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Clinical study distinguishes between gluten-sensitivity and celiac disease

By: Peter on April 25, 2011

Celiac disease has been the subject of extensive scientific research, but work on gluten-sensitivity is only just starting to catch up.  In a collaborative study between four laboratories in Italy and the US,  an attempt was made to separate these two conditions .   The actual article is rather indigestible (!), but I will try to summarize the key points of interest to a general audience.  This was a large study, consisting of 22 patients with gluten-sensitivity, 42 with celiac disease, and 39 control subjects.  AScientific research on gluten-sensitivity and celiac diseasell patients were subjected to a gluten-challenge for four months, followed by a gluten-free diet. While the terms gluten-intolerance and gluten-sensitivity are used differently by different people, the authors set strict criteria for selecting the patients with “gluten-sensitivity”.  These were defined as meeting three criteria: a) little or no intestinal damage after the gluten-challenge (Marsh stage 0 or 1), b) negative for anti-endomysium or anti-tissue-tranglutaminase antibodies  in the blood, and c) their symptoms improved on a gluten-free diet.

HLA DQ2/DQ8 genetics and anti-gliadin antibody status are different for gluten-sensitivity versus celiac disease

The presence of the HLA genes DQ2 or DQ8 is characteristic for almost all celiac patients .   In contrast, in this study, only 43% of the gluten-sensitive patients were DQ2/DQ8 positive, which is similar to that of the general population.

The presence of anti-gliadin antibody in the blood is a common (though not definitive) phenomenon for celiac patients.  In this study, only 43% of patients were antibody-positive.  This implies that anti-gluten antibody is not a good marker for gluten-sensitivity.  Interestingly, a substantial fraction (44%) of the antibody-positive patients lacked DQ2/DQ8, another difference from celiac patients.

No “leaky-gut” in gluten-sensitive patients

Celiac disease is often accompanied by an increase in gut permeability (referred to by some as “leaky-gut”, a term that has unfortunately been picked up by the popular media).  In contrast, this study showed that gluten-sensitive patients actually had less gut permeability than control subjects.

Wheat allergy

None of the gluten-sensitive patients had IgE anti-wheat antibodies—the response to gluten is quite different from an allergic reaction to wheat.

Innate versus adaptive immune system

The results support the idea that in gluten-sensitive patients, gluten activates the “innate” immune system; in other words, the protein is immediately recognized as foreign or toxic.  Celiac disease, in contrast, involves the activation of the “adaptive” immune system, followed by an accidental (autoimmune) reaction to tissue transglutaminase.

Take-home messages

  • Gluten-sensitivity in the absence of celiac disease is a real phenomenon, and can be clearly distinguished at a molecular level.
  • Negative HLA typing for DRQ2/DRQ8 doesn’t rule out the presence of gluten-sensitivity.
  • Negative anti-gliadin antibody tests don’t rule out the presence of gluten-sensitivity.
  • Gluten-free diet resulted in a relief from symptoms in gluten-sensitive patients within a few days, and this lasted for the whole 4 years of the study.
  • Physicians have little to rely on for a diagnosis, other than the reduction in gastrointestinal symptoms following a gluten-free diet.
  • Gluten-sensitive patients do not have “leaky-gut”.

Clearly, this is an exciting field of research, especially since the prevalence of gluten-sensitivity is estimated to be perhaps 6% of the general population —six-fold more common than celiac disease.

Finally, this kind of study may be difficult to repeat, since it involves deliberately subjecting known celiac patients to a further gluten-challenge, but with no obvious clinical benefit to the patient.  These people are to be commended for their generosity for the sake of science.


Ref. 1:  Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 2011; 9: 23 doi:10.1186/1741-7015-9-23 Sapone, A., Lammers, KM., et al.

Ref. 2:  Genetic background of celiac disease and its clinical implications. Am J Gastroenterol. 2008 Jan;103(1):190-5.  Wolters, VM, Wijmenga, C.

Ref. 3:   Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease. Gut 1993 Mar;34(3):354-7. van Elburg, RM., Uil, JJ., et al.

Ref. 4:  University of Maryland School of Medicine Researchers Identify Key Pathogenic Differences Between Celiac Disease & Gluten Sensitivity

21 comments to Mechanism of gluten-sensitivity versus celiac disease

  • Debbie

    Very nice and accurate review!

  • Mildred Smith

    My daughter is gluten sensitive so I found this article to be very informative.
    I on the other hand have had celiac for seven years. I would never think of taking the gluten challenge for four months or four days. Why would I do something that is going to make me sick and do much harm to my body. The celiac challenge is an outdated thing. I am very careful to watch what goes in my mouth, and there will be no gluten for me thank you. Forty two people with celiac taking this is unbelevable to me.

  • Pat M

    For many years I’ve had a dx. of gluten intolerance based on genetic testing and definite improvement on a GF diet. I was negative for both DQ2 and 8 but had two copies of DQ1. I was told then some researchers believed this was positive for gluten intolerance. It’s very nice to see that this diagnosis is now being researched and acknowledged.

    • Peter

      In a preliminary search I have not been able to find any published association between celiac and DQ1 (which is actually a very common haplotype in the general population). If I find anthing more I will update this post.

