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Gluten Sensitivity: What Does It Really Mean?

The views expressed are those of the author and are not necessarily those of Scientific American.

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“Are you the nurse? You look so young,” I said to my mom as I slowly emerged from my anesthesia-induced slumber, apparently not coherent enough to know who she was (but thankful that my drugged speech was so complimentary). I’d just undergone an endoscopy, meaning a doctor had inserted a small, flexible tube through my mouth down into my small intestine. After sampling the intestinal tissue, he’d be able to tell me whether I had celiac disease, an autoimmune disease in which eating gluten-containing food causes the destruction of the small intestine’s inner lining.

Soon, the diagnosis came: negative. My doctor explained that, rather than celiac disease, a “gluten sensitivity” was likely the cause of the bloating and abdominal pain I’d been experiencing. If I removed or reduced the gluten in my diet, I could probably reduce my symptoms. So I did. And for the most part, staying away from gluten meant the discomfort stayed away too.

But eventually my science background got the better of me, and I had to know what was really happening in my body. What does “gluten sensitivity” really mean?

Gluten-free foods. Photo by Julianne Wyrick

Gluten-free foods. Photo by Julianne Wyrick

Unfortunately, there’s no easy answer. When patients without celiac disease exhibit symptoms that improve with a gluten-free diet, they are often categorized as “gluten-sensitive.” These symptoms may range from abdominal pain to bloating to fatigue.

In the past, the very existence of the condition has been questioned because of its unclear diagnosis. However, as the New York Times notes, new studies suggest that gluten sensitivity does exist.

What this and other recent articles haven’t mentioned is that researchers have gained some interesting insights into how it may work. They’ve also discovered that so-called “gluten-sensitivity” may not be caused by gluten at all.

To understand new research on gluten sensitivity, it’s first important to understand the other two gluten-induced conditions, celiac disease and wheat allergy. Both conditions involve the immune system.

In celiac disease, the presence of gluten in the small intestine triggers a response by the adaptive immune system, which is the part of the immune system that reacts to specific invaders by producing antibodies. The unwanted immune reaction ultimately leads the body to attack its own healthy enterocytes, or cells lining the small intestine.

One reason this unwanted response occurs is because individuals with celiac disease have a “leaky gut.”[2] Enterocytes lining the small intestine are normally “glued” together by tight junctions.[2] In people with celiac disease, the glue doesn’t hold. Gluten fragments can sneak through these gaps and provoke an adaptive immune response that damages the intestinal lining (the full mechanism is described in great detail in this 2009 Scientific American article).

The second type of gluten-induced condition, wheat allergy, is also mediated in part by the adaptive immune system. In this condition, gluten results in synthesis of IgE antibodies that cause an inflammation.[1] Inflammation can cause local discomfort and damage to healthy tissue.

People with “gluten sensitivity,” on the other hand, do not show evidence for the type of immune reactions that occur in those with celiac disease or wheat allergy.

So what is causing gluten sensitivity? Some recent research suggests the issue still lies with the immune system. However, instead of the adaptive portion being to blame, the innate immune system is thought to be the culprit.[3,4]

If the adaptive immune system is a tailor who designs custom jackets, the innate immune system uses one-size-fits-all ponchos. Instead of making antibodies that recognize specific invaders, cells of the innate immune system have receptors known as TLRs that recognize broad patterns present on a variety of invaders. Then, the TLRs trigger a quick inflammatory response.

A 2011 study found gluten-sensitive patients have higher expression of the TLRs compared to control patients.[4] This finding suggests the involvement of the innate immune system. In addition, the study supported the idea that the adaptive immune system is not involved in “gluten sensitivity.” Enterocytes of gluten sensitive patients are tightly glued together, unlike those of celiac disease patients. As a result, gluten fragments can’t get in between the cells to activate the adaptive immune system.

But is this innate immune response actually caused by gluten? Data from another study published in December suggest that a family of proteins in wheat may be to blame.[3] The proteins, amalyse-trypsin inhibitors, or ATIs, activated one type of TLR and caused an innate immune response in human immune cells and in live mice.[3]

Interestingly, the ATI content in wheat has dramatically increased in recent years.[3] ATI proteins naturally protect wheat from pests. As wheat is bred to be increasingly pest-resistant, ATI content also increases.[3] An increase in ATIs might explain what appears to be a growing amount of gluten-sensitive people.

ATIs aren’t the only non-gluten molecule accused of being behind so-called “gluten-sensitivity.” Wheat carbohydrates, known as FODMAPs, have also been implicated.[5] However, these molecules don’t cause abdominal discomfort and other symptoms by provoking an immune response. Instead, the indigestible nature of these carbohydrates might cause water retention and gas production in the small intestine, leading to bloating.[5]

While we’ve made some progress towards better understanding what may cause “gluten sensitivity,” many questions remain. In the meantime, for those whose doctors recommend a diet sans gluten, there will be plenty of food to choose from, as the gluten-free market continues to boom.


