Does gluten sensitivity exist? A compilation of randomized controlled trials and results

Firstly, I’d like to make it clear that this article will deal exclusively with so-called non-celiac gluten sensitivity (NCGS) and not with celiac disease (gluten protein intolerance). As most of you probably know, these two conditions are not the same: in the first case, there are as yet no formal diagnostic methods nor identified and proven mechanisms to explain its causes, whilst the second is a recognised and characterised condition. Furthermore, as the title of the article implies, I’m going to focus on a very specific perspective: the most rigorous trials (randomized, double blinded and with a control group) on the supposedly negative symptoms potentially caused by gluten in gluten-tolerant people, as these trials are a good way of pinpointing the degree to which gluten sensitivity exists.

Before I begin, I’d like to point out that in all the trials I’ve found the subjects are chosen from a collective of people diagnosed with irritable bowel syndrome (normally according to Rome III Diagnostic criteria). This is so because even though there is as yet no official diagnosis for gluten sensitivity, the symptoms in both pathologies are considered to be the same or very similar (though response to gluten would have to be added to that list in the case of gluten sensitivity).

So let’s take a look, in chronological order, at each of these studies and their findings.

1."Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial" (2011)

The first rigorous trial on the subject is quite recent, dating from 2011. The 34 subjects selected were randomly divided into two groups (intervention and control). Bread and muffins were added to the diet of both groups for the six following weeks: in the case of the intervention group, the bread and muffins contained gluten, and in the case of the control group, gluten-free.

As an end point, it was established that at least half of the symptoms were to be under control. The symptoms of pain, bloating, stool consistency, tiredness, wind and nausea were measured and reported on by the patients themselves on a visual scale of 0-100 (0 being the absence of symptoms).

After the study, 68% of those who ate the bread and muffins containing gluten reported that symptoms were not adequately controlled, though 40% of those who ate the gluten-free bread and muffins also reported the same.

The following were the results of the average severity of the symptoms reported by each of the two groups:

 The summarized conclusions of the authors were that:

"(...) gluten is indeed a trigger of gut symptoms and tiredness. No evidence for intestinal infl ammation or damage, or for latent celiac disease was found to offer a mechanistic explanation for symptom deterioration caused by gluten"

2. "No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates" (2013).

As the authors of the previous trial were apparently not completely satisfied with the outcome, they subsequently decided to conduct another even more rigorous and systematic study. In this case, they performed a trial of 37 subjects given a 2-week diet of reduced FODMAPs (Fermentable Oligo-saccharides, Disaccharides, Monosaccharides and Polyols, compounds which are known to have a negative effect on irritable bowel syndrome sufferers), to eliminate the possible effect of those substances. Three intervention groups were subsequently defined: the first was placed on a high gluten diet (16 g/day), the second on a low gluten (2 g/day) and whey protein (14 g/day) diet, and the third, exclusively on a whey protein (16 g/day) diet. The 37 subjects were randomly assigned to these 3 groups and subjected to all 3 diets (cross-over and double-blind design).

Some time later, the same participants were invited to take part in a second phase of the study to check the initial results. All subjects once again were subjected to all 3 diets but for three days instead of a week. After the first phase, symptoms were seen to progressively worsen in all 3 groups, regardless of the group in question and with no significant differences between one group and another, as shown below.

Second phase (3-day diet) findings were not at all clear either: results were different from the first phase as gluten-specific gastrointestinal effects were not reproduced.

In short, the authors concluded the following:

"(...) In a placebo-controlled, cross-over rechallenge study, we found no evidence of specific or dose-dependent effects of gluten in patients with NCGS placed diets low in FODMAPs (...)".

3. Small Amounts of Gluten in Subjects with Suspected Non-celiac Gluten Sensitivity: a Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. (2015)

In this trial, 61 gluten-sensitive adults were initially enrolled, asked to follow a gluten-free diet and later divided into two groups; an intervention group and a placebo group. The intervention group were given just over 4 g/day of gluten (less than in other experiments) whilst the placebo group were given the same amount of rice starch, in unmarked capsules in both cases, for one week. After a one-week gluten-free diet, participants crossed over to the other group, i.e. they exchanged capsules, with those who had previously been assigned gluten being given starch and vice-versa. In all cases, a double-blind methodology was followed.

Of 28 symptoms reported on by the authors, differences between the intervention (gluten) group and the placebo group appeared in only 6 symptoms, with intake of gluten increasing symptoms compared with placebo as can be seen in the graphs below:

According to the authors, after analysing the data from the cross-over trials and the differences between the symptoms with gluten and with the placebo, only 3 participants met the requirements previously established to be considered as gluten-sensitive:

In short, the authors concluded the following:

"Most patients showed approximately equal degrees of overall symptoms with either gluten or placebo, although overall symptoms were worsened significantly by gluten in comparison with placebo. Regarding the identification of the true gluten-sensitive patients, it should be interpreted cautiously because of the lack of a control group of non–gluten-sensitive subjects, and it does not represent crucial evidence in favor of the existence of this new syndrome."

