Gluten Sensitivity

What is Causing the Gluten Sensitivity Problem?

What are the possible mechanisms and/or risk factors behind this silent, but spreading condition. We suggest that possible risk factors include human genetics, plant genetic modifications, gluten as a food additive, environmental toxins, hormonal influences, intestinal infections and autoimmune diseases. Each of these postulated risk factors are now briefly discussed, keeping in mind that this is speculative, and not evidenced-based.

Human Genetics

There is no question that a genetic component exists for celiac disease,^[35] but no evidenced-based research has yet been conducted to determine whether the same is true for gluten sensitivity.

Plant Genetic Modifications

Does changing the genetic makeup of wheat proteins through wheat breeding cause problems?

Wheat Breeding Selective breeding has modified wheat over the last 100 years to produce higher yields, improve disease resistance and create better bread-making characteristics.^[36] Wheat flour is preferred over flours from other grains because approximately 80% of its proteins consist of gliadins and glutenins. Dough forms when these proteins in wheat, rye, barley and possibly oat flour combine with water and cross-link predominantly through disulfide bond formation during the manipulation of kneading. The proteins in flours from other grains do not form dough as well as wheat flour and are therefore not preferred for producing baked products.

Improving Gluten Strength Gluten is important to the baking industry because it provides elasticity and shape to dough by forming a network of proteins that entrap rising gas bubbles during the fermentation process, allowing it to rise. Baking then sets the shape of a multitude of baked products through protein denaturation and gelatinization of the starch component.

Plant breeding has improved the 'gluten strength' of wheat varieties. To the baking industry, that means the flour may contain the same amount of protein, but demonstrates the characteristics of flours with higher protein content. This translates into longer dough mixing time, greater loaf volume potential and increased ability to hold shape during baking. The bottom line is that wheat is cheaper if it contains less protein, but yields the same gluten strength.

How Did This Happen? The chemical mechanism behind the immune response to certain proteins in grains is complex.^[37] Tye-Din et al. made a major scientific contribution by mapping the toxic epitopes in protein sequences.^[38] What follows is a summary of Colgrave and colleagues' clear overview on gluten proteins:^[39]

Proteins from the seeds of cereal grains (grasses) are primarily stored as albumins (water soluble extraction), globulins (salt solution), glutelins such as glutenin (weak acid or base) and prolamins such as gliadin (alcohol).^[40] Examples of prolamins found in grasses include gliadin in wheat, hordein in barley, secalin in rye, avenin in oats, orzenin in rice, zein in corn and kafirin in sorghum.^[41] Figure 1 shows the classification of gluten proteins from the grass family. Prolamins found under the Pooideae subfamily, specifically the tribe Triticeae (wheat, barely and rye), and possibly the tribe Avenai (oats), may induce celiac disease in genetically predisposed individuals. Gluten-free grains (and their prolamins) include, but are not limited to, rice (orzenin), corn (zein), sorghum (kafirin) and millet (setarin).

Prolamins derive their name form their high proline and glutamine content that is resistant to proteolysis during digestion.^[42] The major prolamins in wheat are gliadins and glutenins.

Gliadins in wheat flour are further subdivided into α, β, γ and omega-gliadins (and peptides released from α-gliadins). Peptides from α-gliadin induce the greatest immune response (T-cell stimulatory response), which may lead to the development of celiac disease in genetically predisposed individuals. α-gliadin toxicity, and the resulting destructive cascade of immune reactions possibly leading to small intestinal villi damage, is largely mediated by a single glutamine in a single peptide. Colgrave et al. explain that partially hydrolyzed peptides cross the epithelium and gain access to the lamina propria by an unknown mechanism where tissue transglutaminase deaminates the glutamine amino acid that stimulates the immune response.^[43] Mutation of this glutamine to lysine, for example, abolishes the celiac toxicity of α-gliadin.^[39,44]

The α-gliadins are a gene family encoded by the Gli-2, Gli-A2, Gli-B2 and Gli-D2 loci located on the short arms of three homologous chromosomes (6AS, 6BS and 6DS) of hexaploid bread wheat (Triticum aestivum L.). Each of these loci may contain from 25 to 35, or even 150 α-gliadin genes per haploid genome.^[45]