1. Aziz, I., Hadjivassiliou, M., & Sanders, D.S. (2012). Does gluten sensitivity in the absence of coeliac disease exist?. British Medical Journal, 345, e7907.

2. Fasano, A. (2009, August). Surprises from Celiac Disease. Scientific American, 301(2), 54-61.

3. Junker, Y., Zeissig, S., Kim, S., Barisani, D, Wieser, H., Leffler, D., … Schuppan, D. (2012). Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. Journal of Experimental Medicine, 209 (13).

4. Sapone A., Lammers, K.M., Casolaro, V., Cammarota M, Giuliano, M.T. … Fasano, A. (2011). Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Medicine 2011, 9(23).

5. Shepherd, S.J., Parker, F.C., Muir, J.G., & Gibson, P.R. (2008) Dietary triggers of abdominal symptoms in patients with irritable bowel syndrom: randomized placebo-controlled evidence. Clinical Gastroenterology and Hepatology, 6, 765-71.

Julianne Wyrick About the Author: Julianne Wyrick has a bachelor’s in biochemistry and is currently a master’s student in the health and medical journalism program at the University of Georgia, where she also writes about science for the Office of Research Communications. Find her on the web at Follow on Twitter @juliannewyrick.

The views expressed are those of the author and are not necessarily those of Scientific American.

Comments 14 Comments

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  1. 1. nicholasjh1 4:22 pm 03/4/2013

    Okay, Now this means I’m going to have to try some wheat free beers and see if they activate my “Gluten Sensitivity”. (Barley a normal ingredient in beer contains gluten.) I would be forever grateful to Sciam if this turns out to be the case. Now the hard part – figuring out which beers have wheat.

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  2. 2. The Ethical Skeptic 10:27 pm 03/4/2013

    Be careful, SSkeptics have called persons who cited that there is such a thing as a Wheat Allergy and the 2004 New England Journal of Medicine studies on LipoPolySaccharides and the Toll Like Receptor 4 Innate to Adaptive Immune System handoff, they have called it one of their favorite Weapon Words, oh shoot I have it here somewhere in my list of SSkeptic Weapon Words…… (sound of shuffling papers)..

    Oh yes, here it is “Quack Medicine”

    We who suffer from innate cytokine reactions to Wheat and the ensuing antibody damage over chronic years of allergic inflammation, have known this science for a LONG time (2002). I quit Wheat in 2003 and saw immediate improvements to my health (regarding my forthcoming letter of warning over this from the FDA please send to my mailing address: ‘Steven Novella, SkeptBlog New York, NY 10021).

    Well done, and courageous Juliane. Keep us informed as you continue to tackle this fast growth malady.

    OK….now you can say the next Weapon Word in the memorized inventory: “Manufactroversy” Repeat with me now…. Man U fac….tro…… a LONG ‘oh’ sound, that’s right….trohhhh..

    8) hehe
    – TES

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  3. 3. The Ethical Skeptic 11:20 pm 03/4/2013

    For further reading on the SSkeptic pre-emptive garbage attacking those who claim wheat allergies (below the error measure) and as promoting Food Woo, see: The Skeptics Society (, Rational Wiki (, Food Woo (, Quackwatch (, skeptics (, US News (, Skeptic’s Dictionary ( and the list goes on and on – ranging from denying all the associated data to simply claiming that .21% of the population suffer.

    No science will be found mind you (except possibly the first reference which is pretty good), they just want you to know that they are brilliant – and they do not care what you suffer from. It is Woo.

    Another Weapon Word.

    – TES

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  4. 4. digitalbio 12:15 am 03/5/2013

    This is nice article and well researched! Thanks!

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  5. 5. larkalt 7:50 pm 03/5/2013

    I probably have celiac disease and after an elimination diet in 2003 I got quite sick after food challenges. The main symptom was what I described as a groggy stupor – very mentally out of it, and I laid down in bed, and there were other symptoms too, like joint pain, muscle tension, tendency to rage and depression. This was not only with gluten grains, it was all grains, milk, apples and oranges. The stuporous sick feeling lasted about 4 days. I described it as like being drunk and hungover at the same time.
    Then a couple years later there was another stage where I got sick from food challenges with other foods. My food reactions were different this time – I was less severely “foggy”, but still stayed sick about 4 days. Other symptoms were itchiness all over my body, frequent urination, pain in my lower back/kidney area, belly pain, feeling of agitation.
    Point is, “mental fog” sounds like a very vague symptom that might be just normal tiredness or somebody “making up something” – but for me, the “mental fog” felt very concrete, very definite – it started to come on about half an hour after eating the food, came on fully a few hours after eating. “Fog” is a very mild term for it, for me it was more like having a bucket of swamp muck thrown into my mind.
    Before I stopped eating foods I had these reactions to, I was foggy in a more mild chronic way, without even realizing it.

