimore, Maryland, USA. afasano@mbrc.umaryland.edu Abstract

Recent studies indicate that besides digestion and absorption of nutrients and water and electrolytes homeostasis, another key function of the intestine is to regulate the trafficking of environmental antigens across the host mucosal barrier. Intestinal tight junctions (TJs) create gradients for the optimal absorption and transport of nutrients and control the balance between tolerance and immunity to nonself antigens. To meet diverse physiological challenges, intestinal epithelial TJs must be modified rapidly and in a coordinated fashion by regulatory systems that orchestrate the state of assembly of the TJ multiprotein network. While considerable knowledge exists about TJ ultrastructure, relatively little is known about their physiological and pathophysiological regulation. Our discovery of zonulin, the only known physiologic modulator of intercellular TJs described so far, has increased our understanding of the intricate mechanisms that regulate the intestinal epithelial paracellular pathway and has led us to appreciate that its upregulation in genetically susceptible individuals leads to autoimmune diseases.

2012

10) www.ncbi.nlm.nih.gov/pubmed/22902773
Clin Gastroenterol Hepatol. 2012 Oct;10(10)

Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Fasano A. Mucosal Biology Research Center and Center for Celiac Research, University of Maryland School of Medicine, Baltimore, Maryland.

Abstract One of the most important and overlooked functions of the gastrointestinal tract is to provide a dynamic barrier to tightly controlled antigen trafficking through both the transcellular and paracellular pathways. Intercellular tight junctions (TJ) are the key structures regulating paracellular trafficking of macromolecules. Although steady progress has been made in understanding TJ ultrastructure, relatively little is known about their pathophysiological regulation. Our discovery of zonulin, the only known physiological modulator of intercellular TJ described so far, increased understanding of the intricate mechanisms that regulate gut permeability and led us to appreciate that its up-regulation in genetically susceptible individuals may lead to immune-mediated diseases. This information has translational implications, because the zonulin pathway is currently exploited to develop both diagnostic and therapeutic applications pertinent to a variety of immune-mediated diseases.

2011

11) physrev.physiology.org/content/91/1/151.long (full text)
www.ncbi.nlm.nih.gov/pubmed/21248165

Physiol Rev. 2011 Jan;91(1):151-75.
Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer.

Fasano A. Mucosal Biology Research Center and Center for Celiac Research, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
afasano@mbrc.umaryland.edu Abstract

The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a “leaky gut” in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs. Zonulin has been observed to be involved in intestinal innate immunity (53) and to be upregulated in several autoimmune diseases, including celiac disease (CD) and type 1 diabetes (T1D), in which TJ dysfunction seems to be the primary defect

Bottom: quantitative real-time PCR of the CXCR3 gene confirmed an increased expression of the receptor compared with nonceliac controls that decreased after treatment with a gluten-free diet. Note the increased infiltrate of CXCR3-expressing immune cells in celiac disease biopsies compared with nonceliac controls. The nucleus is in blue (DAPI) and the cytoskeleton in green (FITC). Magnification ×60.

Stimuli That Cause Zonulin Release in the Gut

Among the several potential intestinal luminal stimuli that can trigger zonulin release, we identified small intestinal exposure to bacteria and gluten as the two more powerful triggers (Fig. 7).

Enteric infections have been implicated in the pathogenesis of several pathological conditions, including allergic, autoimmune, and inflammatory diseases, by causing impairment of the intestinal barrier. We have generated evidence that small intestines exposed to enteric bacteria secreted zonulin

In addition to bacterial exposure, we have shown that gliadin also affects the intestinal barrier function by releasing zonulin (35). This effect of gliadin is polarized, i.e., gliadin increases intestinal permeability only when administered on the luminal side of the intestinal tissue (35) (Fig. 7). This observation led us to the identification of the chemokine receptor CXCR3 as the target intestinal receptor for gliadin (92).

Our data demonstrate that in the intestinal epithelium, CXCR3 is expressed at the luminal level, is overexpressed in CD patients

Zonulin Is Upregulated in the Intestinal Mucosa of Celiac Disease Patients.