Different species of wheat differ in their number of chromosomes: diploid (two sets of chromosomes, 2N), tetraploid (four sets, 4N) and hexaploid (six sets, 6N). High protein content is associated with an increased proportion of gliadins, including the α-gliadins, while strength is associated with selecting the most appropriate combinations of glutenin alleles. Higher ploidy (more chromosomes) wheats may contain more gluten proteins.^[46]

What is the Effect of Changing Gluten Proteins in Wheat? Does increasing these α-gliadins through selective breeding, or future genetic modification, increase the risk for celiac disease or gluten sensitivity in the population? van den Broeck and colleagues suggested that, "modern wheat breeding practices may have led to an increased exposure to celiac disease epitopes".^[36] However, the level of gluten sensitivity may not be directly related to α-gliadin content. Celiac disease is associated with the presence of epitopes (sequence of Proline–Serine–Glutamein–Glutamine and also Glutamine–Glutamine–Glutamine–Proline) and while present in the gliadin fraction, they may also exist in the glutenin fraction.

Wheat Breeding Decreases Celiac Disease Risk Selection for nontoxic varieties of wheat is possible,^[47] however the toxicity may not be completely eliminated. Some researchers suggest that celiac disease risk can be reduced by breeding wheat for a 'low celiac disease toxic' trait.^[45] Molberg et al. stated that, "a diet based on baking-quality gluten from a wheat species that expresses no or few T-cell stimulatory gluten peptides should be equally well tolerated by the celiac patients and, importantly, also be beneficial for disease prevention".^[48] Frisoni and associates demonstrated 10 years earlier, that wheat with lower gliadin fractions were less toxic in vitro.^[49]

Modified Starches The food industry also alters the chemical structure of starches to create a variety of functions in processed foods. Despite a review suggesting that modified food starches are 'safe',^[50] other researchers document a few cases (four out of 21) of increased breath hydrogen, loose stools and/or nonspecific diarrhea associated with modified food starches used in some baby foods.^[51] Do these starches cause gastrointestinal symptoms and possibly increased inflammation in a small percentage of the population? If so, their susceptible intestines are vulnerable to altered food products, and their clinicians are left wondering what is causing their symptoms.

Future Genetic Modifications In view of the above alterations, our wheat has changed, as we live today by rules laid down by officials and politicians that sometimes have very limited learning in the laws they pass because they lack sufficient scientific training. The questions now presented are not evidence-based, but serve to stimulate future scientific discussion encompassing both supporting and opposing views. Has increasing 'gluten strength' created a serious clinical problem? Are patients with gluten sensitivity, but not celiac disease, predisposed to this condition? Or has the increased gluten in grains created a problem for people that would never have been sensitized if they had remained on a diet of regular 'original' grains? A real problem looms on the horizon if the genetically modified gluten is allowed into the market,^[52] as this protein is already problematic in people with celiac disease, and what appears to be a growing segment of the population with gluten sensitivity.

Gluten as a Food Additive

The potential problem of increasing 'gluten strength' in wheat is overshadowed by the common practice of adding gluten to some foods. Gluten powder can be added to soups, sauces, potato chips, candies, ice cream and meat products.^[36] It can also be added to doughs, dietary supplements, pills and livestock feed. Even inhaling gluten-containing dust particles released during the feeding of cattle can be problematic, and was attributed to the diagnosis of celiac disease in two adults.^[53]

Gluten is currently added to certain food products with either no knowledge and/or concern for the subgroup of the population prone to celiac disease or the growing segment of people with gluten sensitivity. Between 1984 and 1996, an epidemic of celiac disease (from 1 to 3%) occurred in Swedish children under 2 years of age after changes in infant feeding practices.^[54] Gluten content was increased in their milk, cereal drinks and porridges, with a simultaneous recommendation that gluten-containing foods be postponed until 6 months of age after breastfeeding.^[55] Age of introduction is a factor, as Norris et al. reported that children exposed to gluten-containing foods in the first 3 months of life had a fivefold increased risk of developing celiac disease, compared with children exposed at 4–6 months.^[56]

Contaminated Gluten?

The majority of gluten is imported from China and Mexico. Previously, some of this gluten was contaminated with melamine and incorporated into certain US pet foods.^[57] Nitrogen-rich melamine was added to fool food quality inspectors, who often use nitrogen levels to measure protein levels. The resulting kidney failures and deaths in pets made national news followed by a US pet food recall in 2007.^[58] What was not widely reported was that gluten was also incorporated in the feed of farmed fish, thereby entering the human food supply. Did someone investigate whether Americans consumed this melamine-contaminated gluten? Melamine entered the Chinese food supply via powdered infant formula, resulting in over 619 cases of urolithiasis.^[59] In 2008, it surfaced that many types of dairy products in China contained melamine.^[60] Did they also export contaminated gluten and or related products? Prior to this revelation, no one, including the US FDA, knew to even look for the melamine contaminant. Is it possible that melamine contributed to disrupting or triggering an immune reaction in susceptible individuals, or could other chemicals be problematic?

