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Non-celiac gluten sensitivity: are diagnostic criteria around the corner?

The last few years have seen much conflicting evidence on non-celiac gluten sensitivity. This study went deep into physiological responses to gluten, including immune responses and intestinal damage levels.

Study under review: Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease


Over the last two decades, scientists have made tremendous progress in understanding celiac disease. We know that it is an autoimmune disorder with both genetic and environmental underpinnings. We know that the consumption of wheat gluten and related proteins in rye and barley, acting as environmental triggers, cause an immune response in the small intestine that leads to localized inflammation and cell death.

A diagnosis of celiac disease involves testing for various biomarkers, because no one test for celiac disease has perfect sensitivity or specificity. Although not unanimously accepted, some experts in the field have recommended that a celiac disease diagnosis requires four of five criteria[1] be met: typical symptoms of celiac disease when consuming a diet containing gluten, elevated levels of serum IgA and/or IgG antibodies against tissue transglutaminase and deamidated gliadin[2], HLA DQ2 or DQ8 genotypes, damage to the small intestine from gluten exposure, and improvement in symptoms and other diagnostic markers in response to a gluten-free diet.

Common symptoms of celiac disease include chronic diarrhea, weight loss, anemia, osteoporosis, and neurological disturbances. However, some patients are asymptomatic, which is why other tests are required for a diagnosis. Tissue transglutaminase is an enzyme found within and around intestinal cells (as well as other places) that modifies native gliadin into a form that may stimulate the immune system[3] more effectively, called deamidated gliadin. Deamidated gliadin is then presented to T-cells by other immune cells that commonly possess the HLA-DQ2 or DQ8 regions. This begins the autoimmune attack, as the T-cells respond by signaling an attack against the transglutaminase dealing with the gliadin. Since it exists in the mucosal layers of the intestine, the primary antibody to attack is IgA, since this is the main secreted immunoglobulin.

Far more elusive is non-celiac gluten sensitivity (NCGS). While it is estimated that up to 1% of the U.S. population suffers from celiac disease, accurate figures for the prevalence of NCGS are not available. A recent review[4] found NCGS prevalence rates between 0.5 and 13%, with this large discrepancy owed in no small part to the absence of specific biomarkers for diagnosis. Nonetheless, accumulating evidence[5] does suggest that NCGS is a real condition, as explored in Study Deep Dives #7.

Recently, an expert panel[6] provided a consensus on how to confirm a diagnosis of NCGS in the absence of sensitive and specific biomarkers, as summarized in Figure 1. First, the individual must present with persistent intestinal and non-intestinal complaints while consuming a gluten-containing diet but show normal results for celiac disease and wheat allergy-specific blood markers. Then, the individual must show at least a 30% reduction in symptoms after following a gluten-free diet for six weeks. Finally, the patient must undergo a double-blind, placebo-controlled crossover gluten challenge and show at least a 30% variation between the gluten and placebo challenge in symptoms.

Figure 1: Protocol for NCGS diagnosis

Reference: Catassi, C, et al. Nutrients. 2015 Jun

The clinical presentation of NCGS may be multi-systemic and associated with a range of symptoms[7] outside of the intestinal tract, as shown in Figure 2. Some of the most commonly reported include fatigue, headache, anxiety, and an overall lack of wellbeing. Yet, the potential mechanisms behind these symptoms remain unknown.

Figure 2: Percentage of NCGS-suspected patients with non-GI complaints

Reference: Volta, A, et al. BMC Med. 2014 May

A small[8] number[7] of studies[9] have suggested that individuals with NCGS display an immune response toward gluten. And there is evidence (discussed in ERD #8) supporting the idea that gluten increases intestinal permeability in people with NCGS. This could hypothetically allow for microbes or microbial products[10] such as lipopolysaccharides (LPS) to enter into the bloodstream, thus stimulating a systemic immune response.

The current study investigated whether NCGS patients showed signs of an immune response towards microbial products that inappropriately entered the bloodstream. This study also assessed whether this immune response would be associated with the degree of intestinal permeability, and if it would subside upon the elimination of gluten in the diet.

While celiac disease has clear diagnostic criteria based on specific disease biomarkers, non-celiac gluten sensitivity lacks biomarkers for diagnosis and has no established mechanism to explain the commonly reported symptoms unrelated to the GI tract. The current study sought to fill these knowledge gaps.

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