A fast-growing number of diseases are recognized to involve alterations in intestinal permeability related to changes in TJ competency. These comprise autoimmune diseases, including T1D , multiple sclerosis , and rheumatoid arthritis , in which intestinal TJs allow the passage of antigens from the intestinal milieau, challenging the immune system to produce an immune response that can target any organ or tissue in genetically predisposed individuals (1, 13, 57, 58, 70, 151). TJs are also involved in cancer development, infections, and allergies (32, 55, 57, 147). CD and T1D autoimmune models suggest that when the finely tuned trafficking of macromolecules is deregulated in genetically susceptible individuals, autoimmune disorders can occur (56).

This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the intestinal barrier function. The classical paradigm of inflammatory pathogenesis involving specific genetic makeup and exposure to environmental triggers has been challenged recently by the addition of a third element, the loss of intestinal barrier function. Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of intestinal barrier function secondary to the activation of the zonulin pathway by food-derived environmental triggers or changes in gut microbiota all seem to be key ingredients involved in the pathogenesis of inflammation, autoimmunity, and cancer. This new theory implies that once the pathological process is activated, it is not auto-perpetuating. Rather, it can be modulated or even reversed by preventing the continuous interplay between genes and the environment. Since zonulin-dependent TJ dysfunction allows such interactions, new therapeutic strategies aimed at reestablishing the intestinal barrier function by downregulating the zonulin pathway offer innovative and not-yet-explored approaches for the management of these debilitating chronic diseases.

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Leaky Gut and Autoimmune Diseases

12) http://www.celiaccenter.org/documents/publications/Leaky gut and autoimmune diseases, Clinical Reviews in Allergy
full text
Clinic Rev Allerg Immunol Nov 2011
Leaky Gut and Autoimmune Diseases by Alessio Fasano 2011
A fast growing number of diseases, including autoimmune diseases, are recognized to involve alterations in intestinal permeability related to changes in TJ competency.

Molecular Mimicry

The connection between infection and autoimmune disease is often explained by a mechanism known as “molecular mimicry,” whereby microbial antigens are postulated to
resemble self-antigens

Key Points

1. Autoimmune diseases involve a miscommunication between innate and adaptive immunity;

2. Continuous stimulation by environmental triggers (such as gluten) seems to be necessary to perpetuate the auto-immune process. The autoimmune response can theoretically be stopped and reversed if the environmental trigger (gluten) is eliminated.

3. In addition to genetic predisposition and exposure to triggering antigens, the loss of the protective function of mucosal barriers  (Leaky Gut) is necessary for autoimmunity to develop.

Besides celiac disease, several other autoimmune diseases, including type 1 diabetes [13, 14], multiple sclerosis [15, 16], and rheumatoid arthritis [17], are characterized by increased intestinal permeability secondary to noncompetent TJs that allow the passage of antigens from the intestinal flora, challenging the immune system to produce an immune response that can target any organ or tissue in genetically predisposed individuals [18–21].

The Zonulin Pathway-Zonulin discovered by Fasano’s Group

The discovery of zonula occludens toxin (Zot), an enterotoxin elaborated by Vibrio cholerae that reversibly opens TJ.

Zonulin is overexpressed in tissues and sera of subjects affected by autoimmune diseases,

Celiac Disease- Gluten

There are at least 50 toxic epitopes in gluten peptides exerting cytotoxic, immunomodulatory, and gut permeating activities.

Once gluten is removed from the diet, serum zonulin levels decrease, the intestine resumes its baseline barrier function, the autoantibody titers are normalized, the
autoimmune process shuts off and, consequently, the intestinal damage (that represents the biological outcome of the autoimmune process) heals completely.

Schizophrenia and GLuten Sensitivity, Celiac

13) www.ncbi.nlm.nih.gov/pmc/articles/PMC3004201/
Schizophr Bull. 2011 January; 37(1): 94–100.
Prevalence of Celiac Disease and Gluten Sensitivity in the United States Clinical Antipsychotic Trials of Intervention Effectiveness Study Population

Nicola G. Cascella,1,2 Debra Kryszak,3 Bushra Bhatti,3 Patricia Gregory,4 Deanna L. Kelly,5 Joseph P. Mc Evoy,6 Alessio Fasano,3 and William W. Eaton4

