Non-celiac wheat sensitivity: Differential diagnosis, triggers and implications

doi:10.1016/j.bpg.2015.04.002

Best Practice & Research Clinical Gastroenterology

Volume 29, Issue 3, June 2015, Pages 469-476

https://doi.org/10.1016/j.bpg.2015.04.002 Get rights and content

Abstract

Non allergy-non-celiac wheat sensitivity (NCWS) has become a common and often overrated diagnosis. Skepticism mainly relates to patients with prominent intestinal symptoms in the absence of general or intestinal signs of inflammation. There is consensus that the major wheat sensitivities, celiac disease and wheat allergy, have to be ruled out which may be difficult for wheat allergy. The non-inflammatory intolerances to carbohydrates, mainly lactose and FODMAPs (fermentable oligi-, di-, monosaccharides and polyols), which cause bloating or diarrhoea, can usually be excluded clinically or by simple tests. Recent studies and experimental data strongly indicate that NCWS exists in a substantial proportion of the population, that it is an innate immune reaction to wheat and that patients often present with extraintestinal symptoms, such as worsening of an underlying inflammatory disease in clear association with wheat consumption. Wheat amylase-trypsin inhibitors (ATIs) have been identified as the most likely triggers of NCWS. They are highly protease resistant and activate the toll-like receptor 4 (TLR4) complex in monocytes, macrophages and dendritic cells of the intestinal mucosa. Non-gluten containing cereals or staples display no or little TLR4 stimulating activity. Wheat ATIs are a family of up to 17 similar proteins of molecular weights around 15 kD and represent 2–4% of the wheat protein. With oral ingestion they costimulate antigen presenting cells and promote T cell activation in celiac disease, but also in other immune-mediated diseases within and outside the GI tract.

Section snippets

Clinical definitions and differential diagnoses

Non-celiac gluten sensitivity (NCGS) has been described about 40 years ago, being defined as mainly abdominal symptoms related to ingestion of gluten containing cereals, after celiac disease and wheat allergy have been (largely) excluded. Since it is possible if not likely that non-gluten components of wheat, barley and rye induce the disease, we prefer the term non-celiac (non-allergy) wheat sensitivity (NCWS), at least in scientific discussions. An increasing number of subjects claim to

Toxic wheat components?

Much research has been invested in identifying bioactive components in wheat. Apart from allergens, gluten peptides that trigger T cell activation in celiac disease and wheat proteins that activate innate immunity (see below), research has failed to identify toxic constituents, rather described protective protein and non-protein components. Thus dietary plant lectins like wheat germ agglutinin and bean concanavalin A can induce intestinal epithelial shedding in rats, but this activity is

Immunogenicity of wheat

There is no doubt that wheat (and the related barley and rye) has immunogenic properties in a sizable number of human subjects. This also applies to ancient wheat variants like unicorn, emmer and spelt. Thus celiac disease in which defined gluten peptides induce a destructive intestinal T helper 1 (Th1) T cell activation in genetically predisposed individuals is discussed in other chapters of this issue. It affects between 0.5 and 1.5% of most populations worldwide causing significant morbidity

The role of innate immunity in NCWS

There is strong evidence that NCWS is caused by an innate immune response to wheat proteins (different from the adaptive, T cell mediated response to gluten in celiac disease, or to gluten and non-gluten proteins in wheat allergy) [1], [3], [12]. NCWS can usually be separated clinically from food intolerances, mainly lactase deficiency and FODMAP intolerance, conditions that lead to increased fermentation of carbohydrates in the intestine and that do not cause intestinal or general

ATIs as triggers of innate immunity in wheat

In our own studies we could not confirm published gliadin peptides, including alpha-gliadin peptide p31–49, as an activator of innate immunity in intestinal epithelia of myeloid cells, whereas a water soluble fraction and a peptic-tryptic digest of commercial gliadin strongly activated mouse and human myeloid cells in vitro, most potently dendritic cells > macrophages > monocytes. This activity was not due to e.g. lipopolysaccharide (LPS) contamination and not associated with alpha or

Conflict of interest

The authors declare no conflict of interest in relation to this manuscript.

Acknowledgements

Part of this work was supported by the National Institutes of Health (grant 1R21AI078385A1-01 to D. Schuppan).

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Many individuals reduce their bread intake because they believe wheat causes their gastrointestinal (GI) symptoms. Different wheat species and processing methods may affect these responses.
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9Non-celiac wheat sensitivity: Differential diagnosis, triggers and implications

Abstract

Section snippets

Clinical definitions and differential diagnoses

Toxic wheat components?

Immunogenicity of wheat

The role of innate immunity in NCWS

ATIs as triggers of innate immunity in wheat

Conflict of interest

Acknowledgements

Gastroenterology

Gastroenterology

Vet Parasitol

J Food Prot

Food Chem Toxicol

Gastroenterology

FEBS Lett

Biochim Biophys Acta

Gastroenterology

Ann Allergy Asthma Immunol

Spectrum of gluten-related disorders: consensus on new nomenclature and classification

BMC Med

The Oslo definitions for coeliac disease and related terms

Gut

Non-celiac gluten sensitivity: the new frontier of gluten related disorders

Nutrients

Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity

Am J Gastroenterol

Study group for non-celiac gluten Sensitivity. An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity

BMC Med

Irritable bowel syndrome: a clinical review

JAMA

Non-celiac wheat sensitivity as an allergic condition: personal experience and narrative review

Am J Gastroenterol

Food allergy

J Clin Invest

EAACI food allergy and anaphylaxis guidelines group. The diagnosis of food allergy: a systematic review and meta-analysis

Allergy

Food components and irritable bowel syndrome

Gastroenterology

Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome

Gastroenterology

Dietary proteins and functional gastrointestinal disorders

Am J Gastroenterol

Wheat-derived arabinoxylan oligosaccharides with prebiotic effect increase satietogenic gut peptides and reduce metabolic endotoxemia in diet-induced obese mice

Nutr Diabetes

Dietary tricin suppresses inflammation-related colon carcinogenesis in male Crj: CD-1 mice

Cancer Prev Res (Phila)

9
Non-celiac wheat sensitivity: Differential diagnosis, triggers and implications