What Really Causes Gluten Sensitivity?

It's not clear at all whether gluten really causes gluten sensitivity

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When talking about the health condition that many clinicians now call "non-celiac gluten sensitivity," it's easy to focus strictly on the gluten protein. After all, it's gluten that leads to intestinal damage in celiac disease, and so it didn't seem like a major stretch, when this new condition was first described, to assume gluten was to blame for symptoms here, as well.

In addition, the gluten-free diet is well-known largely because people can remember that gluten is the problematic protein in celiac disease. Therefore, if someone gets relief from symptoms by following the gluten-free diet, but that person does not have celiac disease, it's still fairly logical to assume that the person is reacting to gluten.

But what if the culprit causing the symptoms of "gluten sensitivity" isn't gluten? What if, instead, it's some other compound—or even multiple compounds—found in the gluten-containing grains wheat, barley, and rye, and possibly even in other foods, too?

This is an idea that's getting some attention. 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% of those got worse when they unknowingly ingested gluten as part of the study.

The bottom line: 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. 

The bottom line: 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

There's a third component of modern gluten grains that scientists have identified as a potential problem: amylase trypsin inhibitors. These proteins are actually natural pesticides — they're made by the plant to protect itself from insects.

Amylase trypsin inhibitors in gluten grains actually 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.

The bottom line: 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.

A Word from Verywell

It's nowhere near clear right now what might cause the condition we're calling "non-celiac gluten sensitivity." It could wind up being 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 tell us more about what causes non-celiac gluten sensitivity and how many people have it. That, in turn, should help us figure out how to diagnose and treat it. 

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