Abstract Celiac disease (CD) and schizophrenia have approximately the same prevalence, but epidemiologic data show higher prevalence of CD among schizophrenia patients. The reason for this higher co-occurrence is not known, but the clinical knowledge about the presence of immunologic markers for CD or gluten intolerance in schizophrenia patients may have implications for treatment. Our goal was to evaluate antibody prevalence to gliadin (AGA), transglutaminase (tTG), and endomysium (EMA) in a group of individuals with schizophrenia and a comparison group. AGA, tTG, and EMA antibodies were assayed in 1401 schizophrenia patients who were part of the Clinical Antipsychotic Trials of Intervention Effectiveness study and 900 controls. Psychopathology in schizophrenia patients was assessed using the Positive and Negative Symptoms Scale (PANSS). Logistic regression was used to assess the difference in the frequency of AGA, immunoglobulin A (IgA), and tTG antibodies, adjusting for age, sex, and race. Linear regression was used to predict PANSS scores from AGA and tTG antibodies adjusting for age, gender, and race.

Among schizophrenia patients, 23.1% had moderate to high levels of IgA-AGA compared with 3.1% of the comparison group (?2 = 1885, df = 2, P < .001.) Moderate to high levels of tTG antibodies were present in 5.4% of schizophrenia patients vs 0.80% of the comparison group (?2 = 392.0, df = 2, P < .001). Adjustments for sex, age, and race had trivial effects on the differences. Regression analyses failed to predict PANSS scores from AGA and tTG antibodies. Persons with schizophrenia have higher than expected titers of antibodies related to CD and gluten sensitivity.

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14) www.ncbi.nlm.nih.gov/pmc/articles/PMC3467411/ full text

Immune Netw. 2012 August; 12(4): 129–138. Published online 2012 August 31.
Immune Disorders and Its Correlation with Gut Microbiome
Ji-Sun Hwang,1,† Chang-Rok Im,2,† and Sin-Hyeog Im
corresponding author1 1School of Life Sciences and Immune Synapse Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Korea. 2Global Leader Program, Bugil Academy, Cheonan 330-941, Korea.

Allergic disorders such as atopic dermatitis and asthma are common hyper-immune disorders in industrialized countries. Along with genetic association, environmental factors and gut microbiota have been suggested as major triggering factors for the development of atopic dermatitis. Numerous studies support the association of hygiene hypothesis in allergic immune disorders that a lack of early childhood exposure to diverse microorganism increases susceptibility to allergic diseases. Among the symbiotic microorganisms (e.g. gut flora or probiotics), probiotics confer health benefits through multiple action mechanisms including modification of immune response in gut associated lymphoid tissue (GALT). Although many human clinical trials and mouse studies demonstrated the beneficial effects of probiotics in diverse immune disorders, this effect is strain specific and needs to apply specific probiotics for specific allergic diseases. Herein, we briefly review the diverse functions and regulation mechanisms of probiotics in diverse disorders.
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antibodies to gut bacteria in autoimmune diseases 2012

15) www.ncbi.nlm.nih.gov/pmc/articles/PMC3290812/
www.ncbi.nlm.nih.gov/pubmed/22454761
Autoimmune Dis. 2012;2012:539282. Epub 2012 Feb 20.

Autoimmunity in Rheumatic Diseases Is Induced by Microbial Infections via Crossreactivity or Molecular Mimicry.
Rashid T, Ebringer A. Source Analytical Sciences Group, Kings College London, 150 Stamford Street, London SE1 9NN, UK.

Abstract A general consensus supports fundamental roles for both genetic and environmental, mainly microbial, factors in the development of autoimmune diseases. One form of autoimmune rheumatic diseases is confined to a group of nonpyogenic conditions which are usually preceded by or associated with either explicit or occult infections. A previous history of clinical pharyngitis, gastroenteritis/urethritis, or tick-borne skin manifestation can be obtained from patients with rheumatic fever, reactive arthritis, or Lyme disease, respectively, whilst, other rheumatic diseases like rheumatoid arthritis (RA), ankylosing spondylitis (AS), and Crohn’s disease (CD) are usually lacking such an association with a noticeable microbial infection. A great amount of data supports the notion that RA is most likely caused by Proteus asymptomatic urinary tract infections, whilst AS and CD are caused by subclinical bowel infections with Klebsiella microbes. Molecular mimicry is the main pathogenetic mechanism that can explain these forms of microbe-disease associations, where the causative microbes can initiate the disease with consequent productions of antibacterial and crossreactive autoantibodies which have a great impact in the propagation and the development of these diseases.