      • Anne

        Dr. Hadjivassiliou has written about DQ1 and gluten sensitivity in relation to neurological problems. http://jnnp.bmj.com/content/72/5/560.extract “Gluten sensitivity as a neurological illness”

        You can read the full article for free but you will have to register. Here is what it says about DQ1:

        “70% of patients have the HLA DQ2 (30% in the general popu- lation), 9% have the HLA DQ8, and the remainder have HLA DQ1. The finding of an additional HLA marker (DQ1) seen in the remaining 20% of our patients may represent an important difference be- tween the genetic susceptibility of pa- tients with neurological presentation to those with gastrointestinal presentation within the range of gluten sensitivity.”

  • Katie Chalmers

    Thank you for helping get the news out there that gluten sensitivity is for real. My 7 yr old daughter & I are both celiacs, and my other daughter has gluten sensitivity since celiac was just ruled out by recent testing. Interestingly enough, her symptoms (chronic constipation, weight loss, delayed growth, dental enamel defects and skin issues) were way worse than our celiac symptoms overall. Unfortunately when she was tested 3 yrs ago, celiac was ruled out and she was told to stay on a regular diet. If gluten sensitivity had been acknowledged back then she would have started the GF diet at the time and would have escaped all of her growth problems that ensued in that amount of time. Also noteworthy: our current GI docs do NOT acknowledge the reality of gluten sensitivity. Very sad.

    • Peter

      The hard part in this field is that many of the symptoms associated with celiac can also have other causes. I certainly hope that your physician was able to address them. While this website is obviously not intended to be a definitve source of medical diagnosis for a particular situation, my hunch is that in cases like this where there is no admission that a condition even exists (such as gluten-sensitivity), then it’s unlikey that a “treatment” is going to be advised.

      • Katie Chalmers

        I understand what you’re saying, but everything else was ruled out. She’s been on the GF diet since her endoscopy 2.5 weeks ago, and she hasn’t complained of a tummy ache since she started it, (used to be every day) her chronic constipation has resolved and her skin is smoother than ever. Thankfully we did enough research about GS on our own to try the diet and see these changes in her.

  • Barbara H

    Having been gluten free for 30 years, I am so happy that finally the science is catching up with what many of us have known for a long time and that this study was done! However I agree with Mildred’s comment that I cannot imagine going on a gluten challenge for 4 months,although necessary for the study. I wonder the results are affected by the limitation to those that were able to manage a gluten challenge and not become really ill or incapaciatated by it. I am one of those who was clinically diagnosed because the only test available at the time was so invasive compared to the improvements of a week on a gluten free diet that my doctor did not deem a test necessary. However this has left me somewhat in limbo for a diagnosis. It doesn’t matter most of the time since I adhere strictly to a gluten free diet.

    • Peter

      I agree that the authors were very careful about selecting the patients used for this study. SInce they didn’t go into any further detail, it wasn’t clear if they had to rule out a lot of people, which makes it harder to know how well we can extrapolate these results to the general gluten-sensitive population.

  • GoldenStar2

    Let me get this straight.People with NCGS don’t have anti self antibodies, no villi damage, no malabsorption or gut permeability, most don’t have celiac genes, but most say they feel better gluten free. Where is the science behind this kind of diagnosis? It sounds like bad medicine to me….or is it 45 million big ones?

    • Peter

      You raise a couple of interesting points.

      First is the definition of non-celiac gluten sensitivity. The researchers in this study were careful to select a narrow segment of patients for this group. I strongly believe that there is actually more of a spectrum between NCGS and celiac disease. While it helps clinicians to have a strict set of criteria for diagnosis of celiac disease, I suspect that this may result in a lot of people falling between the cracks. I touch on this in the health blog posts before and after this one.

      There is a substantial amount of scientific literature over the past few years showing that gluten can activate the “innate” immune system. This kind of gluten toxicity is quite separate from the “adaptive” immunity which leads to autoimmunity. Studies have shown that a different portion of the gluten protein is responsible for innate immune activation versus adaptive immunity. This is an exciting field because it means that we may be able to come up with new therapeutic approaches. I plan to write a blog where I go into more detail about this important topic, so stay tuned.

  • GoldenStar2

    Peter, As far as I know, there has been only one small study on ncgs so far. I believe it’s the one Dr Fasano took part in. It never said the innate immune system was definately involved, It said it “may” be involved. There’s a big difference between definately and maybe!

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  • Dale

    I have gluten sensitivity/intolerance. I did not test positive for Celiac, but did test positive for the gluten portion. I’ve been going gluten free for about 2 years now, but have found my digestive system far more impacted by gluten than before. I have a hard time believing that only those who have Celiac suffer from leaky gut, I am now unable to eat anything that I do not make myself even if it states on the box, gluten free, without suffering from cramps or feeling like the lower intestine is being stabbed.

    I think more research will eventually shed light for gluten sensitive/intolerance sufferers which will show that gluten sensitive/intolerant people will have the same subset of problems as that of the Celiac counterparts.

    I also have an auto-immune disorder and there is research out there that suggests gluten sensitive/intolerant individuals do not have auto-immune disorders.. then there is also research out there that implies this population in fact often have one or more auto-immune disorders.

    I cannot wait till more solid research is done.

    • Peter

      Hi Dale,
      While website is not intended to provide medical advice (that’s between you and your doctor), I do have a couple of comments.
      —Celiac disease testing is not infallible, and will miss some cases, especially in older people and the young.
      —I am not clear about what you mean when you say “you test positive for gluten”—there is no diagnostic test for (non-celiac) gluten sensitivity.
      —Celiacs who go gluten-free after diagnosis can actually become super-sensitive to traces of gluten.
      —Diagnosis of celiac disease is often hard, and can sometimes take years, so I would encourage you to hang in until you receive a satisfactory resolution to your situation.

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