Non-Celiac Gluten Sensitivity

Non-Celiac Gluten Sensitivity (NCGS)

hidden-epidemic-gluten-sensitivity“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.”[696]

“Non Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a “re-discovered” disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA).”[697]

gluten-free“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.”[696]

Besides celiac disease (CD) and wheat allergy, there are cases of gluten reactions in which neither allergic nor autoimmune mechanisms are involved. These are generally defined as “gluten sensitivity” (GS).[696-701] non-celiac-gluten-sensitivityThere are many individuals who experience symptoms when eating gluten-containing products and show improvement when following a gluten-free diet (GFD). The majority of these patients have GS instead of CD. GS patients are unable to tolerate gluten and develop an adverse reaction when eating gluten that usually, and unlike CD, does not lead to damage to the small intestine. While the gastrointestinal symptoms in GS may resemble those associated with CD, the GI symptoms are not accompanied by the concurrence of tTG autoantibodies and therefore does not lead to intestinal destruction.[696]

five_facts_about_noncoeliac_gluten_sensitivityNCGS: Prevalence

Although the prevalence of NCGS is still unclear, epide- miological data have been gene- rated that can help establish the frequency of this condition. One complicating factor in establishing frequency of NCGS is the overlap in symptoms between irritable bowel syndrome (IBS) and NCGS. However, according to the research of Dr. Alesio Fasano at Center for Celiac Research, one of the preeminent researchers of CD and GS in the U.S., it is estimated that approximately 6% of the U.S. population suffers from non-celiac gluten sensitivity.[696]

gluten_symptomsNCGS: Symptoms

There is a wide range of symptoms that have been associated with non-celiac gluten sensitivity. The symptoms in GS may resemble those associ- ated with CD but with a prevalence of extraintes- tinal symptoms, such as brain and cognitive changes, bone or joint pain, muscle cramps, leg numbness, skin disorders, weight loss and chronic fatigue. To date, there are not many large studies that have examined the various manifestations of gluten sensitivity, however, one study stands out. Between 2004 and 2010, 5,896 patients were seen at the Center for Celiac Research, University of Maryland. The criteria for GS were fulfilled by 347 (1:17; 6%) of the patients seen. Their symptoms included abdominal pain (68%); eczema and/or rash (40%); headache (35%); ‘foggy mind’ (34%); fatigue (33%); diarrhea (33%); depression (22%); anemia (20%); numbness in the legs, arms or fingers 20%; and joint pain (11%).[696]

brain-gluten-effectsNCGS: Neurological Impacts

A recent paper titled, “The Gluten Syndrome: a neurological disease” reported findings that gluten sensitivity that is unassociated with celiac disease or gastrointestinal destruction can cause harm to the brain and nervous system, leading to diverse neurological malfunction.[702] Several studies have suggested a relationship between NCGS and neuropsychiatric disorders, particularly autism and schizophrenia.[703] Patients with schizophrenia have higher than expected titers of anti-gliadin antibody (AGA), which are related to CD and GS, whereas the implementation of a GFD seems to improve the behavior of a subset of children with gluten-sensitivity-GI-brain-symptomsautism spectrum disorders (ASD).[704,705]

It appears that gluten sensitivity is more likely to affect the brain and nervous system than the gastrointestinal tract. Various studies have concluded that neurological manifestations of gluten sensitivity are much more common than gastrointestinal disturbances.

“Thus, scientific literature now shows that gluten-immune reactions or gluten sensitivity not associated with the strict diagnostic criteria of celiac disease is more likely to attack the brain and nervous system than any other tissue.”[706]

sad-face-bread“Patients with an enteropathy [disease of the intestinal tract] represent only a third of patients with neurological manifestations and gluten sensitivity.”[707]

How can gluten, a protein found in common food such as bread, pasta and cereal, affect so many different organs and cause such a wide range of symptoms in the human body?

NCGS: How Does Gluten Cause Symptoms?

