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Gluten is a component of wheat and wheat-related grain products. When you start to talk about gluten withdrawal, is it really gluten withdrawal or is it wheat-product withdrawal or grain-product withdrawal? Grains are complex carbohydrates that have a number of fermentable sugars, which we would frequently remove from patients' diets because most of them are polyglycols -- fructans and galactans. We know from experience that when you withdraw fermentable sugar from patients, they frequently have improvement in symptoms such as bloating, gassy discomfort, and diarrhea.

Now let's focus on celiac disease. The prevalence of celiac disease has increased over the past several decades. Some inferential data suggest that some of it may be related to the hybridization of wheat and related grain products over the past several decades. We may actually be sensitizing more people, causing gluten-sensitive enteropathy or non-celiac gluten sensitivity, which we will discuss later.

We found that gluten-sensitive enteropathy is responsive to gluten withdrawal, but now we are seeing other patients who tell us that they feel better if they withdraw gluten. And they have found this out by going on the Internet or talking to friends and family who have had causal experience with this. Now we have patients out there doing a variety of things on their own accord and without a lot of medical judgment. That is not so good, particularly when you start talking about withdrawal and restrictive diets.

Who Is Affected by Gluten?

Is celiac disease more common in patients with irritable bowel syndrome (IBS)? We see a lot of overlap in the symptoms of gassy discomfort, bloating, and diarrhea. Cash and colleagues[3] published an article in Gastroenterology in 2011 that looked at the prevalence of celiac disease in patients with IBS symptoms and in those without symptoms but who underwent routine colon screening or surveillance. No difference was found in prevalence between the 2 populations. Interestingly, they did find increased markers for an immunologic response to gluten with antibodies against tissue transglutaminase (tTG), gliadin, and endomysium. They were increased with an odds ratio of about 1.5 in people with IBS. Although they did not meet the criteria for celiac disease, these patients were immunologically manifesting some reaction to wheat-related products.

Does this mean that people who have immunologic or some type of phenotypic predisposition to celiac disease have more sensitivity to gluten? A very interesting article that was published about a decade ago looked at patients who had some evidence of diarrhea-dominant irritable bowel syndrome (d-IBS).[4] They looked at the response to gluten withdrawal and found that there was a sizable percentage of people who had phenotypic markers for celiac disease but did not manifest celiac when they did duodenal biopsies. They were positive for the HLA-DQ2 or DQ8 phenotypic markers for celiac disease, but for histologic manifestations they did not meet the criteria for celiac disease. The investigators found that patients with other immunologic responses (eg, antigliadin antibody positive or tTG positive) responded better to withdrawal of gluten. In fact, a subset of patient populations with d-IBS will respond to gluten withdrawal if they have immunologic predisposition by their phenotype in addition to another immunologic manifestation, particularly the IgG antibodies that you see against gluten.

What Is Non-celiac Gluten Sensitivity?

When we talk about non-celiac gluten sensitivity, what are we talking about? We are talking about a patient population that has some form of symptoms or morphologic response after exposure to gluten, and they get withdrawal-related benefit. That would be gluten-sensitive non-celiac disease. Associated symptoms have been described as both classic intestinal (ie, gassy and crampy discomfort, bloating, and diarrhea) and extraintestinal (ie, malaise, fatigue, or attention-deficit disorder). An ataxic gait has also been described with gluten sensitivity.

Now let's take it a step further and ask: In patients who have gluten sensitivity and who feel better after gluten withdrawal, is it real or not real? In a very nice study[5] that was published about 2 years ago, investigators looked at patients with d-IBS in whom all the serologic markers for gluten were negative, but they felt better when they had gluten withdrawal. It was a randomized, double-blind, placebo-controlled trial. They only had 34 patients, but they were randomly assigned to receive bread and a muffin with gluten or bread and a muffin without gluten.

At the end of 6 weeks, there was a significant reduction of symptoms in the group that was receiving gluten-free food compared with the group receiving gluten. Gluten withdrawal resulted in a much more satisfactory response, with resolution of diarrhea, stool composure, gassy discomfort, and pain from bloating. Fatigue was also improved, which is interesting. I wonder if many of these patients were having sleep disruption at night.

How Does Gluten Cause Problems?

How does gluten cause problems? In celiac disease, it causes disruption of intestinal permeability, which is driven by an upregulation of zonulin. Zonulin regulates intestinal permeability. However, no such response is seen in gluten-sensitive non-celiac patients. Then why are these people having problems? I am not ready to say that it's all gluten, but gluten may be part of the problem.

Think about where we see gluten. It's in wheat products and a variety of grain products. For IBS, fermentable sugars can be reduced with the low-FODMAP (fermentable oligo-di-monosaccharides and polyols) diet, which is a reduction in gluten. When you take fructans and galactans -- the gluten or the related grain product itself with the fermentable sugars -- and dump them into an environment that is rich with intestinal flora that can ferment these sugars, you change osmotic load and you change intestinal fluids. You may change upregulation with sensitivity and motility changes, and there may also be microflora changes as you start to have a more acidic environment and you begin to manifest complex short-term fatty acids. These may change the intestinal flora, so it is difficult to say that everything is related to wheat and specific to gluten until we have better trials.
Testing and Treatment

What should we do with these people? If you have a patient who has diarrhea, gas, and bloating, it's very reasonable to do serologic testing. I think celiac disease is still missed in many patients. If you have a celiac patient who is negative for the standard profile and still has symptoms, it's reasonable to do HLA typing and the DQ2 or DQ8 profile. It would certainly give you an idea of whether this patient may do better after withdrawal of gluten, particularly if you could combine it with another marker. If the patient is antigliadin positive and tTG positive, start to look at phenotypic markers as well.

In trying to make patients totally gluten-free, it is very challenging to tell them to be totally restrictive. In my practice, I refer them to a nutritionist. There is very strong evidence that when patients are left on their own, a variety of macro- and micronutrient deficiencies can develop. If you are a patient, talk to your doctor. As a physician, I refer these patients to a nutritionist.

Information from Industry

I think that gluten-sensitive non-celiac disease is going to get considerably more attention. It has been estimated that the industry is shifting to meet this market with approximately $6 billion in gluten-free products. We know that gluten is not only in food products but in things like beer, cosmetics, and postage stamps. The industry is shifting to meet the need, and fanning the fire is the patient's recollection that he feels better without gluten.

The science is there. It is beginning to emerge. It does make sense, but not in everybody, so be aware of it. Talk to your patients and look hard at potentially finding markers for whether they are more likely to have a response.

These patients are no longer lacking the ability to go out and find gluten-free foods or products. If they are truly celiac, then they have to be a line reader. But for people with non-celiac gluten sensitivity, it remains to be seen how much of an antigenic response will be necessary to truly make the patient feel better. I think it's real. We need to pay attention, we need to be a little bit more pragmatic, and our patients will benefit from this as we learn.


O'Brien K. Should we all go gluten-free? The New York Times. November 25, 2011. Accessed February 21, 2013.
Eswaran S, Goel A, Chey WD. What role does wheat play in the symptoms of irritable bowel syndrome? Gastroenterol Hepatol. 2013; 9:85-91.
Cash BD, Rubenstein JH, Young PE, et al. The prevalence of celiac disease among patients with nonconstipated irritable bowel syndrome is similar to controls. Gastroenterology. 2011;141:1187-1193. Abstract
Wahnschaffe U, Schulzke JD, Zeitz M, Ullrich R. Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2007;5:844-850. Abstract
Biesiekierski JR, Newnham ED, Irving PM, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011;106:508-514. Abstract

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