Environmental Toxin?

Logic suggests that the increasing rates of gluten sensitivity stem from an environmental factor. Is there something amiss in the food supply? Is it stronger gluten strength created by adding more gluten molecules to wheat? Or is there a contaminant disrupting our intestinal linings, resulting in a myriad of autoimmune-related medical problems? Does gluten fed to dairy cattle end up in the milk? Has a 'gluten threshold' been reached from the excess use of gluten as a food additive in baked products and processed foods?

Why are our intestines reacting slowly to the staff of life? The important question that this paper encourages people to ask is, 'to what?' Is it gluten, or is the trigger a toxin? Just recently, the American Academy of Pediatrics issued a policy statement stating that the USA needs to do a better job protecting children and pregnant women from toxic chemicals.^[61] Children's advocates are concerned with toxic exposures possibly fueling recent rises in early puberty in girls, allergies, asthma, attention deficit-hyperactivity disorder and autism. Bach states, "epidemiologic data provide strong evidence of a steady rise in the incidence of allergic and autoimmune diseases in developed countries over the past three decades".^[62]

Hormonal Influences

Could hormones trigger increasing numbers of gluten sensitivity cases? Six different types of steroid hormones are currently FDA-approved for use in food production in the USA: estradiol, progesterone, testosterone, zeranol, trenbolone acetate and melengestrol acetate. Although steroid hormones in food were suspected of causing early puberty in girls in some reports, no solid evidence exists to support this relationship. Nevertheless, the EU has banned hormone-treated livestock since 2006 because of food-safety concerns.^[63]

Is it possible that higher estrogen levels obtained through the hormonal use in animal food products might be influencing the higher rates of autoimmune disease, including celiac and gluten sensitivity? Autoimmune conditions often surface after menopause, influenced in part by changing hormonal levels. It is interesting to note that the peaks of celiac disease incidence occur at 0–3 and 44–64 years of age. Is the later peak influenced in part by changing hormone levels in women?^[64] Other factors influencing hormonal levels may be plasticizers (phthalates) and polychlorinated biphenyls associated with earlier breast development and menarche, respectively.^[65] More research is necessary to answer these questions.

Intestinal Infections

Certain intestinal infections and/or illnesses (such as viral gastroenteritis and giardiasis, among others) damaging the small intestine's brush border have long been known to trigger celiac disease^[66] and secondary or acquired lactase deficiency.^[67,68] Stene et al. specifically suggested that repeated gastrointestinal rotavirus infections may increase the risk of celiac disease in genetically predisposed individuals.^[69] Treating giardiasis was reported in one case study to reverse celiac disease from active to latent.^[70]

Chronic diarrhea is a frequent complaint in patients with AIDS, with most cases remaining unexplained. Interestingly, lactose malabsorption is significantly higher in HIV-infected patients (70%) than in controls (34%; p < 0.001).^[71] Taylor et al. suggested that other intestinal disaccharidase deficiencies exist in HIV-infected subjects, not just lactase enzyme.^[72] For example, in vivo hydrolysis of lactose, sucrose and palatinose was impaired in 25–75% of HIV patients compared with controls.

Although researchers demonstrated the beneficial effect of a gluten-free diet on the diarrhea and resulting weight gain in patients with AIDS,^[73] such a diet is not routinely recommended for AIDS patients. It is suggested that other inflammatory diseases involving the GI tract may follow the same scenario: one or more digestive enzymes are compromised by an inflammatory condition triggered by an autoimmune or other conditions. It is known that intestinal inflammation exists in irritable bowel syndrome, and one researcher questioned whether or not gluten sensitivity may be contributing to the symptoms on a subgroup of people with this condition.^[74] Verdu and associates suggest a combined 4.5% prevalence of celiac disease in patients clinically diagnosed with irritable bowel syndrome when Rome I and II criteria are used.^[75–78]

Mechanism? Stpeniack and Koning suggest that the mechanism may be due to the "viral infection and/or tissue damage in the intestine causing inflammation and inducing protective Th1-mediated immunity leading to loss of tolerance for gluten".^[79] They suggested that the gut-associated lymphoid tissue is the largest part of the immune system, and is constantly discriminating between pathogenic microorganisms and harmless bacteria and/or antigens such as dietary compounds. These antigens, passing through, are constantly sampled by intestinal dendritic cells and are presented to the T cells in either Peyer's patches or mesenteric lymph nodes, resulting in the generation of regulatory CD4 T cells.

