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By Van Waffle


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People with non-celiac gluten sensitivity (NCGS) show an immune response distinct from celiac disease. New research from Columbia University revealed differences in the antibodies present, adding evidence that NCGS involves a different kind of inflammation in the gut in response to gluten.

When gluten-containing foods are consumed, celiac disease and NCGS can cause similar symptoms such as bloating, abdominal pain, and fatigue. Currently, the diagnosis of NCGS is only possible with extensive clinical testing. However, the discovery of a distinct signature of antibodies could make it easier for doctors to diagnose NCGS once celiac disease has been ruled out.


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“We found a clear difference in this immune response to gluten,” says principal investigator Armin Alaedini, Ph.D., an immunologist and Assistant Professor of Medicine at Columbia University Medical Center, New York. “Sensitivity to wheat in the absence of celiac disease is a condition distinct from celiac disease, with a biological basis.”

The study in Gastroenterology investigated subclasses of immunoglobulin G (IgG), antibodies produced by B cells in response to dietary gluten, and their relationship to intestinal damage. 

Alaedini says, “The body has its mechanisms to turn on the fire during inflammation. But then it’s got to turn it back down and completely extinguish it, in order to avoid chronic inflammation. The evolution in the body’s production of IgG subclasses during a disease also goes through this process.”

B-cells normally express antibody subclasses in this order: IgG3, then IgG1, then IgG2, then IgG4. Antibody production by B-cells can evolve in this direction but B-cells cannot turn back, just as people cannot get younger. Once a B-cell switches from expressing IgG2 to IgG4, it cannot return to any other subclass. A healthy person goes through this process as the immune system curtails inflammation and returns to normal.


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“Sensitivity to wheat in the absence of celiac disease is a condition distinct from celiac disease, with a biological basis.”

The research included 80 individuals with NCGS compared with 40 people with celiac disease and 40 healthy controls. Patients were newly diagnosed, and eating an unrestricted, gluten-containing diet when they joined the study. Patients with celiac disease showed increased levels of IgG1 and IgG3 antibodies compared to people with NCGS and healthy controls. These are the earlier and usually more inflammatory forms of IgG, appearing alongside extensive gut damage in people with untreated celiac disease.

In contrast, people with NCGS produced higher IgG2 and IgG4. This suggests a distinct, more mature inflammatory condition, in the process of cooling down. However, it remains unknown whether NCGS goes away or is a permanent condition like celiac disease.

A 2016 study from Alaedini’s lab showed that NCGS is associated with a significant increase in intestinal fatty-acid binding protein (FABP2), a marker of intestinal cell damage, at levels that are similar to those found in celiac disease.

“Currently, we have only indirect evidence of damage in NCGS. FABP2 is a highly specific and sensitive marker of intestinal epithelial injury shown to be associated with epithelial cell death and increased turnover in a number of diseases. But the data so far indicate that the type and mechanism of intestinal damage in NCGS is likely very different from celiac disease,” says Alaedini.

Significantly, the study found that FABP2 correlates with IgG4 in NCGS, while correlating with IgG3 in celiac disease.

According to Alaedini, the prominence of IgG3 in celiac disease suggests repeated activation of B cells in response to gluten exposure without generating tolerance to gluten, and without evolving toward the less inflammatory IgG subclasses. The study’s insight into this process offers potential new targets for drug therapy in celiac disease. In contrast, NCGS patients display a more advanced IgG profile. This suggests the immune system has advanced toward limiting inflammation and controlling intestinal damage.


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NCGS inflammation is likely more subtle and might occur in a different part of the gut from where celiac damage is seen during an endoscopy.

Valerie Abadie, PhD, Research Assistant Professor at the University of Chicago, Department of Medicine, Section of Gastroenterology, who is not connected to this research, notes the importance of this finding. The co-occurrence of IgG4 with FABP2 reflects increased permeability of the gut lining in NCGS, which also occurs in celiac disease.

Alaedini says NCGS inflammation is likely more subtle and might occur in a different part of the gut from where celiac damage is seen during an endoscopy. An important goal of further study will be to find out what is happening at the intestinal level.

Current diagnosis of NCGS depends on ruling out celiac disease in a patient who is sensitive to gluten. Alaedini says the most reliable estimates put the prevalence of NCGS at 1% to 2% of the North American population, similar to celiac disease.

Abadie notes that there is not yet any validated blood test to diagnose NCGS, “The high levels of anti-gliadin IgG4 antibodies and FABP2 observed in the current study, although higher compared to the ones found in celiac patients, are not specific to NCGS. However, once a diagnosis of celiac disease has been ruled out, the combined detection of these two markers could indeed help the diagnosis of NCGS, and allow a physician to decide to put the patient on a gluten-free diet.”


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