4. Non-Celiac Gluten Sensitivity Has Narrowed the Spectrum of Irritable Bowel Syndrome: A Double-Blind Randomized Placebo-Controlled Trial  (2015)

After a series of pre-selection phases, 72 patients were divided into two groups. For six weeks, one group was given packages containing powdered gluten and the other, a placebo in the form of gluten-free powder.

After six weeks of the diet, symptoms were controlled only in nine patients (25.7%) in the gluten-containing group, compared to 31 patients (83.8%) in the placebo group.

The authors concluded the following:

"(...) many patients diagnosed as having IBS are clearly gluten-sensitive, and their symptoms could be adequately controlled with a gluten-free diet only. Identifying gluten sensitivity in this group of patients may need to be the first approach".

5. Symptomatic improvement with gluten restriction in irritable bowel syndrome: a prospective, randomized, double blinded placebo controlled trial  (2016)

65 patients were selected for this trial and randomly divided into two groups. All patients were given two slices of bread per day to add to their diet for four weeks. Group 1 patients were given whole-cereal bread, i.e. with gluten, though in a lesser quantity than in other studies, whilst Group 2 patients were given gluten-free bread. 60 patients completed the trial.

Worsening of overall symptoms was recorded in 55.67% of patients in the gluten group, compared to 33.3% of patients in the placebo group. The following chart maps symptom severity throughout the trial for both groups.

Results for specific symptoms were as follows:

The authors concluded the following:

"[...] in patients with IBS, gluten triggers intestinal and systemic symptoms, and the symptom exacerbations occur mostly within a week of gluten rechallenge". 

6. Evidence for the Presence of Non-Celiac Gluten Sensitivity in Patients with Functional Gastrointestinal Symptoms: Results from a Multicenter Randomized Double-Blind Placebo-Controlled Gluten Challenge  (2016)

98 patients were selected and divided into two groups. Both groups were given 7 capsules/ day for one week: in the case of the intervention group, the capsules contained 5.6 g/day of gluten, and in the case of the placebo group, the same quantity of rice starch. As is the nature of a crossover study, after one week, the patients’ capsule diet was switched over.

At the end of the study, 28 patients who had taken gluten reported worsened symptoms, as did 14 of the placebo group. On the basis of these findings, the authors concluded it would be reasonable to think that half of those 28 patients could be considered as gluten-sensitive. Taking this into account, they considered that gluten-sensitive prevalence could be estimated at around 14% of the initial patients with diverse gastrointestinal symptoms.

Their conclusions were as follows:

"Our protocol identified a smaller set of patients with NCGS among the group of GFD-responsive patients and this approach can be the starting point for developing a diagnostic tool for NCGS".

Overall conclusions

So there you have it: a compilation of the findings of the most controlled trials conducted to date on the subject of symptoms suffered by gluten-sensitive people. A bit of a mish mash, wouldn’t you say? Perhaps now you understand better why I hadn’t written anything about this subject before. As you can now see for yourselves, it’s difficult to draw any clear conclusions, but as I imagine some of you will want me to express a (personal and almost certainly biased) opinion on the issue, here goes.

After careful review of all these studies, I would draw the following conclusions.

Firstly, there would seem to be signs that gluten affects some people considered to be non-celiac, though there is no excessively clear evidence of this and its prevalence is probably less frequent and less relevant than what certain people would often have us believe.

Secondly, it’s a much exaggerated issue. The most rigorous studies have produced the most adjusted (or null) results and would suggest there is no need to be unduly alarmist by any means. The fact that placebo group patients always report a high degree of worsening of symptoms would suggest a clear nocebo effect (like the placebo effect but in reverse: when a negative expectation of a phenomenon causes it to have a more negative effect than it otherwise would).

And thirdly, the possible existence of other components distorting less controlled study data and results (such as proteins or the aforementioned FODMAPs, for example). However, if you would rather read more considered opinions of experts and researchers on this subject, there are several reviews you may find interesting, though I would warn you in advance that their views differ widely.

For example, you could see what Alessio Fasano, one of the most senior scientists and frequent writers on gluten sensitivity (and staunch advocate of the existence of this pathology) has to say about it:
Or take a look at this somewhat less enthusiastic scientific review led by the gastroenterologist Jessica R Biesiekierski, of the scientists involved in the first two studies:
Or this very recent document outlining the position of Italian gastroenterologists:
Or if you prefer something a little more specific, this review outlines the overlaps and commonalities of IBS and NCGS:
And in this one, another team of Spanish researchers conducts a much more technical and systematic review on the diagnosis of this pathology, focusing on biomarkers.
And now, it’s up to you to draw your own conclusions.

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