Is Nonceliac Gluten Sensitivity Legit? A Review of the Latest Scientific Evidence on NCGS by Alex Leaf (Guestpost)

Is it scientifically warranted to caution against the consumption of gluten?
A couple weeks ago a paper was published that made headlines on several news outlets, including (of course) some paleo blogs (Di Sabatino. 2015). They all pretty much screamed that nonceliac gluten sensitivity (NCGS) was real in a “See! I told you so!” kind of way. Unfortunately it appears that most of them couldn’t make it past the abstract, so let’s start over.

NCGS is the term used to describe people who show intestinal and extraintestinal symptoms in response to consuming gluten, despite not having celiac disease or a wheat allergy.
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Public awareness of this condition is growing rapidly thanks to the numerous online forums and media outlets encouraging people to stop eating bread and self-diagnose the condition. In fact, as the authors of the current paper so interestingly state,
"Most of the information on NCGS, such as its high prevalence (Sapone. 2012), the activation of the innate immunity as a preferential pathogenic mechanism8,9, the existence of a specific mucosal cytokine profile (Sapone. 2010; Brottveit. 2013), and its clinical spectrum (Volta. 2014; Aziz. 2014; Biesiekierski. 2014), was obtained from patients who are mainly self-reported to be gluten-sensitive" (Di Sabatino. 2015).
The whole purpose of this randomized, double-blind, placebo controlled trial was to see if people self-diagnosed with NCGS were full of sh*t or not. As such, the researchers did a pretty thorough job with their study sample recruitment and screening.

Ultimately, 59 Italians who believed themselves to be NCGS because of symptoms “caused by food containing even low doses of gluten” were randomized for the intervention. Additionally, all of them were eating a gluten-containing diet for at least two months prior. Every day the participants would answer a questionnaire assessing symptom severity over a 5-week period.
Figure 1: Overview of the study design (resized version of the original figure in Di Sabatino. 2015).
During this entire timeframe the participants also followed a strict gluten-free diet. Starting at week 1 (so one week after being on a gluten-free diet), everybody would receive undistinguishable capsules containing 4.375g of gluten (equivalent to about 2 slices of white bread) or a rice starch placebo. All subjects took their pills daily at their preference for one week (W1➞W2), had a 1-week washout period (W2➞W3), took the pills opposite of last time (W3➞W4), and ended with another washout period (W4➞W5).

The primary outcome was differences in 28 symptom scores between the 1-week treatment with gluten and the 1-week treatment with placebo. And sure enough, the researchers found that the median symptom score of the gluten condition was significantly greater than the placebo condition.

So, "gluten is bad for you"!? Is it really that simple?

No, not really. Some outcomes left out of the abstract and overlooked by many people include, for example, the fact that 22 participants (37%) experienced worse symptoms with the placebo than the gluten. Moreover, 31 participants (52%) rated their symptoms for both the placebo and gluten relatively equally. In fact, only 3 persons met the criteria for true NCGS by having a symptomology score of greater than 100 when the placebo score was subtracted from the gluten score.
Figure 2: A significant difference between the symptoms on gluten and placebo was observed only in few subjects (grey circle) - too few to substantiate the claim that gluten would be bad for all of us (Di Sabatino. 2015).
When symptoms were analyzed separately (intestinal vs. extra intestinal), similar results were seen. This important information was apparently overlooked by readers, but important enough to lead the researchers to conclude that,
"…in the vast majority of patients the clinical weight of gluten-dependent symptoms is irrelevant in the light of the comparable degree of symptoms experienced with placebo. If we look at the distribution of delta overall scores (gluten minus placebo), it is not surprising to note that a fair number of patients are victims of the nocebo effect, which was extensively proved through double-blind, placebo-controlled trials (Jewett. 1990; Suarez. 1995)" (Di Sabatino. 2015).
Nonetheless, statistical analysis of each symptom individually did find that five of the 28 symptoms were significantly worsened with gluten: abdominal bloating, abdominal pain, foggy mind, depression, and aphthous stomatitis (canker sores). Also, none of the intestinal or extraintestinal symptoms showed higher average scores during the placebo compared with gluten.

Finally, the researchers also collected and analyzed laboratory parameters, such as serum IgG AGA, fecal calprotectin, intraepithelial lymphocyte density and HLA genotyping, all assessed at baseline under a gluten-containing diet. No associations between any of these markers were found with symptoms scores, meaning that possible biomarkers of NCGS were not identified.
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Bottom line: Statistically speaking, gluten evoked worse symptoms than the rice starch placebo. However, these effects were only pronounced in a small proportion of the study population.

Previous research (Biesiekierski. 2013) has demonstrated that NCGS may be a reaction to fermentable, poorly absorbed, short-chain carbohydrates (fermentable, oligo-, di-, monosaccharides, and polyols [FODMAPs]), and the fact that the current study identified no biomarkers for NCGS and had less than impressive results suggests that FODMAPs may indeed be the problem rather than gluten, per se.

I want to make clear that this study does not deny the realism of NCGS, and if anything it supports it. I also don’t deny the realism of NCGS. However, we need stricter clinical criteria for the condition (Lundin. 2014), and the fact that there is huge overlap with IBS and FODMAP intolerance (Catassi. 2013) strongly suggests that many people may be unfairly demonizing gluten.

So enjoy your wheat... or don’t, whatever makes you feel best. Just please don’t go throwing this study around as proof that NCGS is real.
  • Aziz, Imran, et al. "A UK study assessing the population prevalence of self-reported gluten sensitivity and referral characteristics to secondary care." European journal of gastroenterology & hepatology 26.1 (2014): 33-39.
  • Biesiekierski, Jessica R., et al. "No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates." Gastroenterology 145.2 (2013): 320-328.
  • Catassi, Carlo, et al. "Non-celiac gluten sensitivity: the new frontier of gluten related disorders." Nutrients 5.10 (2013): 3839-3853.
  • Di Sabatino, Antonio, et al. "Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: a Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial." Clinical Gastroenterology and Hepatology (2015).
  • Brottveit, Margit, et al. "Mucosal cytokine response after short-term gluten challenge in celiac disease and non-celiac gluten sensitivity." The American journal of gastroenterology 108.5 (2013): 842-850.
  • Jewett, Don L., George Fein, and Martin H. Greenberg. "A double-blind study of symptom provocation to determine food sensitivity." New England Journal of Medicine 323.7 (1990): 429-433.
  • Lundin, Knut EA. "Non-celiac gluten sensitivity-why worry?." BMC medicine 12.1 (2014): 86.
  • Sapone, Anna, et al. "Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease." International archives of allergy and immunology 152.1 (2010): 75.
  • Sapone, Anna, et al. "Spectrum of gluten-related disorders: consensus on new nomenclature and classification." BMC medicine 10.1 (2012): 13.
  • Suarez, Fabrizis L., Dennis A. Savaiano, and Michael D. Levitt. "A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported severe lactose intolerance." New England Journal of Medicine 333.1 (1995): 1-4.
  • Volta, Umberto, et al. "An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity." BMC medicine 12.1 (2014): 85.
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