Researchers Find Biological Explanation for Wheat Sensitivity

A study reported in the journal ‘Gut‘ may explain why people who do not have celiac disease or wheat allergy nevertheless experience a variety of gastrointestinal and extra-intestinal symptoms after ingesting wheat and related cereals. The findings suggest that these individuals have a weakened intestinal barrier, which leads to a body-wide inflammatory immune response.

“Our study shows that the symptoms reported by individuals with this condition are not imagined, as some people have suggested.  It demonstrates that there is a biological basis for these symptoms in a significant number of these patients.”

  • co-author Peter H. Green, MD, the Phyllis and Ivan Seidenberg Professor of Medicine at CUMC and director of the Celiac Disease Center.

non celiac gluten sensitivityCeliac disease is an autoimmune disorder in which the immune system mistakenly attacks the lining of the small intestine after someone who is genetically susceptible to the disorder ingests gluten from wheat, rye, or barley. This leads to a range of gastrointestinal symptoms, including abdominal pain, diarrhea, and bloating.

Researchers have struggled to determine why some people, who lack the characteristic blood, tissue, or genetic markers of celiac disease, experience celiac-like GI symptoms, as well as certain extra-intestinal symptoms, such as fatigue, cognitive difficulties, or mood disturbance, after ingesting foods that contain wheat, rye, or barley.

One explanation for this condition, known as non-celiac gluten or wheat sensitivity (NCWS), is that exposure to the offending grains somehow triggers acute systemic immune activation, rather than a strictly localized intestinal immune response. Because there are no biomarkers for NCWS, accurate figures for its prevalence are not available, but it is estimated to affect about 1 percent of the population, or 3 million Americans, roughly the same prevalence as celiac disease.

In the new study, the CUMC team examined three groups:

• 80 individuals with NCWS who reported symptoms in response to wheat intake
• 40 individuals with celiac disease
• 40 healthy controls

Blood serum samples from all participants were analysed for markers of intestinal cell damage and systemic immune response to microbial components.

Individuals with celiac disease showed extensive intestinal damage associated with celiac disease however blood markers of innate systemic immune activation were not elevated in the celiac disease group. This suggests that the intestinal immune response in celiac patients is able to neutralize microbes or microbial components that may pass through the damaged intestinal barrier, thereby preventing a systemic inflammatory response against highly immunostimulatory molecules.

The NCWS group was markedly different. They did not have the intestinal cytotoxic T cells seen in celiac patients, but they did have a marker of intestinal cellular damage that correlated with serologic markers of acute systemic immune activation.

The results suggest that the identified systemic immune activation in NCWS is linked to increased translocation of microbial and dietary components from the gut into circulation, in part due to intestinal cell damage and weakening of the intestinal barrier. (Scroll down for the science behind it.)

“A systemic immune activation model would be consistent with the generally rapid onset of the reported symptoms in people with non-celiac wheat sensitivity. The data suggest that, in the future, we may be able to use a combination of biomarkers to identify patients with non-celiac wheat sensitivity, and to monitor their response to treatment.”

  • Study leader Armin Alaedini, PhD, assistant professor of medicine at CUMC.

NCWS patients who followed a diet that excluded wheat and related cereals for six months were able to normalize their levels of immune activation and intestinal cell damage markers, the researchers also found. These changes were associated with significant improvement in both intestinal and non-intestinal symptoms, as reported by the patients in detailed questionnaires.

“These results shift the paradigm in our recognition and understanding of non-celiac wheat sensitivity, and will likely have important implications for diagnosis and treatment. Considering the large number of people affected by the condition and its significant negative health impact on patients, this is an important area of research that deserves much more attention and funding.”

  • Co-author Umberto Volta, MD, professor of internal medicine at the University of Bologna.

In future studies of NCWS, Dr. Alaedini and his team plan to investigate the mechanisms responsible for triggering the intestinal damage and breach of the epithelial barrier and to further characterize the immune cell responses.


The science behind it:  Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals.


The study involved an international collaboration between researchers from Columbia University Medical Center (CUMC)and the University of Bologna, Bologna, Italy. The study involved an international collaboration between researchers at CUMC and the University of Bologna, Bologna, Italy: Melanie Uhde1Mary AjamianGiacomo Caio, Roberto De GiorgioAlyssa IndartPeter H Green, Elizabeth C VernaUmberto VoltaArmin Alaedini