16) www.ncbi.nlm.nih.gov/pubmed/2862470

Lancet. 1985 Aug 10;2(8450):305-7.

Antibodies to proteus in rheumatoid arthritis.
Ebringer A, Ptaszynska T, Corbett M, Wilson C, Macafee Y, Avakian H, Baron P, James DC. Abstract Antibodies to proteus species were measured in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) and in healthy controls by a Coombs agglutination method. The titres to Proteus mirabilis were higher in 30 RA patients being treated with gold than in 24 patients with active AS (p less than 0.001), 28 patients with inactive AS (p less than 0.001), and 41 healthy control subjects (p less than 0.001). Control studies with Klebsiella pneumoniae var oxytoca showed high antibody titres only in active AS patients. MS 2009 BActerial peptides cause MS and other autoimmune diseases

17) users.path.ox.ac.uk/~vdmerwe/Internal/ReprintArchive/2009/harkiolaki.pdf (full pdf) www.ncbi.nlm.nih.gov/pubmed/19303388
Immunity. 2009 Mar 20;30(3):348-57.

T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides.

Harkiolaki M, Holmes SL, Svendsen P, Gregersen JW, Jensen LT, McMahon R, Friese MA, van Boxel G, Etzensperger R, Tzartos JS, Kranc K, Sainsbury S, Harlos K, Mellins ED, Palace J, Esiri MM, van der Merwe PA, Jones EY, Fugger L. Source Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX37BN, UK.

Environmental factors account for 75% of the risk of developing multiple sclerosis (MS). Numerous infections have been suspected as environmental disease triggers, but none of them has consistently been incriminated, and it is unclear how so many different infections may play a role.

We show that a microbial peptide, common to several major classes of bacteria, can induce MS-like disease in humanized mice by crossreacting with a T cell receptor (TCR) that also recognizes a peptide from myelin basic protein, a candidate MS autoantigen. Structural analysis demonstrates this crossreactivity is due to structural mimicry of a binding hotspot shared by self and microbial antigens, rather than to degenerate TCR recognition. Biophysical studies reveal that the autoreactive TCR binding affinity is markedly lower for the microbial (mimicry) peptide than for the autoantigenic peptide.

Thus, these data suggest a possible explanation for the difficulty in incriminating individual infections in the development of MS. Taken altogether, our data suggest that low-affinity hotspot mimicry (limited to a small number of key aspects of the TCRbinding footprint), rather than high-affinity structural mimicry (requiring replication of all features of the binding footprint), may be the more common contributor in the initiation not only of MS but also of other autoimmune diseases, such as rheumatoid arthritis and Type 1 diabetes, in which infections have likewise been implicated. Moreover, the same disease-inducing mimicry peptides can be conserved in many common bacteria, which might explain why it has been difficult to incriminate individual infections in the development of autoimmune diseases.

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Cyrex Labs

18) www.advancedglutentesting.com/intestinal-permeability-test-cyrex-labs-array-2/

Leaky Gut Test – Processed by Cyrex Labs Actomyosin IgG Occludin / Zonulin IgG Occludin / Zonulin IgA Occludin / Zonulin IgM Lipopolysaccharides (LPS) IgG Lipopolysaccharides (LPS) IgA Lipopolysaccharides (LPS) IgM

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SCD-specfic carbohydrate diet for celiac disease

19) scdlifestyle.com/about-the-scd-diet/ What is the Specific Carbohydrate Diet?
scdlifestyle.com/2012/03/the-gluten-free-lie-why-most-celiacs-are-slowly-dying/

The Gluten-Free Lie: Why Most Celiacs Are Slowly Dying

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20) realfoodforager.com/leaky-gut-why-it-happens-and-what-to-do-about-it/

Leaky Gut: Why It Happens and What To Do About It Zonulin is activated by gliadin Gliadin is a protein in wheat, that like gluten, is a trigger for people with the autoimmune disease celiac. However, this study published in the Scandiavian Journal of Gastroenterology in 2006 clearly showed that gliadin can affect zonulin even in people without the genetics for celiac.

