May 2017 Issue

What's Behind Wheat Sensitivities?
By Kate Scarlata, RDN, LDN
Today's Dietitian
Vol. 19, No. 5, P. 28

It's not just about gluten. Learn what other factors may be causing patients troublesome gastrointestinal symptoms.

Wheat, a key ingredient in our favorite crusty bread and delectable pasta dishes, can be enjoyed without consequence for the vast majority of people. Wheat is a complex grain, composed of various molecules of carbohydrates, proteins, and fat—many of which have been associated with putative health benefits such as providing prebiotic fibers, improving glucose homeostasis, and laxation effects. But for some individuals, wheat ingestion is associated with a cascade of symptoms from gastrointestinal (GI) distress such as bloating, cramping, pain, and altered bowel habits to extraintestinal symptoms, including fatigue, and memory and cognitive difficulties.

For those with wheat allergy or celiac disease, wheat intake is prohibited due to deleterious immune-mediated effects resulting in villous atrophy and gut inflammation or potential allergic anaphylactic events. Wheat intolerance occurs in a broad spectrum of individuals with digestive symptoms, and aside from gluten, some of the lesser-known components of wheat that may play a role include fructans and amylase trypsin inhibitors (ATIs).

Wheat Intolerance: Differential Diagnosis
Celiac disease is an immune-mediated condition induced by dietary gluten leading to small bowel inflammation and villous atrophy in genetically susceptible people. Celiac disease impacts about 1% or three million individuals in the United States.1 Wheat allergy, one of the top eight allergens, presents in about 2% of the population and, unlike most food allergies, incidence increases with age.2 Symptoms of wheat allergy such as hives, swelling of the throat, headaches, and nausea and/or vomiting occur quickly after consumption and may result in a life-threatening event.

Wheat intolerance is a diagnosis of exclusion. Wheat intolerance often presents in those who suffer from irritable bowel syndrome (IBS), a common GI motility disorder, as well as in those with nonceliac gluten sensitivity (NCGS). NCGS, or more recently termed nonceliac wheat sensitivity (NCWS), is a condition with both GI and non-GI symptoms related to wheat or gluten intake that occurs in the absence of celiac disease. The term NCGS is taking on the new categorical title NCWS, as this acronym encompasses the many components of wheat implicated in symptom induction. There's no biomarker or diagnostic test for NCWS. Patients with NCWS often have symptoms that mimic those present in IBS but also may present with symptoms outside the GI tract, such as brain fog or headaches and, according to more recent data, with more severe symptoms like worsening of an autoimmune disease. NCWS is estimated to impact 1% to 6% of the population, depending on the resource.2,3

IBS is characterized by alteration in bowel habits, bloating, pain, and sense of incomplete emptying. IBS is the most common diagnosis made by gastroenterologists, affecting up to one in five people in the United States.4 Fifty percent of IBS patients experience postprandial symptom exacerbation.4 There's a growing body of science revealing a complex interaction between food, the gut microbiome, and IBS symptom induction. The low-FODMAP (fermentable oligo-, di-, and monosaccharides and polyols) diet, an evidence-based nutrition therapy, is applied to manage IBS symptoms and includes a reduction in wheat as part of its nutritional tenets. The low-FODMAP diet is an elimination diet that reduces specific carbohydrates including lactose, sorbitol, and the fructans present in wheat. The low-FODMAP diet improves IBS symptoms in about 70% of IBS patients in part because of the reduction in bacterial-derived gas via fermentation of these poorly absorbed carbohydrates.5 The low-FODMAP diet also has been shown to create changes in the metabolome (the total number of metabolites in an organism that may be derived, in part, via gut microbial metabolism), and it's possible that post fermentation bacterial metabolites may play a role in IBS symptom induction. More research is needed to elucidate this connection.6

Fructans, Gluten, and ATIs
Because wheat has several components that may exacerbate undesired symptoms, dietitians need to understand the complexities of wheat to best guide their patients. William D. Chey, MD, AGAF, FACG, FACP, a gastroenterologist at the University of Michigan, says, "When laypersons develop symptoms after eating wheat, they assume it's the consequence of gluten. Indeed, the medical establishment has thrown gas on this fire by labeling such individuals as suffering with 'nonceliac gluten sensitivity.' It's growing increasingly clear that while gluten provides an explanation for symptoms in some patients, it isn't the culprit in many who develop symptoms after eating wheat."