“The pathogenesis of NCGS is largely unknown, but a mixture of factors such as the stimulation of the innate immune system, the direct cytotoxic effects of gluten, and probably the synergy with other wheat molecules, are clues for the complicated puzzle.”[696]

“The diversity of gluten-induced conditions is in line with the notion that the immune system reacts to and deals with the triggering environmental factor, gliadin, in distinct ways.”[696]

NCGS-CD-pathogenesisAs discussed in the Celiac Disease (CD) section above, gluten is a complex protein that does not get completely digested (broken down) in the human digestive tract. It is well accepted that undigested or partly digested gliadin can affect a wide range of human cell functions.[696] Early introduction of gliadin-containing cereals was recently reported to increase the risk of islet cell autoimmunity in humans leading to type 1 diabetes.[708] Animal studies have implicated wheat gliadin as a dietary factor that increases risk of diabetes. As we learned, CD is characterized by enhanced intestinal permeability and an altered tight junction (TJ) structure between epithelial cells, leading to compromised barrier function. When the integrity of the intestinal TJ is compromised, an immune response to environmental antigens that cross-react with host antigens may develop, thereby triggering the onset of CD.[709,710]

the-web-of-gluten-sensitivityHowever, intestinal permeability does not always occur in GS. In a study conducted by Sapone et al., GS subjects showed a normal intestinal permeability compared to celiac patients. In the same GS patients, certain immune markers were observed which suggest an important role of the innate immune system without any involvement of the adaptive immune response as seen in CD.[711] In vitro studies suggest that wheat amylase-trypsin inhibitors (ATIs) could play a major role as triggers of the innate immune response in GS.[696]

How Did People Suddenly Become Sensitive To Gluten?

“It is now becoming apparent that reactions to gluten are not limited to CD, rather we now appreciate the existence of a spectrum of gluten-related disorders. The high frequency and wide range of adverse reactions to gluten raise the question as to why this dietary protein is toxic for so many individuals in the world. One possible explanation is that the selection of wheat varieties with higher gluten content has been a continuous process during the last 10,000 years, with changes dictated more by technological rather than nutritional reasons. Apparently the human organism is still largely vulnerable to the toxic effects of this protein complex, particularly due to a lack of adequate adaptation of the gastrointestinal and immunological responses.”[696]

spectrum-gluten-related-disordersWe don’t know precisely why there is such an increase in gluten sensitivity in recent years. The introduction of gluten-containing grains, which occurred about 10,000 years ago with the advent of agriculture, represented an evolutionary challenge that created the conditions for human diseases related to gluten exposure.[696] Additionally, gluten is one of the most abundant and diffusely spread dietary components for much of the worWheat-Harvestld’s populations, particularly those of European origin. In Europe, the mean consumption of gluten is 10 to 20 grams per day, with segments of the general population consuming as much as 50 grams or more of gluten per day.[712,713] All individuals, even those with a low degree of risk, are therefore susceptible to some form of gluten reaction during their life span.[696]

“Much of the world’s production of wheat is consumed after it has been processed into bread, other baked goods, pasta and noodles, and, in the Middle East and North Africa, bulgur and couscous. In addition, the wide availability of wheat flour and the functional properties of gluten proteins provide the rationale for their wide use as an ingredient in food processing.”[696]

“Therefore, it is not surprising that during the past 50 years we have witnessed an ‘epidemic’ of CD and the surging of new gluten-related disorders, including the most recently described GS.”[696]

questioning-faceWhy Have Rates of Gluten Sensitivity and CD Sky-Rocketed the Past 50 Years?

There appear to be a few factors that may explain this recent increase in gluten-related disorders.

