Causes and Risk Factors of Gluten Sensitivity

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The causes and risk factors for non-celiac gluten sensitivity are unclear and are being researched. Unlike celiac disease, it doesn't have the typical markers or intestine damage used to diagnose that autoimmune disorder, and unlike wheat allergy, it doesn't have the markers of an allergic disorder. While by definition the condition responds to a gluten-free diet, it may possibly be triggered by the gluten protein or by other compounds found in the gluten-containing grains wheat, barley, and rye.

Common Causes

As of yet, there is no explanation for why non-celiac gluten sensitivity occurs and how it might be related to celiac disease. It is possible that gluten sensitivity and celiac disease represent different aspects of the same condition, but they may be completely different.

Gluten sensitivity may affect about 6 percent to 7 percent of the population, according to Dr. Allessio Fasano of the University of Maryland and the Salerno Experts' Panel that helped define non-celiac gluten sensitivity.

Some researchers theorize that the problem in those told they have gluten sensitivity may not be gluten at all. Instead, it may be some other compound found in wheat (and possibly in barley and rye, which are closely related to the grain).

Researchers have identified other compounds in wheat, specifically, that they say could be responsible. Some of these compounds, known as FODMAPS, are found in other foods, such as garlic and onions, as well as in wheat.

What's more, the results of one study suggest that gluten sensitivity symptoms occur because microbes and food proteins are crossing the intestinal barrier into the bloodstream, causing widespread inflammation.

Possible problematic compounds found in those grains include fructans (a complex carbohydrate that can cause symptoms in people with irritable bowel syndrome) and amylase trypsin inhibitors (which are proteins), in addition to the protein gluten.

Here's what the research shows on all of the three grain components, and how they might be related to non-celiac gluten sensitivity.


Gluten is the grain component on which most people focus. It is a protein that grain plants use to store nutrients for the next generation of plants. Found in the seeds of grain plants, it's the part of the plant we think of, and use, as food.

The initial research on non-celiac gluten sensitivity fingered gluten as the problem in the newly described condition. That study said gluten made some people's intestines leaky and inflamed without causing celiac disease. The researchers concluded these people were reacting to gluten in the foods they ate.

Since that initial study, there have been several more studies that used pure wheat gluten to try and induce symptoms in people who believed they were gluten-sensitive. These studies have had mixed results.

One study, for example, removed all gluten grain-based foods from 37 subjects' diets, and then fed them with pure wheat gluten (the subjects didn't know when they were eating gluten and when they were eating a placebo). The people in the study didn't experience digestive symptoms while eating the pure gluten, but some of them did get depression.

Another study used the same technique to "challenge" people who said they were gluten-sensitive with gluten and found that some of them did react to pure gluten. In that study, 101 people said their digestive symptoms improved when following a gluten-free diet, and 14 percent of those got worse when they unknowingly ingested gluten as part of the study.

Some people who say they're sensitive to gluten grains do seem to be reacting to gluten, but many others don't react when fed pure gluten unknowingly. More research on this is needed.


It's possible that the problem with wheat is its fructans. That's what one of the recent studies on gluten sensitivity—the one with the 37 people who didn't get digestive symptoms from pure gluten—concluded.

Fructans are a complex carbohydrate that ferments in your large intestine, potentially causing gas, bloating, cramping, pain, diarrhea, and constipation. This particular study fingered FODMAPs (fermentable, oligo-, di-, monosaccharides and polyols), which are sugars found in wheat grains and multiple other foods when the people in the study did not see their intestinal symptoms worsen with pure gluten.

FODMAPs seem to cause digestive symptoms in many people with irritable bowel syndrome, and a low-FODMAP diet is proven to reduce symptoms in nearly three-quarters of those with IBS. But it's far from clear whether the problem in "gluten sensitivity" is really the FODMAPs, and whether the solution is a low-FODMAP diet, rather than a gluten-free diet. Again, more research is needed.

Amylase Trypsin Inhibitors

The third component of modern gluten grains that scientists have identified as a potential problem are amylase trypsin inhibitors. These proteins are natural pesticides that are made by the plant to protect itself from insects. They make it difficult or impossible for bugs to digest the starches in the grain kernel.

Modern wheat has been bred to have lots more of these proteins. The problem is, amylase trypsin inhibitors in wheat (and possibly other gluten grains) seem to cause inflammation in some people, both in their intestines and elsewhere in their bodies. Researchers studying these proteins speculate that they could play a role in celiac disease, in non-celiac gluten sensitivity, and possibly in other conditions that are driven by inflammation.

Amylase trypsin inhibitors may contribute to or even cause what people call non-celiac gluten sensitivity. However, right now they're the least studied of these three possible causes.


While there are genetic combinations that raise the risk of celiac disease, these don't seem to have much influence on developing non-celiac gluten sensitivity. There needs to be more research in this area. An earlier study by Dr. Alessio Fasano found the genes most implicated in celiac disease, HLA-DQ2 and HLA-DQ8, were present in those with gluten sensitivity more often than in the general population, but still only appeared in 56 percent of patients that met his criteria for gluten sensitivity.

Lifestyle Risk Factors

Currently, the diagnosis of non-celiac gluten sensitivity rests on symptoms improving when you are on a strict gluten-free diet (after excluding celiac disease and other causes) and returning if you consume gluten. Therefore, you are at risk of symptoms if you include gluten in your diet.

It is challenging to maintain a gluten-free diet, especially avoiding cross-contamination. It takes commitment and constant vigilance. Consulting with a dietitian can help you learn what you can eat, what you must avoid, and how to prevent cross-contamination.

A Word from Verywell

It's nowhere near clear right now what might cause non-celiac gluten sensitivity. It could wind up being how your body reacts to gluten, FODMAPs, amylase trypsin inhibitors, some combination of the three, or something else entirely. 

If gluten isn't to blame but something else in gluten grains is, then people who have the condition might need to follow a diet free of all components of wheat, barley, and rye, not just gluten.

Research over the next several years should discover more about what causes non-celiac gluten sensitivity and how many people have it. That, in turn, should improve diagnosis and treatment. 

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Article Sources

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  3. 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):2395-408. doi:10.1084/jem.20102660

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