Fructans, a carbohydrate fraction of wheat, are a known IBS trigger. Chey further elaborates on these short-chain fibers that can induce digestive symptoms. "Wheat contains carbohydrates, which might be responsible for the development of GI symptoms in some individuals," he says. "Wheat is one of the most fertile sources of fructans in the Western diet. Fructans are nondigestible and nonabsorbable by the human GI tract and upon reaching the colon, are fermentable by resident bacteria. In susceptible individuals, like those with IBS, the byproducts of fermentation, gas and short-chain fatty acids, can stimulate a wide range of GI symptoms." It appears that it's the fermentative effects of fructans by gut microbes that contribute to IBS symptom induction. A novel MRI study shows that the microbial gas production post consumption of fructans increases throughout the day, occurring primarily in the colon and resulting in luminal distention. For those with visceral hypersensitivity of the colon and altered brain-gut communication, such as experienced in IBS, the distention causes GI distress.7

Wheat gluten, the main protein fraction of wheat, isn't completely digested, and these "remnants" initiate an immune reaction in those with celiac disease. How they also may play a role in initiating digestive symptoms outside of celiac disease is debated.

Novel research in the area of NCWS is recognizing that ATIs from wheat may initiate GI inflammation. However, ATI ingestion leads to GI inflammation differently from gluten in celiac disease.2,8 "Nongluten proteins in wheat can exert proinflammatory effects in experimental models and could be responsible for the development of symptoms in susceptible patients," Chey says. "For example, ATIs are proteins that confer pest resistance to wheat. ATIs have potent proinflammatory effects and might be involved with the onset and perpetuation of celiac disease and other inflammatory diseases of the GI tract." ATIs activate both the intestinal and extraintestinal innate immune system. The immune system is divided into two categories: the innate immune system and the adaptive immune system. Innate immunity involves the body's first or early arriving defense mechanism that attacks an antigen (a foreign substance that induces an immune response) that appears in the body. The defense mechanisms are active in our skin or at mucosal surfaces, those contact sites between the exterior and interior of the organism. Innate immunity allows immune cells to immediately attack foreign invaders as well as toxic substances. The adaptive immune system acts in a more protracted and complex, but even more powerful, manner. This immune system has to first recognize the specific foreign invader. Adaptive immunity adapts and remembers the foreign invader, allowing subsequent exposures to the invader to be more efficient. The adaptive and innate immune systems often act together; proteins (chemokines and cytokines) in the blood help them communicate with each other to coordinate their response to any foreign substance.

What Researchers Are Learning About ATIs
ATIs make up about 4% of wheat protein and are a group of 17 proteins. ATIs have been linked with NCGS/NCWS symptom exacerbation. Detlef Schuppan, MD, PhD, and his group at Harvard Medical School and Mainz University Medical Center in Germany, have found that ATI proteins in wheat (including barley and rye) target specific proinflammatory receptors on intestinal immune cells. ATIs activate the toll-like receptor 4 (TLR4), a protein that recognizes pathogen-derived danger signals that play a key role in innate immunity activation. ATIs engage the TLR4 complex in monocytes, macrophages, and dendritic cells in the intestinal mucosa and induce their release of proinflammatory cytokines.9 The ATIs in gluten-containing grains (eg, wheat, barley, and rye) are the primary plant-derived ATIs to initiate this immune activation. Notably, these ATIs are resistant to intestinal degradation. While some gluten-free grains contain ATIs, they don't appear to initiate the same immune effects in the GI tract. For this reason, a gluten-free diet can be considered ATI reduced.2,8