Factors that could be contributing to increased prevalence of gluten sensitivity:

  • Hybridization of wheat/GMO foods

  • Gluten deamidation/processing

  • Long-term storage of gluten leading to enterotoxin contamination

wheat-growing-fieldHybridization of Wheat and GMO Foods

The grains we consume now are not the same grains we used to consume as children or that our parents consumed. These are completely different grains and proteins. These grains are artificially-selected for (hybridized) for reasons such as increasing the gluten content of the grains. Hybridization is the process of creating a new protein by combining different strains of wheat together, as opposed to the process of inserting or deleting genes associated with genetic modification. Hybridization involves cross-breeding various species in order to obtain a desired characteristic in the grain. Gluten is not technically genetically modified, but it has been significantly hybridized. This may create as much as 5% of new protein sequences in the new strain that are not found in the original sources. Many people feel that the hybridization of wheat has created a “new wheat” and one that appears to be very immunoreactive, especially to the brain and nervous system.

Gluten Deamidation

“In many industries, wheat isolates have been produced by means of chemical and enzymatic treatments. This treatment induces the solubilization of gliadins in aqeous buffers by means of deamidation to make them more soluble in water. In a double-blinded, placebo-controlled study, subjects did not react to native wheat flour but had severe reactions to deamidated wheat isolates. It is concluded that treatments used for gluten deamidation generate new allergenic epitopes.”[715]

deamidated-gliadin-2The other change that may be contributing to increased immunoreactivity of gluten is the deamidation of gluten. Deamidation of gluten is the product of acid or enzymatic treatment of gluten used by the food-processing industry to make the grains more water-soluble and more easily transformed into various food products. Gliadins are soluble in alcohol and cannot be mixed with other foods (like milk) without changing the food’s qualities. However, the food-processing industry has found that deamidated gliadin is soluble in water and much easier to combine with foods. The bad news is that there is a severe immune response to the processed deamidated gliadin.

wheat-isolates-2“This extensive use of wheat isolates in the food industry may be the major cause of hidden food allergies…The wheat isolates are used as food emulsifiers, gelling agents, film formation aid, stretchability agents in meat products, sauces, soups and as clarifying agents in red wines. Because food isolates or deamidated gluten are new food ingredients, when allergy to wheat is suspected, immune reaction to wheat isolates should be tested…”[716]

Wheat-IsolatesOverall, it is clear that although wheat does not fit the strict definition of a genetically-modified food (GMO), we are not longer consuming the wheat protein we used to eat and that the hybridization and deamidation of wheat protein are causing significant immune activation.

storage-grainsLong-Term Storage of Gluten Leading To Enterotoxin Contamination

The other factor that is likely contributing to gluten sensitivity is long-term storage of these grains in warehouses. Grains are stored in warehouses for years before they are purchased by the food companies. The average grain is stored in bins for about two years. Meanwhile, toxic compounds such as aflotoxins (mold/smut) are known to grow in wheat, which cause immunological reactions in some people. These compounds may denature the proteins and are very inflammatory compounds.

The-Truth-About-Toxic-WheatSo the grains that are now being consumed in our culture are genetically-modified, deamidated, rotten enterotoxin-filled grains. The outcome of this is that we now have a very inflammatory compound in the food supply which is commonly consumed by the average American. When you give this very inflammatory compound to someone with inflammatory disease, such as autoimmunity or any type of systemic inflammation, this tends to enhance their systemic inflammation.

NCGS Assessment

“Given the lack of a NCGS biomarker, there is the need for standardizing the procedure leading to the diagnosis confirmation.”[717]

“A thorough knowledge of the differences and overlap in clinical presentation among gluten-related disorders, and between them and other gastrointestinal disorders, will help clinicians in the process of differential diagnosis.”[718]

gluten-freeNon-celiac gluten sensitivity is still mainly a diagnosis of exclusion, in the absence of clear-cut diagnostic criteria. A pragmatic approach combining findings from the clinical history, symptoms, serological and histological tests is required in order to reach an accurate diagnosis.