The researchers concluded that, Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.

This is extremely significant because it means that anyone who eats food containing gliadin is at risk for developing leaky gut from this food. What foods contain gliadin? Grains contain gliadin. The gluten-free diet is conventional treatment for celiac. Some people do very well with this but there is research that shows that only 66% of celiacs fully heal on the gluten-free diet after 5 years.

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21) pane-of-science.blogspot.com/2012/11/2011-nutrition-4-gluten-sensitivity.html

2011 NUTRITION #4: GLUTEN SENSITIVITY
Originally posted Jan 5, 2012
One of the most surprising lessons for me in 2011 was learning about the whole area of celiac disease, gluten, grain hating, leaky gut, and the whole area of autoimmune diseases. I knew nothing of any of these things in January 2011. This is a summary of my lesson learned and pointers to directions where anyone interested can continue research and reading.

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22)www.freegrab.net/Immune%20Digestive%20System%20Connection.htm

New research is providing a few more answers as to what causes us to feel bad or uncomfortable.

Guilliams: Probiotic Use in Clinical Practice 2011 Probiotic bacteria & your health Tlaskalová: role of gut microbes in diseases 2011 The new medical-health buzz is about the connection between the digestive system, the immune system and bacteria. Human frontiers Listen 2011 This article summarizes information with supporting references about these connections that can cause us to be sick or healthy. Author Sorochan has tried to simplify the complex microbial and bio-chemical information, making it easier for average persons to understand the emerging research information.

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Graves

Graves Hyperthyroidism, Celiac, Gluten, Wheat, Yersinia Abs cross react with TSH Abs, Leaky Gut .  Clinical Case Report of  37 y/o female with Graves Hyperthyroidism and Celiac Dx who becomes euthyroid on Gluten Free Diet

23) http://thyroidscience.com/cases/huang.3.09/huang.et.al.3.16.09.pdf
Case Report: Hyperthyroidism, Iron-deficiency Anemia, and Celiac Disease
Cindy Huang, MD, PGY3, Amy 1 Toscano-Zukor, DO,2 Xiangbing Wang, MD, PhD3
1UMDNJ-Robert Wood Johnson Medical School, Department of Medicine,
One Robert Wood Johnson Place MEB 486, New Brunswick, NJ 08903-0019.
2,3UMDNJ-Robert Wood Johnson Medical School, Department of Endocrinology,
One Robert Wood Johnson Place MEB 384B, New Brunswick, NJ

Abstract.
The objective was to report a case of a woman with celiac disease presenting with hyperthyroidism and iron-deficiency anemia. Methods. We report the clinical course of this patient and her laboratory findings. We highlight the important associations between hyperthyroidism, iron-deficiency anemia, and celiac disease. The literature is reviewed for the typical and atypical presentations of celiac disease in relation to hyperthyroidism
and iron-deficiency anemia. Results. A 37-year-old woman presented with symptoms of hyperthyroidism and was found to have iron-deficiency anemia. During the work up for iron-deficiency anemia, she was diagnosed with celiac disease on small-bowel biopsy. After being placed on a gluten free diet, symptoms of hyperthyroidism improved without anti-thyroid medication.

Conclusion. Our case demonstrates that routine screening for celiac disease should be highly considered for patients with both hyperthyroidism and

Graves and Yersinia

1986

24) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1542330/
Clin Exp Immunol. 1986 May;64(2):249-54.
Thyrotrophin (TSH) binding sites on Yersinia enterocolitica recognized by immunoglobulins from humans with Graves’ disease. Heyma P, Harrison LC, Robins-Browne R. Abstract

Antibodies against the gram negative enteric bacterium Yersinia enterocolitica have been found in a high proportion of persons with autoimmune thyroid disorders, especially in those with Graves’ disease or hyperthyroidism (Shenkman & Bottone, 1981). There is strong evidence that Graves’ disease is caused by receptor autoantibodies which mimic the bioeffects of thyroid stimulating hormone (TSH) on the thyroid (Manley, Knight & Adams, 1982).