Mice fed ATIs show increased release of cytokines and chemokines from the gut and in the blood within one to 12 hours after wheat or ATI ingestion. It appears that ATI sensing is increased in the inflamed gut, suggesting that those with inflammatory bowel disease (IBD) and other autoimmune conditions may benefit from a wheat-free diet.2,8 Schuppan, now director of the Institute of Translational Immunology at University Medical Center of the Johannes Gutenberg University, and other researchers in his lab currently are studying the ATI content and bioactivity of hundreds of wheat varieties along with mouse and human clinical studies on NCWS and immunoglobin E-negative food allergies. Schuppan says, "Given the effect of ATIs on the immune system and the emerging mechanisms by which ATIs not only affect intestinal inflammation but also propagate their inflammatory effect to the periphery, I strongly recommend that those patients with a clearly defined NCWS, ie, with symptoms improving on a wheat-free diet and worsening on a wheat-containing diet, remain on a wheat-free diet. In those who consume wheat regularly, exposure would translate to about 0.5 to 1 g of ATIs daily. In individuals with a healthy gut, this exposure shouldn't elicit symptoms or cause disease. In individuals with existing inflammatory disease states, the uptake of ATIs will 1) be enhanced, and 2) exacerbate symptoms, including those of chronic inflammatory diseases, mainly autoimmune diseases in most instances." Data from Schuppan's research, which are published only as conference abstracts, reveal that in mice ATI intake exacerbates inflammatory and autoimmune conditions such as IBD, systemic lupus, multiple sclerosis, nonalcoholic fatty liver disease, and allergic asthma. Contrary to most cases of allergies and celiac disease, the impact of ATI intake is dose dependent, and it's likely that small amounts of wheat will trigger symptoms in susceptible individuals, but removing the majority of wheat would meet therapeutic goals.2

ATIs in the Food Supply
ATI content varies among modern gluten-containing grains. Determining ATI content in gluten-containing grains is under investigation in the research setting. Some modern wheat has been shown to have levels of immune-activating ATIs that were as much as 100-fold higher than in gluten-free grains.2,8 Wheat, the most widely grown crop, is immensely diverse, with more than 25,000 different cultivars produced globally by plant breeders. Thus, different wheat varietals have varying ATI content.3,8 Baking (heating) or processing doesn't significantly reduce ATI content or immune stimulatory effects. Ancient wheat varieties such as emmer (also known as farro) or einkorn may have lower ATI immune activity, but more research and food analysis is needed to better assess ATI content of a wider range of grains to instruct patients most effectively in clinical practice.2

Clinical Pearls for Dietitians
• Most people can enjoy wheat without GI distress.

• Wheat has many health benefits from blood sugar homeostasis, laxation, and notable prebiotic effects resulting in butyrate production, a short-chain fatty acid shown to aid gut motility and lower colon cancer incidence.

• Wheat may trigger symptoms including intestinal inflammation, painful gas, headaches, and brain fog in some individuals.

• For those with IBS, NCWS, or autoimmune conditions exacerbated by wheat intake, removing or reducing wheat may offer symptom relief and should be considered as part of the therapeutic plan.

• For patients with celiac disease or wheat allergy, it's necessary to remove wheat from the diet.

• A wheat-free diet may result in a reduction of dietary fiber, as many rely on whole grain wheat to meet fiber needs; assess fiber intake and adjust diet to patient's tolerance.

• Some gluten- and wheat-free foods lack the enrichment of vitamins and minerals found in US wheat-based foods, so encourage enriched options as needed to meet nutritional needs.

— Kate Scarlata, RDN, LDN, is a Boston-based dietitian with expertise in food intolerances and digestive health.

1. What is celiac disease? The University of Chicago Medicine Celiac Disease Center website. Accessed March 11, 2017.

2. Schuppan D, Pickert G, Ashfaq-Khan M, Zevallos V. Non-celiac wheat sensitivity: differential diagnosis, triggers and implications. Best Pract Res Clin Gastroenterol. 2015;29(3):469-476.

3. Sapone A, Bai JC, Ciacci C, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012;10:13.

4. Hayes PA, Fraher MH, Quigley EM. Irritable bowel syndrome: the role of food in pathogenesis and management. Gastroenterol Hepatol (N Y). 2014;10(3):164-174.

5. Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology. 2014;146(1):67-75.e5.

6. McIntosh K, Reed DE, Schneider T, et al. FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial [published online March 14, 2016]. Gut. doi: 10.1136/gutjnl-2015-311339.

7. Murray K, Wilkinson-Smith V, Hoad C, et al. Differential effects of FODMAPs (fermentable-oglio-, di-, mono-saccharides and polyols) on small and large intestinal contents in healthy subjects shown by MRI. Am J Gastroenterol. 2014;109(1):110-119.

8. Zevallos VF, Raker V, Tenzer S, et al. Nutritional wheat amylase-trypsin inhibitors promote intestinal inflammation via activation of myeloid cells. Gastroenterology. 2017;152(5):1100-1113.e12.

9. Junker Y, Zeissig S, Kim SJ, et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med. 2012;209(13):2395-2408.