Perhaps certain gastrointestinal infections or stress disrupting intestinal homeostasis play a role in triggering autoimmune diseases? Fasano and colleagues postulate that an enterotoxin (zot) from a bacterium (Vibrio cholerae) can distrupt the tight junctions between intestinal cells.^[80] Bach's review on infections and autoimmune diseases discusses the role of environmental factors in the etiology of several autoimmune diseases, including Guillian–Barré syndrome, where 25% of patients have had a recent Campylobacter jejuni infection.^[81] Other researchers suggest that an autoimmune response triggered atrophy, degeneration and damage of the mucosa (possibly by apoptosis) similar to the nerve tissue injury seen in Guillian–Barré syndrome.^[82] They indicated that this may be due to molecular mimicry of ganglioside-like epitopes, common to both lipopolysacharide coats of certain strains of C. jejuni and gangliosides in the cell structure of the gastrointestinal mucosa. Perhaps some bacteria are more adept at triggering the immune response.^[83] Segmented filamentous bacteria have been postulated as promoting IL-17-dependent immune and autoimmune responses, as well as gut-associated and systemic responses (inflammatory arthritis and experimental autoimmune encephalomyelitis in diabetic mice).^[84]

Failing to immediately treat these microbial-related infections with antibiotics or appropriate medications in a timely manner may increase the risk of further small intestine damage, and the resulting associated irreversible diseases. As a result, delaying diagnosis and defaulting to a series of lengthy tests may very well do the patient more harm than good in cases of microbial infection.

Intestinal Dysbiosis Related to gastrointestinal infections is the possibility of intestinal dysbiosis, a condition characterized by increased Gram-negative bacteria and reduced bifidobacteria. Sanz and colleagues' review indicates that this condition is detected in certain celiac disease patients.^[85] A question for researchers is: does disrupting the delicate intestinal bacterial balance trigger gluten sensitivity, or vice versa?

Digestive Enzyme Compromise The virulence of a Clostridum difficile intestinal infection is dependent on the autoactivation of a toxin cysteine protease.^[86] It has not been asked whether or not toxic proteases from bacterial infection could also break down the body's natural digestive enzymes in what is coined here as a 'digestive enzyme compromise.' Any resulting undigested proteins, lactose or lipids could then be fermented by intestinal bacteria, resulting in gas and abdominal pain. A worst-case scenario occurs when these larger proteins, that should have been digested, cross through the intestinal junctions which are no longer tight due to the inflammation of infection. These substances are then recognized as 'foreign' by the body, which further triggers the immune system. Could one of these substances be gluten or its components?

Autoimmune Diseases

Celiac disease is the only autoimmune condition in which the trigger is known: gluten. Is it possible that other autoimmune diseases have other triggers?^[87] Several autoimmune conditions are related to celiac disease ( Box 3 ). It is known that following a gluten-free diet lowers the risk of autoimmune disease in compliant celiac disease patients (6% at 10 years) versus noncompliant patients (16% at 10 years).^[88] This is particularly important for patients diagnosed with celiac disease early in life, or those having a family history of autoimmunity. It should be noted that a minority (16%), and not a majority, of noncompliant patients exposed to gluten succumb to autoimmune conditions.

Allergic Disease On a related topic is the incidence of a nonceliac gluten sensitivity in patients with allergic disease. Massari and associates found that 29% (77 out of 262) of allergic patients tested positive for mucosal lesions, but not for anti-antigliadin antibody, anti-EMA and DQ2 and DQ8 molecules.^[89] This study was not conducted in the USA, where positive mucosal lesions are not part of the unofficial diagnosis of nonceliac gluten sensitivity. A research question yet to be answered is whether people with allergic diseases have higher prevalence rates of either celiac disease or gluten sensitivity.

Expert Rev Gastroenterol Hepatol. 2012;6(1):43-55. © 2012  Expert Reviews Ltd.