Recently, saturable binding sites for TSH were demonstrated in Y. enterocolitica under non-physiological conditions (Weiss et al., 1983). We have characterized TSH binding sites on Y. enterocolitica under physiological conditions and studied their interaction with Graves’ immunoglobulins (Ig’s). Saturable and specific binding of receptor-purified 125I-TSH to lysozyme/EDTA-treated Y. enterocolitica (serotype 03) was demonstrated under both non-physiological and  physiological conditions. Scatchard binding plots were linear indicating a single class of binding site (Kd 1 X 10(-7) M, maximum of 30,000 binding sites  per cell). In the presence of Graves’ Ig’s the binding of 125I-TSH to Y. enterocolitica was significantly inhibited. Graves’ Ig’s also precipitated a  protein of relative molecular mass (Mr) 64,000 from Triton-solubilized, 125I-labelled Y. enterocolitica, similar in size to one of the proteins precipitated  by Graves’ Ig’s from human thyroid membranes.

These findings are consistent with the hypothesis that thyroid autoimmunity may be triggered by bacterial  infection via a mechanism involving crossreactivity at the level of the TSH receptor. They also suggest that elements of mammalian endocrine systems are  highly conserved and have a function in prokaryotes.

1987

25) http://www.ncbi.nlm.nih.gov/pubmed/3618088
Acta Med Austriaca. 1987;14(1):11-4.
[Antibodies to Yersinia enterocolitica in immunogenic thyroid diseases].
[Article in German] Petru G, Stünzner D, Lind P, Eber O, Möse JR.

In 1976 Shenkman et al. revealed that in patients with thyroid disorders antibodies against Yersinia enterocolitica could be demonstrated in increased frequency. In 1983 Ingbar et al. first established that the gram-negative bacterium Yersinia enterocolitica shows on its surface saturable binding sites for thyrotropin (TSH). If such binding sites resemble immunologically human TSH receptors this would indicate that TSH receptor antibodies could be produced in selected individuals having been infected with bacteria showing TSH receptors. The aim of our study was to compare the incidence of antibodies against Yersinia enterocolitica in two groups of thyroid disorders which are either immunogenic (Graves’ disease and Hashimoto thyroiditis) or non-immunogenic (toxic adenomas, endemic goitre). In our series of 111 patients antibodies against Yersinia enterocolitica were demonstrated in a significantly higher percentage (36.3%) in patients suffering from immunogenic than in patients with non-immunogenic thyroid disorders (19.6%). The antibody titres were mainly directed towards Yersinia subtypes 8 and 3. It may, therefore, be assumed that the gram-negative bacterium Yersinia enterocolitica may have an active part in triggering immunogenic thyroid diseases such as Graves’ disease or Hashimoto thyroiditis.

1990

26) http://www.ncbi.nlm.nih.gov/pubmed/2083529
Endocrinol Jpn. 1990 Aug;37(4):489-500.
Antibodies to Yersinia enterocolitica serotype 3 in autoimmune thyroid diseases.
Takuno H, Sakata S, Miura K. Third Department of Internal Medicine, Gifu University School of Medicine, Japan.

Abstract The prevalence of increased titres of antibodies to Yersinia enterocolitica (serotype 3) has been studied in sera from patients with various thyroid diseases. In contrast to the low prevalences of the antibodies in healty subject (24.3%), titres (greater than 10) of anti-Yersinia enterocolitica (anti-Yersinia) were found more frequently in patients with thyroidal disorders, especially in Graves’ disease (70.0%).

Furthermore, high titres of the antibodies (greater than or equal to 160) were found only in patients with Graves’ disease.

There was no significant correlation between the titers of anti -Yersinia antibodies and those of anti-TSH receptor antibodies in sera from patients with Graves’ disease. In seven individual samples of sera, the anti- Yersinia antibody titer was high before treatment, but the decrease in the anti-TSH receptor antibody titer following treatment was associated with a  simultaneous decline in anti-Yersinia antibodies in all of them. A highly positive and significant correlation between the titers of anti-TSH receptor antibodies and anti-Yersinia antibodies was obtained in each of them. These findings could be merely a reflection of the measurement of the cross-reaction of anti-Yersinia antibodies with anti-TSH receptor antibodies but the possibility of an association between Yersinia infection and the production of anti-TSH receptor antibodies in at least some patients with Graves’ disease cannot be ruled out.