The introduction of a gluten-free diet (GFD) and ‘open challenge’ (that is, the monitored reintroduction of gluten-containing foods) are most often used and continues to be the gold standard for assessing for gluten sensitivity. This requires the adherence to a gluten-free diet (GFD) for a minimum of 2-3 months and involves the reintroduction of gluten. However, there is now reliable immunological testing available to screen for gluten sensitivity that can be used in place of the GFD offered by Cyrex Labs. The Array 3 Comprehensive Gluten Sensitivity Screen involves testing IgA and IgG antibodies to the various wheat fractions that have been identified in gluten immunological reactions. This allows for faster and easier assessment of GS without having to adhere to a GFD for a prolonged period of time.What-doctors-are-saying-about-Cyrex-Array-3

Treatment of GS: Gluten-Free Diet

“The natural history of other gluten-related disorders, such as GS, is still unclear. Further studies are urgently required to clarify whether the spectrum of toxic cereals, the gluten threshold and the disease duration are the same in gluten allergy and/or sensitivity as in CD.”[696]

Gluten-DigestTreatment of gluten-related disorders is based on excluding gluten-containing cereals from the diet. Wheat, barley and rye proteins are completely eliminated from the diet in GS and other gluten-related disorders. Sometimes the practitioner will recommend supplementing with enzymes that are capable of digesting gluten more efficiently and at a faster rate than normally occurs in the intestinal tract. Enzymes such as these can be extremely helpful for both the CD or GS patient to minimize the symptoms associated with accidental gluten exposures.

gluten-freedomCan I Ever Eat Wheat Again?

In cases of CD, since gluten is the trigger of the autoimmune intestinal destruction, it is important the patient refrain from gluten ingestion permanently. However it is not known if patients with gluten sensitivity can safely eat wheat again at some point in time without symptoms. In most cases, it is reasonable to allow the person to ingest a small amount of gluten after following a GFD for a period of time (ie: two to three months) and observe any effects. Most people usually report an increased sensitivity to gluten and an exaggerated symptomatic response when gluten is ingested after following a GFD for a length of time. In such cases, we recommend continued abstinence from gluten. But in most cases of GS, unlike in CD, symptoms are transient and will subside without serious consequences to the health of the individual.

Related Articles

The Gluten Sensitivity, Leaky Gut and Autoimmunity Connection

Intestinal Permeability/Leaky Gut

Inflammatory Bowel Disease (IBD)

Celiac Disease

Autoimmune Disease

Introduction to autoimmune disease: What is it? How common is it? How is it diagnosed? How is it managed?

What are the different types of autoimmune disease? How common is Hashimoto’s hypothyroidism? What is involved in the development of AI disease?

What are the mechanisms and mediators involved in autoimmunity? Intestinal permeability promotes autoimmunity. Gluten sensitivity and autoimmunity connection.

What role do chronic bacterial and viral infections play in autoimmunity?  What role do environmental toxins play?  The role of the glutathione and nitric oxide synthase (NOS) systems and development of autoimmunity.

How do we modulate the autoimmune response? What role do the glutathione and nitric oxide synthase (NOS) systems play in preventing and modulating AI disease?  What role does vitamin D play?