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  6. 6. larkalt 8:10 pm 03/5/2013

    Ethical Skeptic,
    A researcher called Lidy Pelsser found ADHD in children was helped by food elimination
    It’s everyday foods that are the culprit, not usually the pesticides, food additives etc. that alt-med types have blamed a lot.
    Not sure if there’s a gluten connection – I’ve read gluten slightly increases intestinal permeability even in people who don’t have celiac disease, and a gluten-free diet might prevent the food sensitivities that caused ADHD in some children.
    This matter of nonclassical food allergies is a big deal, finally in bits and pieces the research is being done, people have reported these food reactions for many years and it’s been in the province of integrative/alt med.
    I was staggered to find out the huge psychological and physical effects of these immune reactions to food, for me, and blown away that doctors and therapists had been so oblivious of this.

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  7. 7. cellonancy 1:17 am 03/6/2013

    Thank you for this. I value knowing about the immune mechanism described here, but I must point out that this is yet another case of science catching up to holistic health practitioners in the area of nutrition. A naturopath helped me identify gluten sensitivity as a significant cause of inflammation in my system and I’ve had enormous benefit from avoiding it, as has one of my sisters. I hope it works as well for you.

    Looking at the accompanying picture, I also must point out that there are MANY gluten-free foods; they’re called fruits and vegetables. And eggs and fish and meat and nuts and seeds…Just sayin’! :>)

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  8. 8. larkalt 7:56 am 03/6/2013

    Science does way more than “catch up” with naturopaths etc.
    At the very best, a naturopath might give you sensible empirical advice, like “try avoiding gluten for a month or so, see if it helps”.
    However it would often come with attitudes against artificial colorings, preservatives, etc. – a lot of ideologically based advice that is probably irrelevant.
    Someone who came to work on my house said he’d been diagnosed with food allergies by a naturopath – only he’d been told to avoid combinations of foods, not individual foods! This seems like obvious charlatanism – a way to give the customer the impression that something is being done for their problem, while avoiding the unpleasantness of actually eliminating a food. Allergens can have synergistic effects, but this is probably secondary to their individual effect.
    And naturopaths can give destructive advice too. A lot of them advise against vaccination. And the guy who was working on my house had also been advised by his naturopath to take a shale water supplement. I looked it up and found out it had far more than the WHO-recommended max intake of arsenic (or some poisonous element like that).

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  9. 9. larkalt 7:57 am 03/6/2013

    ps I do wish however, that MD’s would more often recommend sensible empirical measures like a hypoallergenic elimination diet followed by food challenges, or perhaps a trial of a gluten-free diet.

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  10. 10. Matusz 1:53 pm 03/6/2013

    It can get even more complicated, too. Fructose malabsorption is also a possibility, triggered by fructans in wheat, but just going gluten-free isn’t sufficient. What’s worse is how many people just get lumped into the “IBS” category and never get a conclusive explanation.

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  11. 11. kmullani 11:49 am 05/29/2013

    This article is a great resource and matches up with a lot of other studies I’ve read. One thing to add about Gluten sensitivity is that even though the gluten particles don’t make it through the intestine wall as in celiac patients, they are still undigested particles traveling through the digestive system. Our small and large intestines are intended to process digested food so anytime something enters that isn’t properly broken down it can cause problems.

    Also, for those who already have damage to their intestines you can still work to repair it. Diet changes can do more than just stop symptoms, they can also give your body a chance to repair itself.

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  12. 12. drcharlesparker 7:13 pm 10/13/2013

    From wheat, to milk, to eggs, the exceedingly important missed common denominator in this discussion is, in a word: measurement. If effective data is available to measure which food antigen is the offender – and measurement data is quite available – why not measure and focus on the Reality of Data vs the hype of Maybe? Why struggle with the vagary of an elimination diet with even more speculation and an insufficient review of exactly which foods are offending or cross reactive?

    I strongly suggest “Grain Brain” by David Perlmutter for those interested in multiple references and the science. Then consider the upcoming complimentary Gluten Summit this November… complimentary with 25 of the world’s leading celiac/gluten/immunity and brain experts – here:

    It’s time to drive to the data, reference the work of many researchers, and measure. Not everyone suffers with these allergies, but those who do exceedingly often appear as untreatable in psychiatric offices globally.

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  13. 13. andipras 5:19 am 12/9/2014

    “People with” gluten sensitivity, “on the other hand, do not show evidence for the type of immune reactions that occur in Reviews those with celiac disease or wheat allergy”
    sentence that I liked. useful information. Thank you very much

    cara mengatasi keputihan

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  14. 14. andipras 2:06 am 01/15/2015

    gluten sensitive it can cause bloating and abdominal pain. wow that is very useful information. solusi wanita frigid

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