2002

27) http://www.ncbi.nlm.nih.gov/pubmed/12193307
Thyroid. 2002 Jul;12(7):613-7.
Relationship between thyroid autoimmunity and Yersinia enterocolitica antibodies.
Corapçioglu D, Tonyukuk V, Kiyan M, Yilmaz AE, Emral R, Kamel N, Erdogan G.
Source Department of Endocrinology and Metabolic Diseases, Ankara University School of Medicine, Ankara, Turkey.

It has previously been proposed that subclinical Yersinia enterocolitica infection may play a role in autoimmune thyroid disease (AITD). In this study, we investigated the relationship between the thyroid autoantibodies and the antibodies that produced against different serotypes of Y. enterocolitica. A total of 215 subjects were included into the study (65 newly diagnosed Graves’ disease [GD], 57 Hashimoto’s thyroiditis [HT], 53 nontoxic diffuse goiter [NTDG], and 40 subjects for control group [CG]). Thyroid receptor antibodies (TRAb), thyroid and agglutinating antibodies against Y. enterocolitica serotype O:3, O:5, O:8, O:9 were measured in the blood samples. The highest incidence of Y. enterocolitica antibody positivity was measured in GD (53.8% for O:3, 29.2%
for O:5, 44.6% for O:8, and 40% for O:9) and followed by HT. In patients with GD, TRAb levels were also higher than in patients with HT, NTDG, and CG. There  was no difference between NTDG and CG in respect to the titer levels and the positivity of both TRAb and Y. enterocolitica antibodies. There was also a weak linear correlation between TRAb level and the titer of antibodies against Y. enterocolitica antigens. It can be concluded that Y. enterocolitica infection may play a role in etiology of GD in Turkey.

2008

28) http://www.ncbi.nlm.nih.gov/pubmed/18284638
Clin Endocrinol (Oxf). 2008 Sep;69(3):491-6. Epub 2008 Feb 18.
Too early to dismiss Yersinia enterocolitica infection in the aetiology of Graves’ disease: evidence from a twin case-control study. Brix TH, Hansen PS, Hegedüs L, Wenzel BE. Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark.

Yersinia enterocolitica (YE) infection has long been implicated in the pathogenesis of Graves’ disease (GD). The association between YE and GD could, however, also be due to common genetic or environmental factors affecting the development of both YE infection and GD. This potential confounding can be minimized by investigation of twin pairs discordant for GD.  We first conducted a classical case-control study of individuals with (61) and without (122) GD, and then a case-control study of twin pairs (36) discordant for GD.  Immunoglobulin (Ig)A and IgG antibodies to virulence-associated Yersinia outer membrane proteins (YOPs) were measured.  The prevalence of YOP IgA and IgG antibodies.

RESULTS: Subjects with GD had a higher prevalence of YOP IgA (49% vs. 34%, P = 0.054) and YPO IgG (51% vs. 35%, P = 0.043) than the external controls. The  frequency of chronic YE infection, reflected by the presence of both IgA and IgG YOP antibodies, was also higher among cases than controls (49%vs. 33%, P = 0.042). Similar results were found in twin pairs discordant for GD. In the case-control analysis, individuals with GD had an increased odds ratio (OR) of YE infection: IgA 1.84 (95% CI 0.99-3.45) and IgG 1.90 (95% CI 1.02-3.55). In the co-twin analysis, the twin with GD also had an increased OR of YE infection: IgA 5.5 (95% CI 1.21-24.81) and IgG 5.0 (95% CI 1.10-22.81).

CONCLUSION: The finding of an association between GD and YE in the case-control study and within twin pairs discordant for GD supports the notion that YE  infection plays an aetiological role in the occurrence of GD, or vice versa.

2011

29) http://online.liebertpub.com/doi/abs/10.1089/thy.2010.0364
http://www.ncbi.nlm.nih.gov/pubmed/21877932
Thyroid. 2011 Nov;21(11):1283-4. Epub 2011 Aug 30.
Bioinformatics support the possible triggering of autoimmune thyroid diseases by Yersinia enterocolitica outer membrane proteins homologous to the human  thyrotropin receptor.  Guarneri F, Carlotta D, Saraceno G, Trimarchi F, Benvenga S.

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