References

  1. Anna Sapone, Julio C Bai, Carolina Ciacci, et al. Spectrum ofgluten-related disorders: consensus on new nomenclature and classification. BMC Med.2012; 10: 13. Published online 2012 February 7. doi: 10.1186/1741-7015-10-13
  2. Carlo Catassi, Julio C. Bai, Bruno Bonaz, et al. Non-CeliacGlutenSensitivity: The New Frontier of Gluten Related Disorders. Nutrients. 2013 October; 5(10): 3839–3853. Published online 2013 September 26. doi: 10.3390/nu5103839
  3. Anderson LA, McMillan SA, Watson RG, et al. Malignancy and mortality in a population-based cohort of patients with coeliac disease or “gluten sensitivity”. World J Gastroenterol.2007;13:146–151.[PMC free article] [PubMed]
  4. Brandtzaeg P, Halstensen TS, Kett K, et al. Immunobiology and immunopathology of human gut mucosa: humoral immunity and intraepithelial lymphocytes. Gastroenterology. 1989;97:1562–1584.[PubMed]
  5. Catassi C, Fasano A. Celiac disease.Curr Opin Gastroenterol.2008;24:687–691. doi: 10.1097/MOG.0b013e32830edc1e. [PubMed] [Cross Ref]
  6. Hoffenberg EJ, MacKenzie T, Barriga KJ, et al. A prospective study of the incidence of childhood celiac disease.J Pediatr.2003;143:308–314. doi: 10.1067/S0022-3476(03)00282-8. [PubMed] [Cross Ref]
  7. Ford RP. The gluten syndrome: a neurological disease. Med Hypotheses. 2009 Sep;73(3):438-40
  8. Carlo Catassi, Julio C. Bai, Bruno Bonaz, et al. Non-CeliacGlutenSensitivity: The New Frontier of Gluten Related Disorders. Nutrients. 2013 October; 5(10): 3839–3853. Published online 2013 September 26. doi: 10.3390/nu5103839
  9. Cascella NG, Kryszak D, Bhatti B, et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population.Schizophr Bull.2011;37:94–100. doi: 10.1093/schbul/sbp055. [PMC free article] [PubMed] [Cross Ref]
  10. de Magistris L, Familiari V, Pascotto A, Sapone A, et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives.J Pediatr Gastroenterol Nutr.2010;51:418–424. doi: 10.1097/MPG.0b013e3181dcc4a5.[PubMed] [Cross Ref]
  11. Hadjivassiliou M, et al. Gluten sensitivity: from gut to brain. Lancet Neurol. 2010 Mar;9(3):318-330
  12. Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry. 2002 May;72(5):560-563
  13. Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies.JAMA.2003;290:1721–1728. doi: 10.1001/jama.290.13.1721. [PubMed] [Cross Ref]
  14. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer.Physiol Rev.2011;91:151–175. doi: 10.1152/physrev.00003.2008.[PubMed] [Cross Ref]
  15. Schumann M, Günzel D, Buergel N, et al. Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease. Gut. 2012;61: 220–228. doi: 10.1136/gutjnl-2011-300123.[PubMed][Cross Ref]
  16. Sapone A, Lammers KM, Casolaro V, et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity.BMC Med.2011;9:23. doi: 10.1186/1741-7015-9-23. [PMC free article] [PubMed] [Cross Ref]
  17. Gibert A, Espadaler M, Angel Canela M, et al. Consumption of gluten-free products: should the threshold value for trace amounts of gluten be at 20, 100 or 200 ppm?Eur J Gastroenterol Hepatol.2006;18:1187–1195. [PubMed]
  18. Catassi C, Fabiani E, Iacono G, et al. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease.Am J Clin Nutr.2007;85:160–166. [PubMed]
  19. Luca Elli, Leda Roncoroni, Maria Teresa Bardella. Non-celiacglutensensitivity: Time for sifting the grain. World J Gastroenterol. 2015 July 21; 21(27): 8221–8226. Published online 2015 July 21.doi: 10.3748/wjg.v21.i27.8221
  20. Anaphylaxis to wheat isolates: immunochemical study of a case proved by means of double-blind, placebo-controlled food challenge. J Allergy Clin Immunol. 2003 Apr; 111(4):897-899
  21. The immunology of immediate and delayed hypersensitivity reaction to gluten. European Journal of Inflammation. 2008 Jan;6(1):1721-1727.
  22. Carlo Catassi, Luca Elli, Bruno Bonaz, et al. Diagnosis ofNon-Celiac Gluten Sensitivity (NCGS): The Salerno Experts’ Criteria. Nutrients.2015 June; 7(6): 4966–4977. Published online 2015 June 18. doi: 10.3390/nu7064966
  23. Luca Elli, Federica Branchi, Carolina Tomba, et al. Diagnosis ofglutenrelated disorders: Celiac disease, wheat allergy and non-celiac gluten sensitivity. World J Gastroenterol. 2015 June 21; 21(23): 7110–7119. Published online 2015 June 21.doi: 10.3748/wjg.v21.i23.7110